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Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection

Open AccessPublished:June 04, 2021DOI:https://doi.org/10.1016/j.jbc.2021.100856
      The nuclear pore complex is the sole gateway connecting the nucleoplasm and cytoplasm. In humans, the nuclear pore complex is one of the largest multiprotein assemblies in the cell, with a molecular mass of ∼110 MDa and consisting of 8 to 64 copies of about 34 different nuclear pore proteins, termed nucleoporins, for a total of 1000 subunits per pore. Trafficking events across the nuclear pore are mediated by nuclear transport receptors and are highly regulated. The nuclear pore complex is also used by several RNA viruses and almost all DNA viruses to access the host cell nucleoplasm for replication. Viruses hijack the nuclear pore complex, and nuclear transport receptors, to access the nucleoplasm where they replicate. In addition, the nuclear pore complex is used by the cell innate immune system, a network of signal transduction pathways that coordinates the first response to foreign invaders, including viruses and other pathogens. Several branches of this response depend on dynamic signaling events that involve the nuclear translocation of downstream signal transducers. Mounting evidence has shown that these signaling cascades, especially those steps that involve nucleocytoplasmic trafficking events, are targeted by viruses so that they can evade the innate immune system. This review summarizes how nuclear pore proteins and nuclear transport receptors contribute to the innate immune response and highlights how viruses manipulate this cellular machinery to favor infection. A comprehensive understanding of nuclear pore proteins in antiviral innate immunity will likely contribute to the development of new antiviral therapeutic strategies.

      Keywords

      Abbreviations:

      AdV (adenovirus), ANE1 (acute necrotizing encephalopathy 1), CA (capsid), cGAMP (cyclic dinucleotide GMP–AMP), cGAS (cyclic GMP–AMP synthase), CoV (coronavirus), COVID-19 (coronavirus disease 2019), CRM1 (chromosomal maintenance 1), DENV (dengue virus), EBOV (Ebola virus), EBV (Epstein–Barr virus), EMCV (encephalomyocarditis virus), ER (endoplasmic reticulum), FG-Nups (Nups that contain phenylalanine–glycine repeats), HBV (hepatitis B virus), HCV (hepatitis C virus), HHV (human herpesvirus), hnRNP (heterogenous nuclear ribonucleoprotein), HPV (human papillomavirus), HRV (human rhinovirus), HSV (herpes simplex virus), IAV (influenza A virus), IFN (interferon), IFN-1 (type I interferon), IL-6 (interleukin-6), IRF3 (interferon-regulatory factor 3), IRF9 (interferon-regulatory factor 9), ISGF3 (interferon-stimulated gene factor 3), JEV (Japanese encephalitis virus), KSHV (Kaposi's sarcoma–associated herpesvirus), L (leader protein), M (matrix protein), MERS (Middle East respiratory syndrome), mRNP (messenger ribonucleoprotein), NES (nuclear export signal), NLS (nuclear localization signal), NSP (nonstructural protein), NTF2 (nuclear transport factor 2), Nup (nucleoporin), NXF1 (nuclear RNA export factor 1), NXT1 (NTF2-like export factor 1), PAMP (pathogen-associated molecular pattern), PRR (pattern-recognition receptor), PV (poliovirus), RIG-I (retinoic acid–inducible gene I), SARS (severe acute respiratory syndrome), STAT (signal transducer and activator of transcription), STING (stimulator of IFN genes), TLR (Toll-like receptor), TMEV (Theiler's murine encephalomyelitis virus), TNF-α (tumor necrosis factor α), TPR (translocated promoter region), TREX (transcription export), VACV (vaccinia virus), VEEV (Venezuelan equine encephalitis virus), Vpr (viral protein R), VSV (vesicular stomatitis virus), ZIKV (Zika virus.)
      A defining feature of all eukaryotic cells is the nuclear envelope, which encloses the cell's genetic material and separates the nucleoplasm, where RNA is synthesized and processed, from the cytoplasm, where mRNA is translated into proteins (
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      ). The nuclear envelope is contiguous with the endoplasmic reticulum (ER), and it contains two membranes, the outer and inner nuclear membranes, which are separated by a luminal space that is contiguous with the lumen of the ER. Within the nuclear envelope, thousands of macromolecular channels are embedded, termed the nuclear pore complexes (
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      ). Mutations and gene fusions of nucleoporins (Nups) cause many diverse human diseases including autoimmune diseases (RanBP2/Nup358) and increased susceptibility to viral infections (translocated promoter region [TPR], Nup153, and RanBP2/Nup358) (
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      ). Despite this, the exact molecular mechanisms by which these mutations contribute to these various pathologies remain mysterious. In this review, we discuss recent advances that reveal how nuclear pore proteins contribute to antiviral innate immunity and highlight how viruses manipulate this cellular machinery to evade the innate immune response and favor viral infection. Finally, we briefly review recent progress that has been made in developing novel antiviral therapeutics that target nucleocytoplasmic transport.

      Overview of the cellular nuclear transport machinery

      The nuclear pore complex is one of the largest protein complexes in the cell, with an estimated molecular mass of 50 MDa in yeast and 110 to 125 MDa in metazoans and an outer diameter of 80 to 120 nm and an inner diameter of ∼40 nm (
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      ). Across this membrane, and within the lumen of the nuclear envelope, a circular scaffold known as the luminal ring surrounds the nuclear pore complex (
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      ).
      Figure thumbnail gr1
      Figure 1Schematic representation of the nuclear pore complex and the nuclear import and export cycles. A, the nuclear pore complex is embedded into the nuclear envelope and composed of nucleoporins (Nups) that are structurally arranged into the inner ring, cytoplasmic and nuclear rings, cytoplasmic filaments, and nuclear basket. Within the lumen of the nuclear envelope, a circular scaffold known as the luminal ring surrounds the nuclear pore complex. The central channel of the pore is lined with Nups that contain phenylalanine–glycine repeats (FG-Nups). B, the movement of macromolecules and complexes across the nuclear envelope is facilitated by nuclear transport receptors. In the canonical nuclear import pathway, a cargo is recognized by nuclear import receptors importin-α (imp-α) and importin-β (imp-β) and is ferried across the pore. Once in the nucleus, the binding of Ran-GTP to importin-β causes the disassembly of the import complex and releases the cargo. Importin-β bound to Ran-GTP is transported back to the cytoplasm, whereas importin-α is recycled by CAS protein (also known as exportin2). GTP hydrolysis of Ran releases importin-β for the next round of import. For nuclear export, a cargo with nuclear export signal is usually bound by CRM1 (also known as exportin1). After the export complex enters the cytoplasm, Ran-GTP is hydrolyzed to Ran-GDP, and this promotes dissociation of the complex. The export of mRNAs is different from that of proteins because mRNAs are bound by many proteins in the form of messenger ribonucleoprotein (mRNP) complexes. mRNA export requires the nuclear transport receptor NXF1/NXT1 (also known as TAP/p15). Following the completion of export, the mRNP undergoes remodeling events where the transport receptors and many bound proteins are removed, whereas other protein factors such as ribosomes join. CAS, cellular apoptosis susceptibility; CRM1, chromosomal maintenance 1; imp-α, importin-α; imp-β, importin-β; mRNP, messenger ribonucleoprotein; NXF1, nuclear RNA export factor 1; NXT1, nuclear transport factor 2-like export factor 1.
      The central channel of the pore is lined with Nups that contain phenylalanine–glycine repeats (FG-Nups). These repeats interact with one another to form a meshwork, which appears to phase separate from the bulk solution and thus acts as a permeability barrier (
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      Transport selectivity of nuclear pores, phase separation, and membraneless organelles.
      ). The meshwork prevents the movement of macromolecules and complexes that are larger than ∼30 to 40 kDa (e.g., proteins, RNAs, and viruses). To cross the pore, these macromolecules need to be ferried by nuclear transport receptors (also known as importins, exportins, transportins, or karyopherins) (
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      In general, the formation and disassembly of nuclear transport receptors with their macromolecular cargos are regulated by the small Ras-like GTPase Ran, which cycles between GDP-bound and GTP-bound states. The conversion from GDP- to GTP-bound state is promoted by the guanine nuclear exchange factor regulator of chromosome condensation 1, which resides in the nucleus, whereas the hydrolysis of GTP to GDP is catalyzed by Ran's intrinsic GTPase activity that is stimulated by Ran GTPase–activating protein 1, which is tightly associated with the cytoplasmic filament protein RanBP2/Nup358. As a result of these two locally restricted reactions, the ratio of Ran-GTP/Ran-GDP is ∼200-fold higher in the nucleus than in the cytoplasm (
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      ). In addition to this “Ran-GTP gradient,” overall Ran concentration is kept relatively high in the nucleus and low in the cytoplasm because of the activity of nuclear transport factor 2 (NTF2), which associates with Ran-GDP in the cytosol, then ferries it into the nucleus where upon GTP hydrolysis releases Ran (
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      ). As such, the nucleoplasm acts as a sink for Ran, and this is catalyzed by the energy released by the GTP hydrolysis reaction.
      GTP hydrolysis drives all Ran-dependent import and export. Proteins that are imported contain nuclear localization signals (often referred to as NLSs), which are recognized by specialized sets of import receptors in the cytoplasm. Importin-α (also known as karyopherin-α) binds to canonical NLSs, which consist of one or more clusters of basic amino acids (
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      ). As such, the nucleoplasm becomes a sink for nuclear import substrate proteins. The importin-β–Ran-GTP complex can then diffuse back to the cytoplasm, whereas importin-α is recycled back by cellular apoptosis susceptibility protein (also known as exportin2) (
      • Kutay U.
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      ). Subsequent GTP hydrolysis, stimulated by Ran GTPase–activating protein 1, releases importin-β for the next round of import (Fig. 1B). In some cases, proteins may contain noncanonical NLSs. For proteins that contain proline–tyrosine NLSs, such as heterogenous nuclear ribonucleoproteins (hnRNPs), they are imported by transportin-1 (also known as importin-β2) (
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      ). CRM1 interacts with FG repeats and thus ferries its cargoes across the pore. After this complex enters the cytoplasm, GTP hydrolysis of Ran promotes the dissociation of the export complex and the release of cargo (Fig. 1B). As such, the cytosol acts as a sink for these protein cargoes. Cargo-free CRM1 is then free to diffuse back across the pore into the nucleoplasm. For the export of most noncoding RNAs and some proteins, CRM1 does not bind to these cargos directly but is instead recruited to the RNAs by adapter proteins such as PHAX (phosphorylated adapter RNA export protein) (
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      ).
      The export of mRNAs is different from that of proteins and most noncoding RNAs because mRNAs are associated with a dynamic repertoire of proteins in the form of large messenger ribonucleoprotein (mRNP) complexes (
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      ,
      • Björk P.
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      ). Most mRNAs do not rely on CRM1 and Ran for export but instead require the nuclear transport receptor heterodimer nuclear RNA export factor 1 (NXF1)/NTF2-like export factor 1 (NXT1), which is structurally related to NTF2 (
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      ). NXF1/NXT1 (also known as TAP/p15) is recruited to the mRNP by the transcription export (TREX) complex and serine and arginine-rich proteins. TREX is typically recruited to the mRNA during transcription and RNA processing, whereas serine and arginine-rich proteins bind to particular motifs in the mRNA (
      • Björk P.
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      ). As is the case with NTF2, NXF1/NXT1 directly binds to FG-Nups and thus facilitates movement across the pore. Following the completion of translocation, the DEAD-box protein Dbp5 and mRNA export factor RAE1/Gle1, which are associated with the cytoplasmic filaments of the nuclear pore, are thought to remove the transport receptors from the mRNP in an ATP-dependent manner and prevent the mRNA from returning to the nucleus (
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      ) (Fig. 1B). This exchange of mRNA-associated proteins during export is commonly referred to as mRNP remodeling, and this likely plays key roles in regulating mRNA export and mRNA translation (
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      ).
      Other critical complexes are TREX2 (
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      • Pereira G.
      • Rácz A.
      • Schiebel E.
      • Hurt E.
      Yeast centrin Cdc31 is linked to the nuclear mRNA export machinery.
      ,
      • Rodríguez-Navarro S.
      • Fischer T.
      • Luo M.-J.
      • Antúnez O.
      • Brettschneider S.
      • Lechner J.
      • Pérez-Ortín J.E.
      • Reed R.
      • Hurt E.
      Sus1, a functional component of the SAGA histone acetylase complex and the nuclear pore-associated mRNA export machinery.
      ,
      • Faza M.B.
      • Kemmler S.
      • Jimeno S.
      • González-Aguilera C.
      • Aguilera A.
      • Hurt E.
      • Panse V.G.
      Sem1 is a functional component of the nuclear pore complex–associated messenger RNA export machinery.
      ), whose components bind to the nuclear basket components TPR and Nup153 (
      • Umlauf D.
      • Bonnet J.
      • Waharte F.
      • Fournier M.
      • Stierle M.
      • Fischer B.
      • Brino L.
      • Devys D.
      • Tora L.
      The human TREX-2 complex is stably associated with the nuclear pore basket.
      ,
      • Jani D.
      • Valkov E.
      • Stewart M.
      Structural basis for binding the TREX2 complex to nuclear pores, GAL1 localisation and mRNA export.
      ), and are required for efficient nuclear mRNA export (
      • Lee E.S.
      • Wolf E.J.
      • Ihn S.S.J.
      • Smith H.W.
      • Emili A.
      • Palazzo A.F.
      TPR is required for the efficient nuclear export of mRNAs and lncRNAs from short and intron-poor genes.
      ,
      • Aksenova V.
      • Smith A.
      • Lee H.
      • Bhat P.
      • Esnault C.
      • Chen S.
      • Iben J.
      • Kaufhold R.
      • Yau K.C.
      • Echeverria C.
      • Fontoura B.
      • Arnaoutov A.
      • Dasso M.
      Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway.
      ,
      • Zuckerman B.
      • Ron M.
      • Mikl M.
      • Segal E.
      • Ulitsky I.
      Gene architecture and sequence composition underpin selective dependency of nuclear export of long RNAs on NXF1 and the TREX complex.
      ); however, the exact details of how these function remain unclear although they likely play roles in mRNP remodeling.

      The interaction of the innate immune response with nuclear pore proteins and nuclear transport receptors

      The innate immune system is the first line of host defense and evolutionarily conserved across vertebrates. It utilizes a limited number of pattern-recognition receptors (PRRs) to detect and defend against microbial pathogens. PRRs recognize various conserved molecular structures termed pathogen-associated molecular patterns (PAMPs) (
      • Janeway C.A.
      Approaching the asymptote? Evolution and revolution in immunology.
      ). As DNA and RNA either carry genetic information or act as replication intermediates for all microbial pathogens, they serve as PAMPs and are the major targets identified by the innate immune system. In general, PRRs that sense nucleic acids are divided into membrane-bound Toll-like receptors (TLRs), cytosolic DNA sensors, and RNA sensors.
      Membrane-bound TLRs recognize dsRNA, ssRNA, or unmethylated CpG DNA in the endosomal lumen, initiating signaling axes that culminate in the activation and nuclear translocation of transcription factors including interferon (IFN)-regulatory factor 3 (IRF3), interferon regulatory factor 7, and/or NF-κB (consisting of p65 and p50), to stimulate the transcription of specific genes such as type I interferon (IFN-I), and proinflammatory cytokine genes (
      • Kawai T.
      • Akira S.
      The role of pattern-recognition receptors in innate immunity: Update on toll-like receptors.
      ) (Fig. 2).
      Figure thumbnail gr2
      Figure 2Nucleic acid recognition by distinct pattern-recognition receptors (PRRs) and activation of interferon (IFN)-stimulated genes (ISGs). Upon recognition of pathogen-derived nucleic acids, all the PRRs initiate distinct signaling cascades that culminates in the activation and nuclear translocation of transcription factors, including IFN-regulatory factor 3 (IRF3), IRF7, and/or NF-κB (consisting of p65 and p50), to stimulate the transcription of specific genes, such as type I interferon (IFN-I), and proinflammatory cytokine genes. IFN-I then initiates antiviral signaling in the infected cell and neighboring cells by directly binding to the interferon I receptor (IFNAR) at the cell surfaces, which culminates in the expression of numerous interferon-stimulated genes to repress the replication and assembly of pathogens. cGAMP, cyclic dinucleotide GMP–AMP; cGAS, cyclic GMP-AMP synthase; ER, endoplasmic reticulum; IFN-I, type I interferon; IFNAR, IFN-I receptor; ISGF3, IFN-stimulated gene factor 3; ISRE, interferon-stimulated response element; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation–associated gene 5; RIG-I, retinoic acid–inducible gene I; STAT, signal transducer and activator of transcription; STING, stimulator of IFN genes; TLR, Toll-like receptor.
      Nucleic acid–sensing TLRs are expressed and function mostly in human immune cells. In addition, there are more general cytosolic DNA and RNA sensors that are ubiquitously expressed that can activate innate immune responses in response to viral infection.
      Cytoplasmic RNAs derived from pathogens are mainly detected by retinoic acid–inducible gene I (RIG-I) or by melanoma differentiation–associated gene 5 (
      • Wu B.
      • Peisley A.
      • Richards C.
      • Yao H.
      • Zeng X.
      • Lin C.
      • Chu F.
      • Walz T.
      • Hur S.
      Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5.
      ). This then leads to the stimulation of mitochondrial antiviral signaling protein on the mitochondrial membrane to activate IRF3 or NF-κB (p50/p65) and promote their nuclear translocation to induce the production of IFN-I and other antiviral molecules such as inflammatory cytokines (
      • Hou F.
      • Sun L.
      • Zheng H.
      • Skaug B.
      • Jiang Q.-X.
      • Chen Z.J.
      MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response.
      ) (Fig. 2). In addition, cyclic GMP–AMP synthase (cGAS) recognizes cytosolic dsDNA, either derived from DNA viruses or generated through the reverse transcription of retrovirus RNA genomes, and activates the production of cyclic dinucleotide GMP-AMP (cGAMP) from ATP and GTP (
      • Gao D.
      • Wu J.
      • Wu Y.-T.
      • Du F.
      • Aroh C.
      • Yan N.
      • Sun L.
      • Chen Z.J.
      Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses.
      ,
      • Li X.-D.
      • Wu J.
      • Gao D.
      • Wang H.
      • Sun L.
      • Chen Z.J.
      Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects.
      ,
      • Sun L.
      • Wu J.
      • Du F.
      • Chen X.
      • Chen Z.J.
      Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.
      ,
      • Schoggins J.W.
      • MacDuff D.A.
      • Imanaka N.
      • Gainey M.D.
      • Shrestha B.
      • Eitson J.L.
      • Mar K.B.
      • Richardson R.B.
      • Ratushny A.V.
      • Litvak V.
      • Dabelic R.
      • Manicassamy B.
      • Aitchison J.D.
      • Aderem A.
      • Elliott R.M.
      • et al.
      Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity.
      ). Being a small molecule, cGAMP not only activates downstream signals in the infected cell but also is packaged into new virions, where it can activate signals in subsequently infected cells (
      • Bridgeman A.
      • Maelfait J.
      • Davenne T.
      • Partridge T.
      • Peng Y.
      • Mayer A.
      • Dong T.
      • Kaever V.
      • Borrow P.
      • Rehwinkel J.
      Viruses transfer the antiviral second messenger cGAMP between cells.
      ,
      • Gao P.
      • Ascano M.
      • Zillinger T.
      • Wang W.
      • Dai P.
      • Serganov A.A.
      • Gaffney B.L.
      • Shuman S.
      • Jones R.A.
      • Deng L.
      • Hartmann G.
      • Barchet W.
      • Tuschl T.
      • Patel D.J.
      Structure-function analysis of STING activation by c[G(2’,5’)pA(3’,5’)p] and targeting by antiviral DMXAA.
      ,
      • Gentili M.
      • Kowal J.
      • Tkach M.
      • Satoh T.
      • Lahaye X.
      • Conrad C.
      • Boyron M.
      • Lombard B.
      • Durand S.
      • Kroemer G.
      • Loew D.
      • Dalod M.
      • Théry C.
      • Manel N.
      Transmission of innate immune signaling by packaging of cGAMP in viral particles.
      ,
      • Xu S.
      • Ducroux A.
      • Ponnurangam A.
      • Vieyres G.
      • Franz S.
      • Müsken M.
      • Zillinger T.
      • Malassa A.
      • Ewald E.
      • Hornung V.
      • Barchet W.
      • Häussler S.
      • Pietschmann T.
      • Goffinet C.
      cGAS-Mediated innate immunity spreads intercellularly through HIV-1 Env-induced membrane fusion sites.
      ). cGAMP binds to stimulator of IFN genes (STING), causing its relocalization from the ER to the ER–Golgi intermediate compartment and the Golgi complex. There, STING recruits kinases to activate IRF3 and NF-κB (p50/p65), which go on to activate transcription of IFN-I and proinflammatory cytokine genes (
      • Wu J.
      • Sun L.
      • Chen X.
      • Du F.
      • Shi H.
      • Chen C.
      • Chen Z.J.
      Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA.
      ,
      • Dobbs N.
      • Burnaevskiy N.
      • Chen D.
      • Gonugunta V.K.
      • Alto N.M.
      • Yan N.
      STING activation by translocation from the ER is associated with infection and autoinflammatory disease.
      ,
      • Ishikawa H.
      • Ma Z.
      • Barber G.N.
      STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
      ,
      • Liu S.
      • Cai X.
      • Wu J.
      • Cong Q.
      • Chen X.
      • Li T.
      • Du F.
      • Ren J.
      • Wu Y.-T.
      • Grishin N.V.
      • Chen Z.J.
      Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation.
      ) (Fig. 2).
      Once induced, newly synthesized IFN-I then functions via autocrine and paracrine signaling by directly binding to the interferon I receptor at the cell surface to initiate signaling, which in turn leads to the phosphorylation of signal transducer and activator of transcriptions (STATs) and the formation of STAT1/STAT2 heterodimer. The heterodimer further recruits interferon-regulatory factor 9 (IRF9) to form the interferon-stimulated gene factor 3 (ISGF3) complex. The ISGF3 complex then rapidly translocates into the nucleus in an importin-dependent manner and binds to IFN-stimulated response elements of IFN-stimulated genes to activate their transcription (
      • Stark G.R.
      • Darnell J.E.
      The JAK-STAT pathway at twenty.
      ) (Fig. 2). Consequently, this stimulates the production of proteins that establish a robust immune response to repress the replication and assembly of pathogens (
      • Bowie A.G.
      • Unterholzner L.
      Viral evasion and subversion of pattern-recognition receptor signalling.
      ,
      • Yan N.
      • Chen Z.J.
      Intrinsic antiviral immunity.
      ).
      The innate immune system has been extensively reviewed elsewhere (
      • Gürtler C.
      • Bowie A.G.
      Innate immune detection of microbial nucleic acids.
      ,
      • Tan X.
      • Sun L.
      • Chen J.
      • Chen Z.J.
      Detection of microbial infections through innate immune sensing of nucleic acids.
      ,
      • Wu J.
      • Chen Z.J.
      Innate immune sensing and signaling of cytosolic nucleic acids.
      ), so in the next section, we will discuss how these systems interface with the nuclear pore complex. As described previously, during the innate antiviral immune response, the production of IFNs, proinflammatory cytokines, and IFN-stimulated genes depends on the nuclear translocation of key innate immunity signal transducers. Unsurprisingly, signal transducers, such as IRF3, NF-κB (p50/p65), and STATs, interact with distinct Nups and/or nuclear transport receptors in order to traffic from the cytoplasm to the nucleus through nuclear pore complexes in response to the activation of PRRs (Table 1).
      Table 1The interaction of Nups or nuclear transport receptors with signal transducers of innate immunity
      Signal transducersNups/nuclear transport receptorsRoles of nuclear pore–associated proteins in innate immune responsesReferences
      IRF3Importin-β1The main nuclear import receptor for IRF3(
      • Gagné B.
      • Tremblay N.
      • Park A.Y.
      • Baril M.
      • Lamarre D.
      Importin β1 targeting by hepatitis C virus NS3/4A protein restricts IRF3 and NF-κB signaling of IFNB1 antiviral response.
      )
      Importin-α3 and importin-α4Promoting nuclear import of IRF3(
      • Ye J.
      • Chen Z.
      • Li Y.
      • Zhao Z.
      • He W.
      • Zohaib A.
      • Song Y.
      • Deng C.
      • Zhang B.
      • Chen H.
      • Cao S.
      Japanese encephalitis virus NS5 inhibits type I interferon (IFN) production by blocking the nuclear translocation of IFN regulatory factor 3 and NF-κB.
      )
      NF-κBImportin-β1The main nuclear import receptor for NF-κB (p65)(
      • Gagné B.
      • Tremblay N.
      • Park A.Y.
      • Baril M.
      • Lamarre D.
      Importin β1 targeting by hepatitis C virus NS3/4A protein restricts IRF3 and NF-κB signaling of IFNB1 antiviral response.
      )
      Importin-α3 and importin-α4Promoting nuclear import of NF-κB(
      • Ye J.
      • Chen Z.
      • Li Y.
      • Zhao Z.
      • He W.
      • Zohaib A.
      • Song Y.
      • Deng C.
      • Zhang B.
      • Chen H.
      • Cao S.
      Japanese encephalitis virus NS5 inhibits type I interferon (IFN) production by blocking the nuclear translocation of IFN regulatory factor 3 and NF-κB.
      ,
      • Fagerlund R.
      • Kinnunen L.
      • Köhler M.
      • Julkunen I.
      • Melén K.
      NF-κB is transported into the nucleus by importin α3 and importin α4.
      )
      Nup214–Nup88 complexPromoting the translocation of NF-κB (p65) from the cytoplasm to the nucleus(
      • Xylourgidis N.
      • Roth P.
      • Sabri N.
      • Tsarouhas V.
      • Samakovlis C.
      The nucleoporin Nup214 sequesters CRM1 at the nuclear rim and modulates NFκB activation in Drosophila.
      ,
      • Yi S.
      • Chen Y.
      • Wen L.
      • Yang L.
      • Cui G.
      Downregulation of nucleoporin 88 and 214 induced by oridonin may protect OCIM2 acute erythroleukemia cells from apoptosis through regulation of nucleocytoplasmic transport of NF-κB.
      )
      Nup62Stabilizing Nup88 and its interaction with NF-κB (p65) to induce inflammatory responses(
      • Singh U.
      • Samaiya A.
      • Mishra R.K.
      Overexpressed Nup88 stabilized through interaction with Nup62 promotes NFκB dependent pathways in cancer.
      )
      SET-Nup214 and DEK-Nup214Inhibiting NF-κB activation by tethering the complex, including p65 and its inhibitor IκB, in the nucleus(
      • Saito S.
      • Cigdem S.
      • Okuwaki M.
      • Nagata K.
      Leukemia-associated Nup214 fusion proteins disturb the XPO1-mediated nuclear-cytoplasmic transport pathway and thereby the NF-κB signaling pathway.
      )
      Nup98-HOXA9 and Nup98-DDX10Causing nuclear accumulation of NF-κB (p65), thus promoting NF-κB–mediated transcription(
      • Takeda A.
      • Sarma N.J.
      • Abdul-Nabi A.M.
      • Yaseen N.R.
      Inhibition of CRM1-mediated nuclear export of transcription factors by leukemogenic NUP98 fusion proteins.
      )
      Nup98-IQCGInhibiting the CRM1-mediated nuclear export of p65, thus enhancing the transcriptional activity of NF-κB(
      • Pan M.
      • Zhang Q.
      • Liu P.
      • Huang J.
      • Wang Y.
      • Chen S.
      Inhibition of the nuclear export of p65 and IQCG in leukemogenesis by NUP98-IQCG.
      )
      POM121Inhibiting phosphorylated p65 (phos-p65) nuclear translocation, thus the macrophage inflammatory response(
      • Ge W.
      • Yue Y.
      • Xiong S.
      POM121 inhibits the macrophage inflammatory response by impacting NF-κB P65 nuclear accumulation.
      )
      Nup153 and RanBP2/Nup358Promoting IκBα nuclear import and subsequently terminating NF-κB activation(
      • Liu Y.
      • Trnka M.J.
      • Guan S.
      • Kwon D.
      • Kim D.-H.
      • Chen J.-J.
      • Greer P.A.
      • Burlingame A.L.
      • Correia M.A.
      A novel mechanism for NF-κB-activation via IκB-aggregation: Implications for hepatic Mallory-Denk-body induced inflammation.
      )
      STATs (including STAT1 and STAT2)Importin-α3Promoting the nuclear import of unphosphorylated STAT2/IRF9 complex(
      • Banninger G.
      • Reich N.C.
      STAT2 nuclear trafficking.
      )
      Importin-α4Promoting the nuclear import of unphosphorylated STAT2/IRF9 complex(
      • Banninger G.
      • Reich N.C.
      STAT2 nuclear trafficking.
      )
      Importin-α5Promoting the nuclear import of activated STAT1 and STAT2(
      • Nardozzi J.
      • Wenta N.
      • Yasuhara N.
      • Vinkemeier U.
      • Cingolani G.
      Molecular basis for the recognition of phosphorylated STAT1 by importin alpha5.
      ,
      • Reid S.P.
      • Valmas C.
      • Martinez O.
      • Sanchez F.M.
      • Basler C.F.
      Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin α proteins with activated STAT1.
      )
      Importin-α6Promoting the nuclear import of activated STAT1 and STAT2(
      • Reid S.P.
      • Valmas C.
      • Martinez O.
      • Sanchez F.M.
      • Basler C.F.
      Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin α proteins with activated STAT1.
      )
      Importin-α7Promoting the nuclear import of activated STAT1 and unphosphorylated STAT2/IRF9 complex(
      • Reid S.P.
      • Valmas C.
      • Martinez O.
      • Sanchez F.M.
      • Basler C.F.
      Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin α proteins with activated STAT1.
      ,
      • Banninger G.
      • Reich N.C.
      STAT2 nuclear trafficking.
      )
      Nup153 and Nup214Promoting the nucleocytoplasmic translocation of latent STAT1(
      • Marg A.
      • Shan Y.
      • Meyer T.
      • Meissner T.
      • Brandenburg M.
      • Vinkemeier U.
      Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1.
      ,
      • Meyer T.
      • Vinkemeier U.
      Nucleocytoplasmic shuttling of STAT transcription factors.
      )
      CRM1Promoting the nuclear export of the unphosphorylated STAT1 and STAT2(
      • Banninger G.
      • Reich N.C.
      STAT2 nuclear trafficking.
      )

      IRF3

      IRF3 is a key transcription factor employed by various innate immunity pathways including RIG-I-like receptors, cGAS/STING signaling, and TLR3 signaling. It turns on the transcription of IFN-I genes in response to the activation of PRRs. To date, three nuclear transport receptors, importin-β1, importin-α3, and importin-α4, are known to promote IRF3 nuclear transport (
      • Gagné B.
      • Tremblay N.
      • Park A.Y.
      • Baril M.
      • Lamarre D.
      Importin β1 targeting by hepatitis C virus NS3/4A protein restricts IRF3 and NF-κB signaling of IFNB1 antiviral response.
      ,
      • Ye J.
      • Chen Z.
      • Li Y.
      • Zhao Z.
      • He W.
      • Zohaib A.
      • Song Y.
      • Deng C.
      • Zhang B.
      • Chen H.
      • Cao S.
      Japanese encephalitis virus NS5 inhibits type I interferon (IFN) production by blocking the nuclear translocation of IFN regulatory factor 3 and NF-κB.
      ) (Table 1).

      NF-κB

      NF-κB (p50/p65) is another crucial downstream signal transducer that transcriptionally activates IFN-I and proinflammatory cytokines upon PPR activation. It is imported into the nucleus by importin-β1, importin-α3, and importin-α4 (
      • Gagné B.
      • Tremblay N.
      • Park A.Y.
      • Baril M.
      • Lamarre D.
      Importin β1 targeting by hepatitis C virus NS3/4A protein restricts IRF3 and NF-κB signaling of IFNB1 antiviral response.
      ,
      • Ye J.
      • Chen Z.
      • Li Y.
      • Zhao Z.
      • He W.
      • Zohaib A.
      • Song Y.
      • Deng C.
      • Zhang B.
      • Chen H.
      • Cao S.
      Japanese encephalitis virus NS5 inhibits type I interferon (IFN) production by blocking the nuclear translocation of IFN regulatory factor 3 and NF-κB.
      ,
      • Fagerlund R.
      • Kinnunen L.
      • Köhler M.
      • Julkunen I.
      • Melén K.
      NF-κB is transported into the nucleus by importin α3 and importin α4.
      ) and requires the Nups Nup88, Nup214, Nup98, Nup153, RanBP2/Nup358, and POM121. The close link between nuclear porins and NF-κB appears to be ancient as it is conserved in Drosophila (
      • Xylourgidis N.
      • Roth P.
      • Sabri N.
      • Tsarouhas V.
      • Samakovlis C.
      The nucleoporin Nup214 sequesters CRM1 at the nuclear rim and modulates NFκB activation in Drosophila.
      ,
      • Yi S.
      • Chen Y.
      • Wen L.
      • Yang L.
      • Cui G.
      Downregulation of nucleoporin 88 and 214 induced by oridonin may protect OCIM2 acute erythroleukemia cells from apoptosis through regulation of nucleocytoplasmic transport of NF-κB.
      ,
      • Saito S.
      • Cigdem S.
      • Okuwaki M.
      • Nagata K.
      Leukemia-associated Nup214 fusion proteins disturb the XPO1-mediated nuclear-cytoplasmic transport pathway and thereby the NF-κB signaling pathway.
      ,
      • Takeda A.
      • Sarma N.J.
      • Abdul-Nabi A.M.
      • Yaseen N.R.
      Inhibition of CRM1-mediated nuclear export of transcription factors by leukemogenic NUP98 fusion proteins.
      ,
      • Pan M.
      • Zhang Q.
      • Liu P.
      • Huang J.
      • Wang Y.
      • Chen S.
      Inhibition of the nuclear export of p65 and IQCG in leukemogenesis by NUP98-IQCG.
      ). Interestingly, several chromosome translocation mutations result in the formation of fusion proteins involving Nups and a diverse set of proteins, which often impact the nucleocytoplasmic transport of NF-κB (p50/p65) and the activation of innate immune responses (Table 1). NF-κB activity can be inhibited by CRM1, which mediates p65 nuclear export (
      • Wong P.M.C.
      • Chung S.W.
      A functional connection between RanGTP, NF-kappaB and septic shock.
      ). Recently, it has been suggested that overexpression of Nup62 stabilizes overexpressed Nup88 and its interaction with NF-κB (p65) to induce inflammatory signaling (
      • Singh U.
      • Samaiya A.
      • Mishra R.K.
      Overexpressed Nup88 stabilized through interaction with Nup62 promotes NFκB dependent pathways in cancer.
      ). Another recent study revealed that POM121 inhibits the nuclear translocation of phosphorylated p65 (phos-p65) and consequently impairs the macrophage inflammatory response (
      • Ge W.
      • Yue Y.
      • Xiong S.
      POM121 inhibits the macrophage inflammatory response by impacting NF-κB P65 nuclear accumulation.
      ). Another report suggested that RanBP2/Nup358, which is one of the main components of the cytoplasmic filaments on the nuclear pore complex, and Nup153, which is part of the nuclear pore basket, formed a complex (RanBP2/Nup358–RanGDP-Nup153–IκBα-SUMO) in response to tumor necrosis factor α (TNF-α) stimulation. This complex facilitates the nuclear import of IκBα, allowing its binding to NF-κB (p50/p65). IκBα binding, in turn, masks the nuclear localization signal and the DNA-binding domain of NF-κB (p50/p65), thus downregulating innate immune responses (
      • Liu Y.
      • Trnka M.J.
      • Guan S.
      • Kwon D.
      • Kim D.-H.
      • Chen J.-J.
      • Greer P.A.
      • Burlingame A.L.
      • Correia M.A.
      A novel mechanism for NF-κB-activation via IκB-aggregation: Implications for hepatic Mallory-Denk-body induced inflammation.
      ).

      STATs

      The nucleocytoplasmic trafficking of STATs (such as STAT1 and STAT2) plays a central role in activating IFN-stimulated gene expression to repress viral replication and assembly. In general, this process is accomplished via two distinct pathways. In the first, tyrosine-phosphorylated STAT dimers utilize importins to enter the nucleus upon cytokine stimulation. In the second pathway, latent unphosphorylated STATs employ karyopherin-independent and energy-free translocation mechanisms by directly interacting with FG-Nups without cytokine stimulation (
      • Marg A.
      • Shan Y.
      • Meyer T.
      • Meissner T.
      • Brandenburg M.
      • Vinkemeier U.
      Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1.
      ,
      • Meyer T.
      • Vinkemeier U.
      Nucleocytoplasmic shuttling of STAT transcription factors.
      ,
      • Meyer T.
      • Vinkemeier U.
      STAT nuclear translocation: Potential for pharmacological intervention.
      ). To date, several transport receptors and Nups have been shown to contribute to the nucleocytoplasmic transport of phosphorylated or unphosphorylated STATs (Table 1).
      Upon IFN-I stimulation, both STAT1 and STAT2 are phosphorylated by Janus kinases and subsequently form a STAT1/STAT2 heterodimer. During heterodimer formation, STAT1 undergoes a conformational change that exposes a dimer-specific nuclear localization signal within its DNA-binding domain (
      • Fagerlund R.
      • Mélen K.
      • Kinnunen L.
      • Julkunen I.
      Arginine/lysine-rich nuclear localization signals mediate interactions between dimeric STATs and importin alpha 5.
      ,
      • McBride K.M.
      • Banninger G.
      • McDonald C.
      • Reich N.C.
      Regulated nuclear import of the STAT1 transcription factor by direct binding of importin-α.
      ). Unlike conventional NLSs, which binds to importin-α (
      • Conti E.
      • Uy M.
      • Leighton L.
      • Blobel G.
      • Kuriyan J.
      Crystallographic analysis of the recognition of a nuclear localization signal by the nuclear import factor karyopherin alpha.
      ,
      • Dingwall C.
      • Laskey R.A.
      Nuclear import: A tale of two sites.
      ,
      • Pumroy R.A.
      • Cingolani G.
      Diversification of importin-α isoforms in cellular trafficking and disease states.
      ), this dimer-specific nuclear localization signal interacts with importin-α5 (
      • Nardozzi J.
      • Wenta N.
      • Yasuhara N.
      • Vinkemeier U.
      • Cingolani G.
      Molecular basis for the recognition of phosphorylated STAT1 by importin alpha5.
      ), importin-α6, and importin-α7 (
      • Reid S.P.
      • Valmas C.
      • Martinez O.
      • Sanchez F.M.
      • Basler C.F.
      Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin α proteins with activated STAT1.
      ), which then facilitates the nuclear translocation of the STAT1/STAT2/IRF9 complex (also known as the ISGF3 complex). In the nucleus, the ISGF3 complex binds to the IFN-stimulated response element promoter site to activate the transcription of various IFN-stimulated genes. In addition, the binding of STAT1 to target DNA releases importin-α5 back to the cytoplasm for recycling (
      • McBride K.M.
      • Banninger G.
      • McDonald C.
      • Reich N.C.
      Regulated nuclear import of the STAT1 transcription factor by direct binding of importin-α.
      ,
      • McBride K.M.
      • McDonald C.
      • Reich N.C.
      Nuclear export signal located within the DNA-binding domain of the STAT1transcription factor.
      ).
      One important concept that has emerged from the literature is that upon cytokine stimulation, the amount of nuclear accumulated STATs is often influenced by their nuclear retention rather than by the rate of their nuclear import (
      • Meyer T.
      • Vinkemeier U.
      Nucleocytoplasmic shuttling of STAT transcription factors.
      ). It was observed that phosphorylated STAT1 can reside in the nucleus for around 30 min, and that the duration of its nuclear accumulation is affected by several phosphatases, such as 45-kDa T cell protein tyrosine phosphatase splice variant and SH2 domain–containing protein tyrosine phosphatase 2 (
      • Haspel R.L.
      • Salditt-Georgieff M.
      • Darnell J.E.
      The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase.
      ,
      • ten Hoeve J.
      • Ibarra-Sanchez M.
      • de J.
      • Fu Y.
      • Zhu W.
      • Tremblay M.
      • David M.
      • Shuai K.
      Identification of a nuclear Stat1 protein tyrosine phosphatase.
      ,
      • Wu T.R.
      • Hong Y.K.
      • Wang X.-D.
      • Ling M.Y.
      • Dragoi A.M.
      • Chung A.S.
      • Campbell A.G.
      • Han Z.-Y.
      • Feng G.-S.
      • Chin Y.E.
      SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei.
      ). Once dephosphorylated, STAT1 interacts with CRM1 via an exposed leucine-rich NES in its DNA-binding domain and in turn is exported back to the cytoplasm for subsequent activation–inactivation cycles (
      • Banninger G.
      • Reich N.C.
      STAT2 nuclear trafficking.
      ).
      It was assumed that latent unphosphorylated STATs are trapped in the cytoplasm and do not shuttle in and out of the nucleus in resting cells. However, this idea has been challenged by several studies (
      • Marg A.
      • Shan Y.
      • Meyer T.
      • Meissner T.
      • Brandenburg M.
      • Vinkemeier U.
      Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1.
      ,
      • Meyer T.
      • Vinkemeier U.
      Nucleocytoplasmic shuttling of STAT transcription factors.
      ,
      • Meyer T.
      • Gavenis K.
      • Vinkemeier U.
      Cell type-specific and tyrosine phosphorylation-independent nuclear presence of STAT1 and STAT3.
      ). It should be noted that only a third of all the STAT1 protein is tyrosine phosphorylated at any given time during cytokine stimulation (
      • Haspel R.L.
      • Salditt-Georgieff M.
      • Darnell J.E.
      The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase.
      ). Although the conventional STAT1 nuclear localization signal requires phosphorylation to be active, unphosphorylated STAT1 still shuttles between cytosol and nucleus by directly binding to FG-Nups like Nup153 and Nup214 in a cytokine-independent manner (
      • Marg A.
      • Shan Y.
      • Meyer T.
      • Meissner T.
      • Brandenburg M.
      • Vinkemeier U.
      Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1.
      ,
      • Meyer T.
      • Vinkemeier U.
      Nucleocytoplasmic shuttling of STAT transcription factors.
      ).
      STAT2 is another critical transcription factor in the IFN-I signaling pathway. Unlike other STATs, STAT2 is constitutively bound by the transcriptional activator IRF9. Upon IFN-I stimulation, phosphorylated STAT2 joins the ISGF3 complex and is transported into the nucleus as described previously. Thus, STAT1 is essential for the nuclear translocation of activated STAT2 (
      • Banninger G.
      • Reich N.C.
      STAT2 nuclear trafficking.
      ). Like STAT1, the recycling of STAT2 to the cytoplasm is catalyzed by its dephosphorylation by 45-kDa T cell protein tyrosine phosphatase splice variant and SH2 domain–containing protein tyrosine phosphatase 2. This causes the dissociation of STAT2/IRF9 from both STAT1 and the DNA. STAT2, which has its own nuclear export sequence, is then ferried out of the nucleus by CRM1. Like STAT1, STAT2 is believed to translocate into the nucleus even when it is unphosphorylated. However, unlike other STAT family members, this is not mediated by STAT2 directly, but rather its binding partner IRF9 (
      • Martinez-Moczygemba M.
      • Gutch M.J.
      • French D.L.
      • Reich N.C.
      Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-α-stimulated transcription factor ISGF3.
      ), suggesting that the nuclear translocation of the unphosphorylated STAT2 differs from that of unphosphorylated STAT1. Indeed, the import of STAT2 is dependent on IRF9 interactors, which include importin-α3, importin-α4, and importin-α7 (
      • Banninger G.
      • Reich N.C.
      STAT2 nuclear trafficking.
      ).

      The interaction of viruses with nuclear pore proteins and nuclear transport receptors

      As discussed previously, the nucleocytoplasmic shuttling of signal transducers is regulated by distinct nuclear pore proteins and nuclear transport receptors. This regulation is critical for the host innate immune response upon viral infection. Therefore, it is not surprising that different viruses subvert the nucleocytoplasmic transport machinery to evade antiviral innate immunity. In the next sections, we discuss different viral proteins that interact and interfere with nuclear pore complexes and nuclear transport receptors, organized by viral families (summarized in Table 2).
      Table 2Viral subversion of nuclear pore proteins/nuclear transport receptors to interfere with host antiviral innate immune responses
      Virus group (Baltimore classification)Virus familyVirusNups and nuclear transport receptors employed by the virus (References)Proposed interaction between virus and nuclear pore–associated proteins that interferes with host antiviral innate immune responses
      I (dsDNA viruses)HerpesviridaeHSV-1RanBP2/Nup358 and Nup214 (
      • Copeland A.M.
      • Newcomb W.W.
      • Brown J.C.
      Herpes simplex virus replication: Roles of viral proteins and nucleoporins in capsid-nucleus attachment.
      ,
      • Jovasevic V.
      • Liang L.
      • Roizman B.
      Proteolytic cleavage of VP1-2 is required for release of herpes simplex virus 1 DNA into the nucleus.
      ,
      • Pasdeloup D.
      • Blondel D.
      • Isidro A.L.
      • Rixon F.J.
      Herpesvirus capsid association with the nuclear pore complex and viral DNA release involve the nucleoporin CAN/Nup214 and the capsid protein pUL25.
      ,
      • Preston V.G.
      • Murray J.
      • Preston C.M.
      • McDougall I.M.
      • Stow N.D.
      The UL25 gene product of herpes simplex virus type 1 is involved in uncoating of the viral genome.
      )); Nup62 (
      • Malik P.
      • Tabarraei A.
      • Kehlenbach R.H.
      • Korfali N.
      • Iwasawa R.
      • Graham S.V.
      • Schirmer E.C.
      Herpes simplex virus ICP27 protein directly interacts with the nuclear pore complex through Nup62, inhibiting host nucleocytoplasmic transport pathways.
      ); Nup153 (
      • Ray N.
      • Enquist L.W.
      Transcriptional response of a common permissive cell type to infection by two diverse alphaherpesviruses.
      ,
      • Leuzinger H.
      • Ziegler U.
      • Schraner E.M.
      • Fraefel C.
      • Glauser D.L.
      • Heid I.
      • Ackermann M.
      • Mueller M.
      • Wild P.
      Herpes simplex virus 1 envelopment follows two diverse pathways.
      ,
      • Moroianu J.
      • Blobel G.
      • Radu A.
      RanGTP-mediated nuclear export of karyopherin α involves its interaction with the nucleoporin Nup153.
      ); TAP/NXF1 (
      • Johnson L.A.
      • Sandri-Goldin R.M.
      Efficient nuclear export of herpes simplex virus 1 transcripts requires both RNA binding by ICP27 and ICP27 interaction with TAP/NXF1.
      ,
      • Johnson L.A.
      • Li L.
      • Sandri-Goldin R.M.
      The cellular RNA export receptor TAP/NXF1 is required for ICP27-mediated export of herpes simplex virus 1 RNA, but the TREX complex adaptor protein Aly/REF appears to be dispensable.
      ,
      • Koffa M.D.
      • Clements J.B.
      • Izaurralde E.
      • Wadd S.
      • Wilson S.A.
      • Mattaj I.W.
      • Kuersten S.
      Herpes simplex virus ICP27 protein provides viral mRNAs with access to the cellular mRNA export pathway.
      )
      Unknown
      EBVNup62 and Nup153 (
      • Chang C.-W.
      • Lee C.-P.
      • Huang Y.-H.
      • Yang P.-W.
      • Wang J.-T.
      • Chen M.-R.
      Epstein-Barr virus protein kinase BGLF4 targets the nucleus through interaction with nucleoporins.
      ,
      • Chang C.-W.
      • Lee C.-P.
      • Su M.-T.
      • Tsai C.-H.
      • Chen M.-R.
      BGLF4 kinase modulates the structure and transport preference of the nuclear pore complex to facilitate nuclear import of Epstein-Barr virus lytic proteins.
      )
      Unknown
      AdenoviridaeAdenovirusesNup214, RanBP2/Nup358, and Nup62 (
      • Strunze S.
      • Engelke M.F.
      • Wang I.-H.
      • Puntener D.
      • Boucke K.
      • Schleich S.
      • Way M.
      • Schoenenberger P.
      • Burckhardt C.J.
      • Greber U.F.
      Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection.
      ); CRM1 (
      • Schmid M.
      • Gonzalez R.A.
      • Dobner T.
      CRM1-dependent transport supports cytoplasmic accumulation of adenoviral early transcripts.
      ); TAP/NXF1 (
      • Yatherajam G.
      • Huang W.
      • Flint S.J.
      Export of adenoviral late mRNA from the nucleus requires the Nxf1/tap export receptor.
      ,
      • Blanchette P.
      • Kindsmüller K.
      • Groitl P.
      • Dallaire F.
      • Speiseder T.
      • Branton P.E.
      • Dobner T.
      Control of mRNA export by adenovirus E4orf6 and E1B55K proteins during productive infection requires E4orf6 ubiquitin ligase activity.
      ,
      • Woo J.L.
      • Berk A.J.
      Adenovirus ubiquitin-protein ligase stimulates viral late mRNA nuclear export.
      )
      Unknown
      PoxviridaeVACVImportin-α1 (
      • Pallett M.A.
      • Ren H.
      • Zhang R.-Y.
      • Scutts S.R.
      • Gonzalez L.
      • Zhu Z.
      • Maluquer de Motes C.
      • Smith G.L.
      Vaccinia virus BBK E3 ligase adaptor A55 targets importin-dependent NF-κB activation and inhibits CD8+ T-cell memory.
      )
      Blocking the nuclear translocation of NF-κB
      PapillomaviridaeHPVImportin-α1, importin-β2, and importin-β3 (
      • Nelson L.M.
      • Rose R.C.
      • Moroianu J.
      The L1 major capsid protein of human papillomavirus type 11 interacts with kap β2 and kap β3 nuclear import receptors.
      ,
      • Darshan M.S.
      • Lucchi J.
      • Harding E.
      • Moroianu J.
      The L2 minor capsid protein of human papillomavirus type 16 interacts with a network of nuclear import receptors.
      )
      Unknown
      IV ((+) ssRNA viruses)CoronaviridaeSARS-CoVImportin-α1 and importin-β1 (
      • Frieman M.
      • Yount B.
      • Heise M.
      • Kopecky-Bromberg S.A.
      • Palese P.
      • Baric R.S.
      Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane.
      ,
      • Kopecky-Bromberg S.A.
      • Martínez-Sobrido L.
      • Frieman M.
      • Baric R.A.
      • Palese P.
      Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists.
      )
      Blocking the nuclear translocation of STAT1
      MERSImportin-α3 (
      • Canton J.
      • Fehr A.R.
      • Fernandez-Delgado R.
      • Gutierrez-Alvarez F.J.
      • Sanchez-Aparicio M.T.
      • García-Sastre A.
      • Perlman S.
      • Enjuanes L.
      • Sola I.
      MERS-CoV 4b protein interferes with the NF-κB-dependent innate immune response during infection.
      )
      Blocking the nuclear translocation of NF-κB-p65 subunit
      SARS-CoV-2Nup37, Nup54, Nup58, Nup62, Nup88, Nup93, Nup160, Nup188, Nup210, Nup214, Nup98-RAE1, NUTF2, IPO5, IPO8, RanBP6, importin-β1, CRM1, XPOT, THOC3, RanBP2/Nup358 (
      • Wong P.M.C.
      • Chung S.W.
      A functional connection between RanGTP, NF-kappaB and septic shock.
      ,
      • Gordon D.E.
      • Jang G.M.
      • Bouhaddou M.
      • Xu J.
      • Obernier K.
      • White K.M.
      • O’Meara M.J.
      • Rezelj V.V.
      • Guo J.Z.
      • Swaney D.L.
      • Tummino T.A.
      • Hüttenhain R.
      • Kaake R.M.
      • Richards A.L.
      • Tutuncuoglu B.
      • et al.
      A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
      ,
      • Li J.
      • Guo M.
      • Tian X.
      • Wang X.
      • Yang X.
      • Wu P.
      • Liu C.
      • Xiao Z.
      • Qu Y.
      • Yin Y.
      • Wang C.
      • Zhang Y.
      • Zhu Z.
      • Liu Z.
      • Peng C.
      • et al.
      Virus-host interactome and proteomic survey reveal potential virulence factors influencing SARS-CoV-2 pathogenesis.
      ,
      • Miorin L.
      • Kehrer T.
      • Sanchez-Aparicio M.T.
      • Zhang K.
      • Cohen P.
      • Patel R.S.
      • Cupic A.
      • Makio T.
      • Mei M.
      • Moreno E.
      • Danziger O.
      • White K.M.
      • Rathnasinghe R.
      • Uccellini M.
      • Gao S.
      • et al.
      SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling.
      ,
      • Lee J.-G.
      • Huang W.
      • Lee H.
      • van de Leemput J.
      • Kane M.A.
      • Han Z.
      Characterization of SARS-CoV-2 proteins reveals Orf6 pathogenicity, subcellular localization, host interactions and attenuation by Selinexor.
      ,
      • Addetia A.
      • Lieberman N.A.P.
      • Phung Q.
      • Hsiang T.-Y.
      • Xie H.
      • Roychoudhury P.
      • Shrestha L.
      • Loprieno M.A.
      • Huang M.-L.
      • Gale M.
      • Jerome K.R.
      • Greninger A.L.
      SARS-CoV-2 ORF6 disrupts bidirectional nucleocytoplasmic transport through interactions with Rae1 and Nup98.
      ,
      • Bock J.-O.
      • Ortea I.
      Re-analysis of SARS-CoV-2-infected host cell proteomics time-course data by impact pathway analysis and network analysis: A potential link with inflammatory response.
      )
      Blocking the nuclear export of host antiviral mRNAs and nuclear translocation of STAT1
      PicornaviridaeHRVNup62, Nup98, Nup153, Nup214, and RanBP2/Nup358 (
      • Castelló A.
      • Izquierdo J.M.
      • Welnowska E.
      • Carrasco L.
      RNA nuclear export is blocked by poliovirus 2A protease and is concomitant with nucleoporin cleavage.
      ,
      • Gustin K.E.
      • Sarnow P.
      Effects of poliovirus infection on nucleo-cytoplasmic trafficking and nuclear pore complex composition.
      ,
      • Gustin K.E.
      • Sarnow P.
      Inhibition of nuclear import and alteration of nuclear pore complex composition by rhinovirus.
      ,
      • Park N.
      • Katikaneni P.
      • Skern T.
      • Gustin K.E.
      Differential targeting of nuclear pore complex proteins in poliovirus-infected cells.
      ,
      • Park N.
      • Skern T.
      • Gustin K.E.
      Specific cleavage of the nuclear pore complex protein Nup62 by a viral protease.
      ,
      • Ghildyal R.
      • Jordan B.
      • Li D.
      • Dagher H.
      • Bardin P.G.
      • Gern J.E.
      • Jans D.A.
      Rhinovirus 3C protease can localize in the nucleus and alter active and passive nucleocytoplasmic transport.
      ,
      • Walker E.J.
      • Younessi P.
      • Fulcher A.J.
      • McCuaig R.
      • Thomas B.J.
      • Bardin P.G.
      • Jans D.A.
      • Ghildyal R.
      Rhinovirus 3C protease facilitates specific nucleoporin cleavage and mislocalisation of nuclear proteins in infected host cells.
      )
      Unknown
      PVNup62, Nup98, and Nup153 (
      • Castelló A.
      • Izquierdo J.M.
      • Welnowska E.
      • Carrasco L.
      RNA nuclear export is blocked by poliovirus 2A protease and is concomitant with nucleoporin cleavage.
      ,
      • Gustin K.E.
      • Sarnow P.
      Effects of poliovirus infection on nucleo-cytoplasmic trafficking and nuclear pore complex composition.
      ,
      • Gustin K.E.
      • Sarnow P.
      Inhibition of nuclear import and alteration of nuclear pore complex composition by rhinovirus.
      ,
      • Park N.
      • Katikaneni P.
      • Skern T.
      • Gustin K.E.
      Differential targeting of nuclear pore complex proteins in poliovirus-infected cells.
      ,
      • Park N.
      • Skern T.
      • Gustin K.E.
      Specific cleavage of the nuclear pore complex protein Nup62 by a viral protease.
      )
      Unknown
      EMCVRan-GTPase, Nup62, Nup153, and Nup214 (
      • Porter F.W.
      • Palmenberg A.C.
      Leader-induced phosphorylation of nucleoporins correlates with nuclear trafficking inhibition by cardioviruses.
      ,
      • Porter F.W.
      • Bochkov Y.A.
      • Albee A.J.
      • Wiese C.
      • Palmenberg A.C.
      A picornavirus protein interacts with Ran-GTPase and disrupts nucleocytoplasmic transport.
      )
      Unknown
      TMEVRan-GTPase, Nup98 (
      • Ricour C.
      • Delhaye S.
      • Hato S.V.
      • Olenyik T.D.
      • Michel B.
      • van Kuppeveld F.J.M.
      • Gustin K.E.
      • Michiels T.
      Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler’s virus leader protein.
      )
      Unknown
      FlaviviridaeDengue virusImportin-α and importin-β (
      • Johansson M.
      • Brooks A.J.
      • Jans D.A.
      • Vasudevan S.G.
      A small region of the dengue virus-encoded RNA-dependent RNA polymerase, NS5, confers interaction with both the nuclear transport receptor importin-beta and the viral helicase, NS3.
      ); Nup153, Nup98, and Nup62 (
      • De Jesús-González L.A.
      • Cervantes-Salazar M.
      • Reyes-Ruiz J.M.
      • Osuna-Ramos J.F.
      • Farfán-Morales C.N.
      • Palacios-Rápalo S.N.
      • Pérez-Olais J.H.
      • Cordero-Rivera C.D.
      • Hurtado-Monzón A.M.
      • Ruíz-Jiménez F.
      • Gutiérrez-Escolano A.L.
      • del Ángel R.M.
      The nuclear pore complex: A target for NS3 protease of dengue and Zika viruses.
      )
      Unknown
      ZIKANup98, Nup153, and TPR (
      • De Jesús-González L.A.
      • Cervantes-Salazar M.
      • Reyes-Ruiz J.M.
      • Osuna-Ramos J.F.
      • Farfán-Morales C.N.
      • Palacios-Rápalo S.N.
      • Pérez-Olais J.H.
      • Cordero-Rivera C.D.
      • Hurtado-Monzón A.M.
      • Ruíz-Jiménez F.
      • Gutiérrez-Escolano A.L.
      • del Ángel R.M.
      The nuclear pore complex: A target for NS3 protease of dengue and Zika viruses.
      ); importin-α7 (
      • Yang L.
      • Wang R.
      • Yang S.
      • Ma Z.
      • Lin S.
      • Nan Y.
      • Li Q.
      • Tang Q.
      • Zhang Y.-J.
      Karyopherin alpha 6 is required for replication of porcine reproductive and respiratory syndrome virus and Zika virus.
      )
      Unknown
      HCVImportin-β1 (
      • Gagné B.
      • Tremblay N.
      • Park A.Y.
      • Baril M.
      • Lamarre D.
      Importin β1 targeting by hepatitis C virus NS3/4A protein restricts IRF3 and NF-κB signaling of IFNB1 antiviral response.
      ,
      • Germain M.-A.
      • Chatel-Chaix L.
      • Gagné B.
      • Bonneil É.
      • Thibault P.
      • Pradezynski F.
      • de Chassey B.
      • Meyniel-Schicklin L.
      • Lotteau V.
      • Baril M.
      • Lamarre D.
      Elucidating novel hepatitis C virus–host interactions using combined mass spectrometry and functional genomics approaches.
      )
      Blocking the nuclear translocation of STAT1, IRF3, and NF-κB-p65
      JEVImportin-α3 and importin-α4 (
      • Ye J.
      • Chen Z.
      • Li Y.
      • Zhao Z.
      • He W.
      • Zohaib A.
      • Song Y.
      • Deng C.
      • Zhang B.
      • Chen H.
      • Cao S.
      Japanese encephalitis virus NS5 inhibits type I interferon (IFN) production by blocking the nuclear translocation of IFN regulatory factor 3 and NF-κB.
      )
      Blocking the nuclear translocation of NF-κB and IRF3
      V ((−) ssRNA viruses)FiloviridaeEBOVImportin-α5, importin-α6, and importin-α7 (
      • Reid S.P.
      • Valmas C.
      • Martinez O.
      • Sanchez F.M.
      • Basler C.F.
      Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin α proteins with activated STAT1.
      ,
      • Mateo M.
      • Reid S.P.
      • Leung L.W.
      • Basler C.F.
      • Volchkov V.E.
      Ebolavirus VP24 binding to karyopherins is required for inhibition of interferon signaling.
      ,
      • Reid S.P.
      • Leung L.W.
      • Hartman A.L.
      • Martinez O.
      • Shaw M.L.
      • Carbonnelle C.
      • Volchkov V.E.
      • Nichol S.T.
      • Basler C.F.
      Ebola virus VP24 binds karyopherin α1 and blocks STAT1 nuclear accumulation.
      ,
      • Xu W.
      • Edwards M.R.
      • Borek D.M.
      • Feagins A.R.
      • Mittal A.
      • Alinger J.B.
      • Berry K.N.
      • Yen B.
      • Hamilton J.
      • Brett T.J.
      • Pappu R.V.
      • Leung D.W.
      • Basler C.F.
      • Amarasinghe G.K.
      Ebola virus VP24 targets a unique NLS-binding site on karyopherin5 to selectively compete with nuclear import of phosphorylated STAT1.
      )
      Blocking the nuclear import of PY-STAT1
      OrthomyxoviridaeIAVImportin-α/β (
      • Wu W.W.
      • Sun Y.-H.B.
      • Panté N.
      Nuclear import of influenza A viral ribonucleoprotein complexes is mediated by two nuclear localization sequences on viral nucleoprotein.
      ), CRM1 (
      • Neumann G.
      • Hughes M.T.
      • Kawaoka Y.
      Influenza A virus NS2 protein mediates vRNP nuclear export through NES-independent interaction with hCRM1.
      ,
      • Chase G.P.
      • Rameix-Welti M.-A.
      • Zvirbliene A.
      • Zvirblis G.
      • Götz V.
      • Wolff T.
      • Naffakh N.
      • Schwemmle M.
      Influenza virus ribonucleoprotein complexes gain preferential access to cellular export machinery through chromatin targeting.
      ), NXF1/NXT1, RAE1, and Nup98 (
      • Zhang K.
      • Xie Y.
      • Muñoz-Moreno R.
      • Wang J.
      • Zhang L.
      • Esparza M.
      • García-Sastre A.
      • Fontoura B.M.A.
      • Ren Y.
      Structural basis for influenza virus NS1 protein block of mRNA nuclear export.
      ,
      • Satterly N.
      • Tsai P.-L.
      • van Deursen J.
      • Nussenzveig D.R.
      • Wang Y.
      • Faria P.A.
      • Levay A.
      • Levy D.E.
      • Fontoura B.M.A.
      Influenza virus targets the mRNA export machinery and the nuclear pore complex.
      ,
      • Chen J.
      • Huang S.
      • Chen Z.
      Human cellular protein nucleoporin hNup98 interacts with influenza A virus NS2/nuclear export protein and overexpression of its GLFG repeat domain can inhibit virus propagation.
      )
      Blocking the nuclear export of host antiviral mRNAs
      RhabdoviridaeVSVRAE1 and Nup98 (
      • Faria P.A.
      • Chakraborty P.
      • Levay A.
      • Barber G.N.
      • Ezelle H.J.
      • Enninga J.
      • Arana C.
      • van Deursen J.
      • Fontoura B.M.A.
      VSV disrupts the Rae1/mrnp41 mRNA nuclear export pathway.
      ,
      • Rajani K.R.
      • Pettit Kneller E.L.
      • McKenzie M.O.
      • Horita D.A.
      • Chou J.W.
      • Lyles D.S.
      Complexes of vesicular stomatitis virus matrix protein with host Rae1 and Nup98 involved in inhibition of host transcription.
      ,
      • von Kobbe C.
      • null
      • van Deursen J.M.
      • null
      • Rodrigues J.P.
      • Sitterlin D.
      • Bachi A.
      • Wu X.
      • Wilm M.
      • Carmo-Fonseca M.
      • Izaurralde E.
      Vesicular stomatitis virus matrix protein inhibits host cell gene expression by targeting the nucleoporin Nup98.
      )
      Unknown
      BunyaviridaeHTNVImportin-α1, importin-α2, and importin-α3 (
      • Taylor S.L.
      • Frias-Staheli N.
      • García-Sastre A.
      • Schmaljohn C.S.
      Hantaan virus nucleocapsid protein binds to importin α proteins and inhibits tumor necrosis factor alpha-induced activation of nuclear factor kappa B.
      )
      Blocking the nuclear translocation of NF-κB
      VI (ssRNA-RT viruses)RetroviridaeHIV-1Importin-α1, importin-α3, importin-α5 (
      • Gallay P.
      • Stitt V.
      • Mundy C.
      • Oettinger M.
      • Trono D.
      Role of the karyopherin pathway in human immunodeficiency virus type 1 nuclear import.
      ,
      • Gallay P.
      • Hope T.
      • Chin D.
      • Trono D.
      HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway.
      ,
      • Nitahara-Kasahara Y.
      • Kamata M.
      • Yamamoto T.
      • Zhang X.
      • Miyamoto Y.
      • Muneta K.
      • Iijima S.
      • Yoneda Y.
      • Tsunetsugu-Yokota Y.
      • Aida Y.
      Novel nuclear import of Vpr promoted by importin α is crucial for human immunodeficiency virus type 1 replication in macrophages.
      ,
      • Ao Z.
      • Danappa Jayappa K.
      • Wang B.
      • Zheng Y.
      • Kung S.
      • Rassart E.
      • Depping R.
      • Kohler M.
      • Cohen E.A.
      • Yao X.
      Importin alpha3 interacts with HIV-1 integrase and contributes to HIV-1 nuclear import and replication.
      ,
      • Popov S.
      • Rexach M.
      • Zybarth G.
      • Reiling N.
      • Lee M.-A.
      • Ratner L.
      • Lane C.M.
      • Moore M.S.
      • Blobel G.
      • Bukrinsky M.
      Viral protein R regulates nuclear import of the HIV-1 pre-integration complex.
      ,
      • Khan H.
      • Sumner R.P.
      • Rasaiyaah J.
      • Tan C.P.
      • Rodriguez-Plata M.T.
      • Van Tulleken C.
      • Fink D.
      • Zuliani-Alvarez L.
      • Thorne L.
      • Stirling D.
      • Milne R.S.
      • Towers G.J.
      HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport.
      ), importin-7 (
      • Ao Z.
      • Huang G.
      • Yao H.
      • Xu Z.
      • Labine M.
      • Cochrane A.W.
      • Yao X.
      Interaction of human immunodeficiency virus type 1 integrase with cellular nuclear import receptor importin 7 and its impact on viral replication.
      ), transportin-3 (
      • Christ F.
      • Thys W.
      • De Rijck J.
      • Gijsbers R.
      • Albanese A.
      • Arosio D.
      • Emiliani S.
      • Rain J.-C.
      • Benarous R.
      • Cereseto A.
      • Debyser Z.
      Transportin-SR2 imports HIV into the nucleus.
      ), CRM1 (
      • Bogerd H.P.
      • Echarri A.
      • Ross T.M.
      • Cullen B.R.
      Inhibition of human immunodeficiency virus Rev and human T-cell leukemia virus Rex function, but not Mason-Pfizer monkey virus constitutive transport element activity, by a mutant human nucleoporin targeted to Crm1.
      ), Nup62, Nup153, Nup98, Nup214, RanBP2/Nup358, and hCG1 (
      • Xu W.
      • Edwards M.R.
      • Borek D.M.
      • Feagins A.R.
      • Mittal A.
      • Alinger J.B.
      • Berry K.N.
      • Yen B.
      • Hamilton J.
      • Brett T.J.
      • Pappu R.V.
      • Leung D.W.
      • Basler C.F.
      • Amarasinghe G.K.
      Ebola virus VP24 targets a unique NLS-binding site on karyopherin5 to selectively compete with nuclear import of phosphorylated STAT1.
      ,
      • Woodward C.L.
      • Prakobwanakit S.
      • Mosessian S.
      • Chow S.A.
      Integrase interacts with nucleoporin NUP153 to mediate the nuclear import of human immunodeficiency virus type 1.
      ,
      • Varadarajan P.
      • Mahalingam S.
      • Liu P.
      • Ng S.B.H.
      • Gandotra S.
      • Dorairajoo D.S.K.
      • Balasundaram D.
      The functionally conserved nucleoporins Nup124p from fission yeast and the human Nup153 mediate nuclear import and activity of the Tf1 retrotransposon and HIV-1 Vpr.
      ,
      • Ebina H.
      • Aoki J.
      • Hatta S.
      • Yoshida T.
      • Koyanagi Y.
      Role of Nup98 in nuclear entry of human immunodeficiency virus type 1 cDNA.
      ,
      • Le Rouzic E.
      • Mousnier A.
      • Rustum C.
      • Stutz F.
      • Hallberg E.
      • Dargemont C.
      • Benichou S.
      Docking of HIV-1 Vpr to the nuclear envelope is mediated by the interaction with the nucleoporin hCG1.
      ,
      • König R.
      • Zhou Y.
      • Elleder D.
      • Diamond T.L.
      • Bonamy G.M.C.
      • Irelan J.T.
      • Chiang C.
      • Tu B.P.
      • De Jesus P.D.
      • Lilley C.E.
      • Seidel S.
      • Opaluch A.M.
      • Caldwell J.S.
      • Weitzman M.D.
      • Kuhen K.L.
      • et al.
      Global analysis of host-pathogen interactions that regulate early stage HIV-1 replication.
      ,
      • Zolotukhin A.S.
      • Felber B.K.
      Nucleoporins nup98 and nup214 participate in nuclear export of human immunodeficiency virus type 1 Rev..
      ,
      • Hutten S.
      • Wälde S.
      • Spillner C.
      • Hauber J.
      • Kehlenbach R.H.
      The nuclear pore component Nup358 promotes transportin-dependent nuclear import.
      ,
      • Ao Z.
      • Jayappa K.D.
      • Wang B.
      • Zheng Y.
      • Wang X.
      • Peng J.
      • Yao X.
      Contribution of host nucleoporin 62 in HIV-1 integrase chromatin association and viral DNA integration.
      ,
      • Di Nunzio F.
      • Danckaert A.
      • Fricke T.
      • Perez P.
      • Fernandez J.
      • Perret E.
      • Roux P.
      • Shorte S.
      • Charneau P.
      • Diaz-Griffero F.
      • Arhel N.J.
      Human nucleoporins promote HIV-1 docking at the nuclear pore, nuclear import and integration.
      ,
      • Rasaiyaah J.
      • Tan C.P.
      • Fletcher A.J.
      • Price A.J.
      • Blondeau C.
      • Hilditch L.
      • Jacques D.A.
      • Selwood D.L.
      • James L.C.
      • Noursadeghi M.
      • Towers G.J.
      HIV-1 evades innate immune recognition through specific co-factor recruitment.
      )
      Blocking the nuclear translocation of NF-κB and IRF3
      VII (dsDNA-RT viruses)HepadnaviridaeHBVImportin-α/β (
      • Kann M.
      • Sodeik B.
      • Vlachou A.
      • Gerlich W.H.
      • Helenius A.
      Phosphorylation-dependent binding of hepatitis B virus core particles to the nuclear pore complex.
      ,
      • Rabe B.
      • Vlachou A.
      • Panté N.
      • Helenius A.
      • Kann M.
      Nuclear import of hepatitis B virus capsids and release of the viral genome.
      ), importin-α5 (
      • Chen J.
      • Wu M.
      • Zhang X.
      • Zhang W.
      • Zhang Z.
      • Chen L.
      • He J.
      • Zheng Y.
      • Chen C.
      • Wang F.
      • Hu Y.
      • Zhou X.
      • Wang C.
      • Xu Y.
      • Lu M.
      • et al.
      Hepatitis B virus polymerase impairs interferon-α-induced STA T activation through inhibition of importin-α5 and protein kinase C-δ.
      ), and Nup153 (
      • Schmitz A.
      • Schwarz A.
      • Foss M.
      • Zhou L.
      • Rabe B.
      • Hoellenriegel J.
      • Stoeber M.
      • Panté N.
      • Kann M.
      Nucleoporin 153 arrests the nuclear import of hepatitis B virus capsids in the nuclear basket.
      )
      Blocking the nuclear translocation of STAT1/2

      Herpesviruses

      Members of herpesviruses belong to Herpesviridae, which is a large family of dsDNA viruses that cause diseases in a wide range of hosts, including humans. There are nine herpesvirus types known to infect humans, including herpes simplex viruses (HSVs) type 1 and 2 (HSV-1 and HSV-2 or human herpesvirus 1 [HHV-1] and HHV-2), varicella-zoster virus (or HHV-3), Epstein–Barr virus (EBV or HHV-34), human cytomegalovirus (or HHV-5), HHV-6A and HHV-6B, HHV-7, and Kaposi's sarcoma–associated herpesvirus (KSHV or HHV-8). Most humans are infected with HSV-1, a member of alpha-herpesvirus subfamily, which causes clinical symptoms, such as cold sores, in roughly one-third of all humans.
      It has been observed that certain proteins encoded by HSV-1 interact with distinct nuclear pore proteins and nuclear transport receptors. The capsid (CA)-tethered tegument protein pUL36, and the minor CA protein pUL25, binds to RanBP2/Nup358 and Nup214, respectively, to dock the viral capsids at the cytoplasmic face of the nuclear pore, which subsequently facilitates the uncoating and release of the viral genome into the nucleus (
      • Copeland A.M.
      • Newcomb W.W.
      • Brown J.C.
      Herpes simplex virus replication: Roles of viral proteins and nucleoporins in capsid-nucleus attachment.
      ,
      • Jovasevic V.
      • Liang L.
      • Roizman B.
      Proteolytic cleavage of VP1-2 is required for release of herpes simplex virus 1 DNA into the nucleus.
      ,
      • Pasdeloup D.
      • Blondel D.
      • Isidro A.L.
      • Rixon F.J.
      Herpesvirus capsid association with the nuclear pore complex and viral DNA release involve the nucleoporin CAN/Nup214 and the capsid protein pUL25.
      ,
      • Preston V.G.
      • Murray J.
      • Preston C.M.
      • McDougall I.M.
      • Stow N.D.
      The UL25 gene product of herpes simplex virus type 1 is involved in uncoating of the viral genome.
      ). pUL25 may have other functions, as viruses bearing a mutant form of this protein did not efficiently trigger cGAS signaling in infected cells. This mutation did not affect the attachment of CA to the nuclear pores but instead significantly delayed the expression of viral proteins (
      • Huffman J.B.
      • Daniel G.R.
      • Falck-Pedersen E.
      • Huet A.
      • Smith G.A.
      • Conway J.F.
      • Homa F.L.
      The C terminus of the herpes simplex virus UL25 protein is required for release of viral genomes from capsids bound to nuclear pores.
      ). It has also been reported that HSV-1 infection inhibits Nup153 expression (
      • Ray N.
      • Enquist L.W.
      Transcriptional response of a common permissive cell type to infection by two diverse alphaherpesviruses.
      ) and alters its subcellular localization, sending this nuclear basket protein to the cytoplasm (
      • Leuzinger H.
      • Ziegler U.
      • Schraner E.M.
      • Fraefel C.
      • Glauser D.L.
      • Heid I.
      • Ackermann M.
      • Mueller M.
      • Wild P.
      Herpes simplex virus 1 envelopment follows two diverse pathways.
      ). This observation suggests that HSV-1 interferes with nuclear import by repressing Nup153 (
      • Moroianu J.
      • Blobel G.
      • Radu A.
      RanGTP-mediated nuclear export of karyopherin α involves its interaction with the nucleoporin Nup153.
      ). ICP27 is another HSV-1 protein that interacts directly with Nup62 and blocks host protein import via importin-α, importin-β1, and importin-β2 nuclear import pathways (
      • Malik P.
      • Tabarraei A.
      • Kehlenbach R.H.
      • Korfali N.
      • Iwasawa R.
      • Graham S.V.
      • Schirmer E.C.
      Herpes simplex virus ICP27 protein directly interacts with the nuclear pore complex through Nup62, inhibiting host nucleocytoplasmic transport pathways.
      ). In addition, ICP27 interacts with both the RNA export receptor TAP/NXF1 and the TREX complex adaptor protein Aly/REF, to preferentially export HSV-1 RNA over endogenous mRNAs (
      • Johnson L.A.
      • Sandri-Goldin R.M.
      Efficient nuclear export of herpes simplex virus 1 transcripts requires both RNA binding by ICP27 and ICP27 interaction with TAP/NXF1.
      ,
      • Johnson L.A.
      • Li L.
      • Sandri-Goldin R.M.
      The cellular RNA export receptor TAP/NXF1 is required for ICP27-mediated export of herpes simplex virus 1 RNA, but the TREX complex adaptor protein Aly/REF appears to be dispensable.
      ,
      • Koffa M.D.
      • Clements J.B.
      • Izaurralde E.
      • Wadd S.
      • Wilson S.A.
      • Mattaj I.W.
      • Kuersten S.
      Herpes simplex virus ICP27 protein provides viral mRNAs with access to the cellular mRNA export pathway.
      ). Moreover, ICP27-like proteins encoded by other related herpesviruses, including human cytomegalovirus, KSHV, EBV, varicella-zoster virus, also facilitate nuclear export of viral mRNAs (
      • Boyne J.R.
      • Colgan K.J.
      • Whitehouse A.
      Recruitment of the complete hTREX complex is required for Kaposi’s sarcoma–associated herpesvirus intronless mRNA nuclear export and virus replication.
      ,
      • Hiriart E.
      • Bardouillet L.
      • Manet E.
      • Gruffat H.
      • Penin F.
      • Montserret R.
      • Farjot G.
      • Sergeant A.
      A region of the Epstein-Barr virus (EBV) mRNA export factor EB2 containing an arginine-rich motif mediates direct binding to RNA.
      ,
      • Lischka P.
      • Toth Z.
      • Thomas M.
      • Mueller R.
      • Stamminger T.
      The UL69 transactivator protein of human cytomegalovirus interacts with DEXD/H-box RNA helicase UAP56 to promote cytoplasmic accumulation of unspliced RNA.
      ,
      • Ote I.
      • Lebrun M.
      • Vandevenne P.
      • Bontems S.
      • Medina-Palazon C.
      • Manet E.
      • Piette J.
      • Sadzot-Delvaux C.
      Varicella-zoster virus IE4 protein interacts with SR proteins and exports mRNAs through the TAP/NXF1 pathway.
      ,
      • Williams B.J.L.
      • Boyne J.R.
      • Goodwin D.J.
      • Roaden L.
      • Hautbergue G.M.
      • Wilson S.A.
      • Whitehouse A.
      The prototype γ-2 herpesvirus nucleocytoplasmic shuttling protein, ORF 57, transports viral RNA through the cellular mRNA export pathway.
      ).
      The gamma-herpesvirus EBV also modulates nucleocytoplasmic transport. One of its proteins, BGLF4, is a serine–threonine protein kinase that directly binds and phosphorylates Nup62 and Nup153 to modulate nuclear pore complex organization (
      • Chang C.-W.
      • Lee C.-P.
      • Huang Y.-H.
      • Yang P.-W.
      • Wang J.-T.
      • Chen M.-R.
      Epstein-Barr virus protein kinase BGLF4 targets the nucleus through interaction with nucleoporins.
      ,
      • Chang C.-W.
      • Lee C.-P.
      • Su M.-T.
      • Tsai C.-H.
      • Chen M.-R.
      BGLF4 kinase modulates the structure and transport preference of the nuclear pore complex to facilitate nuclear import of Epstein-Barr virus lytic proteins.
      ). Consequently, BGLF4 blocks general nuclear import by impairing importin-β1 nuclear targeting, while simultaneously facilitating the nuclear import of certain EBV lytic proteins (
      • Chang C.-W.
      • Lee C.-P.
      • Su M.-T.
      • Tsai C.-H.
      • Chen M.-R.
      BGLF4 kinase modulates the structure and transport preference of the nuclear pore complex to facilitate nuclear import of Epstein-Barr virus lytic proteins.
      ).
      Even though herpesviruses contain proteins that interact with nuclear pore complexes and nuclear transport receptors (as described previously), whether these interactions engage in the regulation of host innate immunity is unknown.

      Adenoviruses

      The family Adenoviridae is a large group of nonenveloped dsDNA viruses that infect a broad range of vertebrate hosts, including humans, and cause diseases, such as respiratory, gastrointestinal, urogenital, and ocular diseases. The entry of adenoviruses (AdVs) into the cell starts with the association of viral fiber proteins with host cell receptors (known as coxsackievirus AdV receptors) (
      • Tomko R.P.
      • Xu R.
      • Philipson L.
      HCAR and MCAR: The human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses.
      ), followed by receptor-mediated endocytosis and virion escape into the cytoplasm (
      • Puntener D.
      • Engelke M.F.
      • Ruzsics Z.
      • Strunze S.
      • Wilhelm C.
      • Greber U.F.
      Stepwise loss of fluorescent core protein V from human adenovirus during entry into cells.
      ). Subsequently, these virions travel along microtubules through their interaction with the molecular motor dynein (
      • Scherer J.
      • Vallee R.B.
      Adenovirus recruits dynein by an evolutionary novel mechanism involving direct binding to pH-primed hexon.
      ). In this way, virions make their way to the nuclear envelope where they dock onto the cytoplasmic filaments of the nuclear pore by interacting with Nup214. Then the viral CA is disassembled in a kinesin-I–dependent manner (
      • Strunze S.
      • Engelke M.F.
      • Wang I.-H.
      • Puntener D.
      • Boucke K.
      • Schleich S.
      • Way M.
      • Schoenenberger P.
      • Burckhardt C.J.
      • Greber U.F.
      Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection.
      ), releasing the viral genome into the nucleus. In addition, studies have indicated that AdVs displace cytoplasmic nuclear pore filament proteins (RanBP2/Nup358, Nup214, and Nup62) into the cytoplasm to increase nuclear envelope permeability and thereby facilitate the nuclear import of viral DNA (
      • Strunze S.
      • Engelke M.F.
      • Wang I.-H.
      • Puntener D.
      • Boucke K.
      • Schleich S.
      • Way M.
      • Schoenenberger P.
      • Burckhardt C.J.
      • Greber U.F.
      Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection.
      ). In the nucleus, viral DNA is transcribed into adenoviral early mRNA, which is exported to the cytosol in a CRM1-dependent manner (
      • Schmid M.
      • Gonzalez R.A.
      • Dobner T.
      CRM1-dependent transport supports cytoplasmic accumulation of adenoviral early transcripts.
      ), and adenoviral late transcripts, which are exported by the export receptor TAP/NXF1 (
      • Yatherajam G.
      • Huang W.
      • Flint S.J.
      Export of adenoviral late mRNA from the nucleus requires the Nxf1/tap export receptor.
      ). Two adenoviral proteins, E1B-55K and E4orf6, not only inhibit NXF1-mediated host mRNAs export but also promote adenoviral late mRNA export by binding to the host protein E1B-AP5 (also known as hnRNPUL1), which interacts with NXF1 (
      • Blanchette P.
      • Kindsmüller K.
      • Groitl P.
      • Dallaire F.
      • Speiseder T.
      • Branton P.E.
      • Dobner T.
      Control of mRNA export by adenovirus E4orf6 and E1B55K proteins during productive infection requires E4orf6 ubiquitin ligase activity.
      ,
      • Woo J.L.
      • Berk A.J.
      Adenovirus ubiquitin-protein ligase stimulates viral late mRNA nuclear export.
      ).
      The stepwise process of docking AdV CAs at the nuclear pore and uncoating of the virion to release viral genome into the nucleus may allow AdV to evade host antiviral innate immune responses by restricting viral DNA exposure in the cytoplasm. In addition, the disruption of host nucleocytoplasmic trafficking system may help interfere with the nuclear import of crucial factors involved in innate immunity (
      • Le Sage V.
      • Mouland A.J.
      Viral subversion of the nuclear pore complex.
      ,
      • Suomalainen M.
      • Greber U.F.
      Uncoating of non-enveloped viruses.
      ,
      • Tessier T.M.
      • Dodge M.J.
      • Prusinkiewicz M.A.
      • Mymryk J.S.
      Viral appropriation: Laying claim to host nuclear transport machinery.
      ). Further studies are needed to determine whether the interaction between AdVs and host nucleocytoplasmic transport system contributes to viral evasion of the host innate immune response.

      Poxviruses

      The family Poxviridae is a large group of dsDNA viruses that replicate in the cytoplasm and infect humans, vertebrates, and arthropods. Poxviruses are currently divided into 22 genera and 83 species. Among them, variola virus and vaccinia virus (VACV) are commonly known. Variola virus causes an acute contagious disease called smallpox and was responsible for a large number of deaths throughout human history. VACV, a lab-grown strain of poxvirus, was used as a live vaccine that helped to eradicate smallpox. VACV can stimulate a strong immune response and encodes a number of proteins that inhibit NF-κB activation to evade the host immune response (
      • Smith G.L.
      • Benfield C.T.O.
      • Maluquer de Motes C.
      • Mazzon M.
      • Ember S.W.J.
      • Ferguson B.J.
      • Sumner R.P.
      Vaccinia virus immune evasion: Mechanisms, virulence and immunogenicity.
      ). Recently, it was shown that VACV protein A55 competes with NF-κB for importin-α1 binding, thereby preventing the nuclear import of NF-κB and inhibiting downstream gene transcription (
      • Pallett M.A.
      • Ren H.
      • Zhang R.-Y.
      • Scutts S.R.
      • Gonzalez L.
      • Zhu Z.
      • Maluquer de Motes C.
      • Smith G.L.
      Vaccinia virus BBK E3 ligase adaptor A55 targets importin-dependent NF-κB activation and inhibits CD8+ T-cell memory.
      ) (Fig. 4).

      Papillomaviruses

      Papillomaviruses (Papillomaviridae family) are a large family of small, nonenveloped, and icosahedral DNA viruses with a single molecule of 8 kb double-stranded circular DNA (
      • Doorbar J.
      • Gallimore P.H.
      Identification of proteins encoded by the L1 and L2 open reading frames of human papillomavirus 1a.
      ). Human papillomavirus (HPV) includes low-risk HPVs, such as HPV-6 and HPV-11, causing benign exophytic condylomas, and high-risk HPVs, such as HPV-16, HPV-18, HPV-31, and HPV-45, which are associated with anogenital cancers, oropharyngeal cancers, and skin cancers (
      • zur Hausen H.
      Papillomaviruses causing cancer: Evasion from host-cell control in early events in carcinogenesis.
      ).
      To date, the L1 major and L2 minor CA proteins of HPV-11 and HPV-16 have been revealed to interact with nuclear transport receptors. The HPV-11 L1 protein binds to importin-α1 and enters into the nucleus through the classical importin-α1/β1-mediated import system (
      • Nelson L.M.
      • Rose R.C.
      • Moroianu J.
      The L1 major capsid protein of human papillomavirus type 11 interacts with kap β2 and kap β3 nuclear import receptors.
      ). In addition, L1 from both HPV-11 and HPV-16 binds to importin-β2 and importin-β3, inhibiting their nuclear import activities (
      • Nelson L.M.
      • Rose R.C.
      • Moroianu J.
      The L1 major capsid protein of human papillomavirus type 11 interacts with kap β2 and kap β3 nuclear import receptors.
      ). The L2 minor CA protein of HPV-16 is transported into the nucleus by interacting with either importin-β2, importin-β3, or the importin-α1/importin-β1 heterodimer (
      • Darshan M.S.
      • Lucchi J.
      • Harding E.
      • Moroianu J.
      The L2 minor capsid protein of human papillomavirus type 16 interacts with a network of nuclear import receptors.
      ). Although HPV-11 and HPV-16 associate with host nuclear import pathways, whether these interactions subvert host antiviral immune systems remain unknown.

      Coronaviruses

      Coronaviruses (CoVs) are enveloped, single-stranded, positive-sense RNA viruses under the family of Coronaviridae. CoV genomes are approximately 30 kb with the first two-thirds of the genome encoding two large polyproteins important for replicase function and the last third of the genome encoding multiple structural and accessory proteins. CoVs are divided into four genera named alpha-, beta-, gamma-, and delta-coronavirus (
      • Woo P.C.Y.
      • Lau S.K.P.
      • Lam C.S.F.
      • Lau C.C.Y.
      • Tsang A.K.L.
      • Lau J.H.N.
      • Bai R.
      • Teng J.L.L.
      • Tsang C.C.C.
      • Wang M.
      • Zheng B.-J.
      • Chan K.-H.
      • Yuen K.-Y.
      Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus.
      ) and can infect a wide range of hosts, such as bats, birds, mice, dogs, as well as humans (
      • de Groot R.J.
      • Baker S.C.
      • Baric R.S.
      • Brown C.S.
      • Drosten C.
      • Enjuanes L.
      • Fouchier R.A.M.
      • Galiano M.
      • Gorbalenya A.E.
      • Memish Z.A.
      • Perlman S.
      • Poon L.L.M.
      • Snijder E.J.
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