Immunology
Viperin: An ancient radical SAM enzyme finds its place in modern cellular metabolism and innate immunity
Viperin plays an important and multifaceted role in the innate immune response to viral infection. Viperin is also notable as one of very few radical SAM–dependent enzymes present in higher animals; however, the enzyme appears broadly conserved across all kingdoms of life, which suggests that it represents an ancient defense mechanism against viral infections. Although viperin was discovered some 20 years ago, only recently was the enzyme's structure determined and its catalytic activity elucidated.Coordinated regulation of scaffold opening and enzymatic activity during CARD11 signaling
The activation of key signaling pathways downstream of antigen receptor engagement is critically required for normal lymphocyte activation during the adaptive immune response. CARD11 is a multidomain signaling scaffold protein required for antigen receptor signaling to NF-κB, c-Jun N-terminal kinase, and mTOR. Germline mutations in the CARD11 gene result in at least four types of primary immunodeficiency, and somatic CARD11 gain-of-function mutations drive constitutive NF-κB activity in diffuse large B cell lymphoma and other lymphoid cancers.The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation
Pregnenolone is a steroid hormone precursor that is synthesized in various steroidogenic tissues, in the brain, and in lymphocytes. In addition to serving as the precursor for other steroid hormones, pregnenolone exerts its own effect as an anti-inflammatory molecule to maintain immune homeostasis in various inflammatory conditions. Pregnenolone and its metabolic derivatives have been shown to have beneficial effects in the brain, including enhancing memory and learning, reversing depressive disorders, and modulating cognitive functions.Parkin negatively regulates the antiviral signaling pathway by targeting TRAF3 for degradation
Chronic neuroinflammation is a characteristic of Parkinson's disease (PD). Previous investigations have shown that Parkin gene mutations are related to the early-onset recessive form of PD and isolated juvenile-onset PD. Further, Parkin plays important roles in mitochondrial quality control and cytokine-induced cell death. However, whether Parkin regulates other cellular events is still largely unknown. In this study, we performed overexpression and knockout experiments and found that Parkin negatively regulates antiviral immune responses against RNA and DNA viruses.Cereblon suppresses the lipopolysaccharide-induced inflammatory response by promoting the ubiquitination and degradation of c-Jun
Chronic inflammation is associated with multiple human disorders, such as rheumatoid arthritis, metabolic diseases, and neurodegenerative diseases. Therefore, alleviation of inflammation induced by environmental stimuli is important for disease prevention or treatment. Cereblon (CRBN) functions as a substrate receptor of the cullin-4 RING E3 ligase to mediate protein ubiquitination and degradation. Although it has been reported that CRBN reduces the inflammatory response through its nonenzymatic function, its role as a substrate receptor of the E3 ligase is not explored in mediating this process.The fructose-2,6-bisphosphatase TIGAR suppresses NF-κB signaling by directly inhibiting the linear ubiquitin assembly complex LUBAC
The systems integration of whole-body metabolism and immune signaling are central homeostatic mechanisms necessary for maintenance of normal physiology, and dysregulation of these processes leads to a variety of chronic disorders. However, the intracellular mechanisms responsible for cell-autonomous cross-talk between the inflammatory signaling pathways and metabolic flux have remained enigmatic. In this study, we discovered that the fructose-2,6-bisphosphatase TIGAR (Tp53-induced glycolysis and apoptosis regulator) critically regulates NF-κB activation.The Brucella effector protein TcpB induces degradation of inflammatory caspases and thereby subverts non-canonical inflammasome activation in macrophages
The inflammasome contains intracellular receptors that recognize various pathogen-associated molecular patterns and play crucial roles in innate immune responses to invading pathogens. Non-canonical inflammasome activation is mediated by caspase-4/11, which recognizes intracellular LPS and promotes pyroptosis and secretion of proinflammatory cytokines. Brucella species are infectious intracellular pathogens that replicate in professional and non-professional phagocytic cells and subvert immune responses for chronic persistence in the host.Nucleotide-binding oligomerization domain (NOD) signaling defects and cell death susceptibility cannot be uncoupled in X-linked inhibitor of apoptosis (XIAP)-driven inflammatory disease
The X-linked inhibitor of apoptosis (XIAP) protein has been identified as a key genetic driver of two distinct inflammatory disorders, X-linked lymphoproliferative syndrome 2 (XLP-2) and very-early-onset inflammatory bowel disease (VEO-IBD). Molecularly, the role of XIAP mutations in the pathogenesis of these disorders is unclear. Recent work has consistently shown XIAP to be critical for signaling downstream of the Crohn's disease susceptibility protein nucleotide-binding oligomerization domain-containing 2 (NOD2); however, the reported effects of XLP-2 and VEO-IBD XIAP mutations on cell death have been inconsistent.Innate immune signaling in Drosophila is regulated by transforming growth factor β (TGFβ)-activated kinase (Tak1)-triggered ubiquitin editing
Coordinated regulation of innate immune responses is necessary in all metazoans. In Drosophila the Imd pathway detects Gram-negative bacterial infections through recognition of diaminopimelic acid (DAP)-type peptidoglycan and activation of the NF-κB precursor Relish, which drives robust antimicrobial peptide gene expression. Imd is a receptor-proximal adaptor protein homologous to mammalian RIP1 that is regulated by proteolytic cleavage and Lys-63-polyubiquitination. However, the precise events and molecular mechanisms that control the post-translational modification of Imd remain unclear.Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon
Adenosine deaminase acting on RNA 1 (ADAR1) catalyzes RNA editing of cellular and viral RNAs. Besides RNA editing, ADAR1 has recently been shown to play important roles in maintaining the body balance, including tissue homoeostasis, organ development, and autoimmune regulations, by inhibiting both IFN production and subsequent IFN-activated pathways. Accordingly, the question was raised how IFN signaling induced by viral infections overcomes the inhibitory effect of constitutively expressed ADAR1 (ADAR1-P110) to execute efficient antiviral activity.Amphiregulin Confers Regulatory T Cell Suppressive Function and Tumor Invasion via the EGFR/GSK-3β/Foxp3 Axis
Previous studies mainly focused on the role of the epidermal growth factor receptor (EGFR) in tumor cells, whereas the effects of the EGFR on immune responses has not been determined. Our study shows that the EGFR signaling pathway play a role in the regulation of regulatory T cells (Treg cells) in cancer patients. The EGF-like growth factor Amphiregulin (AREG) protein was frequently up-regulated in a tissue microarray, which was associated with worse overall survival. Additionally, in sera, tissue specimens, and effusions of lung or gastric cancer patients, up-regulated AREG protein enhanced the suppressive function of Treg cells.Toll-like Receptor 4 Ligands Down-regulate Fcγ Receptor IIb (FcγRIIb) via MARCH3 Protein-mediated Ubiquitination
Monocytes and macrophages are critical for the effectiveness of monoclonal antibody therapy. Responses to antibody-coated tumor cells are largely mediated by Fcγ receptors (FcγRs), which become activated upon binding to immune complexes. FcγRIIb is an inhibitory FcγR that negatively regulates these responses, and it is expressed on monocytes and macrophages. Therefore, deletion or down-regulation of this receptor may substantially enhance therapeutic outcomes. Here we screened a panel of Toll-like receptor (TLR) agonists and found that those selective for TLR4 and TLR8 could significantly down-regulate the expression of FcγRIIb.TRAF5-mediated Lys-63-linked Polyubiquitination Plays an Essential Role in Positive Regulation of RORγt in Promoting IL-17A Expression
Background: RORγt is required for Th17 cell function and differentiation.Results: TRAF5 stabilizes RORγt by ubiquitination and augments RORγt-mediated transcriptional expression of IL-17A.Conclusion: TRAF5 is a positive regulator for RORγt.Significance: TRAF5 could be a novel target for modulating RORγt-mediated inflammation and autoimmune diseases, including systemic lupus erythematosus.Itch WW Domains Inhibit Its E3 Ubiquitin Ligase Activity by Blocking E2-E3 Ligase Trans-thiolation
Background: The activity of Itch and related E3 ligases is restricted by autoinhibition.Results: Itch autoinhibition is maintained by an intramolecular interaction between its WW and HECT domains, and Ndfip1 relieves this interaction to allow trans-thiolation.Conclusion: The primary role of Ndfip is to relieve autoinhibition of Itch and related ligases.Significance: We describe a novel mechanism that regulates the activity of several catalytic E3 ligases.
