Protein Synthesis and Degradation
The cap-proximal RNA secondary structure inhibits preinitiation complex formation on HAC1 mRNA
Translation of HAC1 mRNA in the budding yeast Saccharomyces cerevisiae is derepressed when RNase Ire1 removes its intron via nonconventional cytosolic splicing in response to accumulation of unfolded proteins inside the endoplasmic reticulum. The spliced HAC1 mRNA is translated into a transcription factor that changes the cellular gene expression patterns to increase the protein folding capacity of cells. Previously, we showed that a segment of the intronic sequence interacts with the 5′-UTR of the unspliced mRNA, resulting in repression of HAC1 translation at the initiation stage.The prohibitin-binding compound fluorizoline affects multiple components of the translational machinery and inhibits protein synthesis
Fluorizoline (FLZ) binds to prohibitin-1 and -2 (PHB1/2), which are pleiotropic scaffold proteins known to affect signaling pathways involved in several intracellular processes. However, it is not yet clear how FLZ exerts its effect. Here, we show that exposure of three different human cancer cell lines to FLZ increases the phosphorylation of key translation factors, particularly of initiation factor 2 (eIF2) and elongation factor 2 (eEF2), modifications that inhibit their activities. FLZ also impaired signaling through mTOR complex 1, which also regulates the translational machinery, e.g.The mammalian host protein DAP5 facilitates the initial round of translation of Coxsackievirus B3 RNA
During enteroviral infections, the canonical translation factor eukaryotic translation initiation factor 4 γ I (eIF4GI) is cleaved by viral protease 2A. The resulting C-terminal fragment is recruited by the viral internal ribosome entry site (IRES) for efficient translation of the viral RNA. However, the 2A protease is not present in the viral capsid and is synthesized only after the initial round of translation. This presents the conundrum of how the initial round of translation occurs in the absence of the C-terminal eIF4GI fragment.Mitosis-related phosphorylation of the eukaryotic translation suppressor 4E-BP1 and its interaction with eukaryotic translation initiation factor 4E (eIF4E)
Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) inhibits cap-dependent translation in eukaryotes by competing with eIF4G for an interaction with eIF4E. Phosphorylation at Ser-83 of 4E-BP1 occurs during mitosis through the activity of cyclin-dependent kinase 1 (CDK1)/cyclin B rather than through canonical mTOR kinase activity. Here, we investigated the interaction of eIF4E with 4E-BP1 or eIF4G during interphase and mitosis. We observed that 4E-BP1 and eIF4G bind eIF4E at similar levels during interphase and mitosis.Estrogen receptor α promotes protein synthesis by fine-tuning the expression of the eukaryotic translation initiation factor 3 subunit f (eIF3f)
Approximately two thirds of all breast cancer cases are estrogen receptor (ER)–positive. The treatment of this breast cancer subtype with endocrine therapies is effective in the adjuvant and recurrent settings. However, their effectiveness is compromised by the emergence of intrinsic or acquired resistance. Thus, identification of new molecular targets can significantly contribute to the development of novel therapeutic strategies. In recent years, many studies have implicated aberrant levels of translation initiation factors in cancer etiology and provided evidence that identifies these factors as promising therapeutic targets.Molecular mechanism of poliovirus Sabin vaccine strain attenuation
Recruitment of poliovirus (PV) RNA to the human ribosome requires the coordinated interaction of the viral internal ribosome entry site (IRES) and several host cellular initiation factors and IRES trans-acting factors (ITAFs). Attenuated PV Sabin strains contain point mutations in the PV IRES domain V (dV) that inhibit viral translation. Remarkably, attenuation is most apparent in cells of the central nervous system, but the molecular basis to explain this is poorly understood. The dV contains binding sites for eukaryotic initiation factor 4G (eIF4G) and polypyrimidine tract–binding protein (PTB).The 3′ mRNA I-shaped structure of maize necrotic streak virus binds to eukaryotic translation factors for eIF4F-mediated translation initiation
Unlike the mRNAs of their eukaryotic hosts, many RNAs of viruses lack a 5′ m7GpppN cap and the 3′ polyadenosine tail, and yet they are translated efficiently. Plant RNA viruses, in particular, have complex structures within their mRNA UTRs that allow them to bypass some cellular translation control steps. In the 3′ UTR of maize necrotic streak virus (MNeSV), an I-shaped RNA structure (ISS) has been shown to bind eukaryotic initiation factor (eIF)4F and to mediate viral translation initiation. A 5′–3′ RNA “kissing-loop” interaction is required for optimal translation.Function of inhibitor of Bruton's tyrosine kinase isoform α (IBTKα) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response
Nonalcoholic fatty liver disease (steatosis) is the most prevalent liver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify the α isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress.Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response
Translation regulation largely occurs during initiation, which features ribosome assembly onto mRNAs and selection of the translation start site. Short, upstream ORFs (uORFs) located in the 5′-leader of the mRNA can be selected for translation. Multiple transcripts associated with stress amelioration are preferentially translated through uORF-mediated mechanisms during activation of the integrated stress response (ISR) in which phosphorylation of the α subunit of eIF2 results in a coincident global reduction in translation initiation.Eukaryotic Initiation Factor eIFiso4G1 and eIFiso4G2 Are Isoforms Exhibiting Distinct Functional Differences in Supporting Translation in Arabidopsis
The eukaryotic translation initiation factor (eIF) 4G is required during protein synthesis to promote the assembly of several factors involved in the recruitment of a 40S ribosomal subunit to an mRNA. Although many eukaryotes express two eIF4G isoforms that are highly similar, the eIF4G isoforms in plants, referred to as eIF4G and eIFiso4G, are highly divergent in size, sequence, and domain organization but both can interact with eIF4A, eIF4B, eIF4E isoforms, and the poly(A)-binding protein. Nevertheless, eIF4G and eIFiso4G from wheat exhibit preferences in the mRNAs they translate optimally.eIF4F: A Retrospective
The original purification of the heterotrimeric eIF4F was published over 30 years ago (Grifo, J. A., Tahara, S. M., Morgan, M. A., Shatkin, A. J., and Merrick, W. C. (1983) J. Biol. Chem. 258, 5804–5810). Since that time, numerous studies have been performed with the three proteins specifically required for the translation initiation of natural mRNAs, eIF4A, eIF4B, and eIF4F. These have involved enzymatic and structural studies of the proteins and a number of site-directed mutagenesis studies. The regulation of translation exhibited through the mammalian target of rapamycin (mTOR) pathway is predominately seen as the phosphorylation of 4E-BP, an inhibitor of protein synthesis that functions by binding to the cap binding subunit of eIF4F (eIF4E).Evidence That Base-pairing Interaction between Intron and mRNA Leader Sequences Inhibits Initiation of HAC1 mRNA Translation in Yeast
Background: Hac1 protein, encoded by a cytoplasmically spliced mRNA, activates the unfolded protein response to maintain cellular protein homeostasis and alleviate endoplasmic reticulum stress.Results: Under non-stress conditions, translation initiation on the HAC1 mRNA is repressed.Conclusion: Base-pairing interaction between the 5′ leader and intron represses translation initiation on the HAC1 mRNA.Significance: A unique mechanism of intron-mediated inhibition of ribosomal scanning.
