Abstract
The regulation of gene expression is fundamental for life. Whereas the role of transcriptional regulation of gene expression has been studied for several decades, it has been clear over the past two decades that post-transcriptional regulation of gene expression, of which translation regulation is a major part, can be equally important. Translation can be divided into four main stages: initiation, elongation, termination and ribosome recycling. Translation is controlled mainly during its initiation, a process which culminates in a ribosome positioned with an initiator tRNA over the start codon and, thus, ready to begin elongation of the protein chain. mRNA translation has emerged as a powerful tool for the development of innovative therapies, yet the detailed mechanisms underlying the complex process of initiation remain unclear. Recent studies in yeast and mammals have started to shed light on some previously unclear aspects of this process. In this Review, we discuss the current state of knowledge on eukaryotic translation initiation and its regulation in health and disease. Specifically, we focus on recent advances in understanding the processes involved in assembling the 43S pre-initiation complex and its recruitment by the cap-binding complex eukaryotic translation initiation factor 4F (eIF4F) at the 5′ end of mRNA. In addition, we discuss recent insights into ribosome scanning along the 5′ untranslated region of mRNA and selection of the start codon, which culminates in joining of the 60S large subunit and formation of the 80S initiation complex.
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References
Harnett, D. et al. A critical period of translational control during brain development at codon resolution. Nat. Struct. Mol. Biol. 29, 1277–1290 (2022).
Schwanhäusser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).
Byrne, R., Levin, J. G., Bladen, H. A. & Nirenberg, M. W. The in vitro formation of a DNA–ribosome complex. Proc. Natl Acad. Sci. USA 52, 140–148 (1964).
Kohler, R., Mooney, R. A., Mills, D. J., Landick, R. & Cramer, P. Architecture of a transcribing–translating expressome. Science 356, 194–197 (2017).
Wang, C. et al. Structural basis of transcription–translation coupling. Science 369, 1359–1365 (2020).
Webster, M. W. et al. Structural basis of transcription–translation coupling and collision in bacteria. Science 369, 1355–1359 (2020).
Aitken, C. E. & Lorsch, J. R. A mechanistic overview of translation initiation in eukaryotes. Nat. Struct. Mol. Biol. 19, 568–576 (2012).
Hashem, Y. & Frank, J. The jigsaw puzzle of mRNA translation initiation in eukaryotes: a decade of structures unraveling the mechanics of the process. Annu. Rev. Biophys. https://doi.org/10.1146/annurev-biophys-070816-034034 (2018).
Hinnebusch, A. G. The scanning mechanism of eukaryotic translation initiation. Annu. Rev. Biochem. 83, 779–812 (2014).
Valášek, L. S. et al. Embraced by eIF3: structural and functional insights into the roles of eIF3 across the translation cycle. Nucleic Acids Res. 45, 10948–10968 (2017).
Bohlen, J., Fenzl, K., Kramer, G., Bukau, B. & Teleman, A. A. Selective 40S footprinting reveals cap-tethered ribosome scanning in human cells. Mol. Cell https://doi.org/10.1016/j.molcel.2020.06.005 (2020). This study presents the first clear evidence that scanning can be cap-tethered in human cells.
Brito Querido, J. et al. Structure of a human 48S translational initiation complex. Science 369, 1220–1227 (2020). This structure reveals how eIF4F interacts with the 43S complex.
Chiluiza, D., Bargo, S., Callahan, R. & Rhoads, R. E. Expression of truncated eukaryotic initiation factor 3e (eIF3e) resulting from integration of mouse mammary tumor virus (MMTV) causes a shift from cap-dependent to cap-independent translation. J. Biol. Chem. 286, 31288–31296 (2011).
Grifo, J. A., Tahara, S. M., Morgan, M. A., Shatkin, A. J. & Merrick, W. C. New initiation factor activity required for globin mRNA translation. J. Biol. Chem. 258, 5804–5810 (1983).
Kumar, P., Hellen, C. U. T. & Pestova, T. V. Toward the mechanism of eIF4F-mediated ribosomal attachment to mammalian capped mRNAs. Genes Dev. 30, 1573–1588 (2016). This study presents strong evidence to support the threading model of mRNA recruitment to the 43S complex in mammals.
Llácer, J. L. et al. Conformational differences between open and closed states of the eukaryotic translation initiation complex. Mol. Cell 59, 399–412 (2015).
Marintchev, A. et al. Topology and regulation of the human eIF4A/4G/4H helicase complex in translation initiation. Cell 136, 447–460 (2009).
Pestova, T. V. & Kolupaeva, V. G. The roles of individual eukaryotic translation initiation factors in ribosomal scanning and initiation codon selection. Genes Dev. 16, 2906–2922 (2002).
Brito Querido, J. et al. The structure of a human translation initiation complex reveals two independent roles for the helicase eIF4A. Nat. Struct. Mol. Biol. https://doi.org/10.1038/s41594-023-01196-0 (2024). This study reveals that in addition to the eIF4A molecule that is part of the eIF4F complex, there is a second molecule of eIF4A in the 48S complex, which functions separately from eIF4F.
Villa, N., Do, A., Hershey, J. W. B. & Fraser, C. S. Human eukaryotic initiation factor 4G (eIF4G) protein binds to eIF3c, -d, and -e to promote mRNA recruitment to the ribosome. J. Biol. Chem. 288, 32932–32940 (2013).
Berthelot, K., Muldoon, M., Rajkowitsch, L., Hughes, J. & McCarthy, J. E. G. Dynamics and processivity of 40S ribosome scanning on mRNA in yeast. Mol. Microbiol. 51, 987–1001 (2004).
Kozak, M. Role of ATP in binding and migration of 40S ribosomal subunits. Cell 22, 459–467 (1980).
Nielsen, K. H. et al. Functions of eIF3 downstream of 48S assembly impact AUG recognition and GCN4 translational control. EMBO J. 23, 1166–1177 (2004).
Shirokikh, N. E., Dutikova, Y. S., Staroverova, M. A., Hannan, R. D. & Preiss, T. Migration of small ribosomal subunits on the 5’ untranslated regions of capped messenger RNA. Int. J. Mol. Sci. 20, 4464 (2019).
Simonetti, A., Guca, E., Bochler, A., Kuhn, L. & Hashem, Y. Structural insights into the mammalian late-stage initiation complexes. Cell Rep. 31, 107497 (2020).
Wang, J. et al. Rapid 40S scanning and its regulation by mRNA structure during eukaryotic translation initiation. Cell 185, 4474–4487 (2022). This study reveals the kinetics of scanning and finds that multiple copies of eIF4A can have a role during mRNA recruitment.
Yi, S.-H. et al. Conformational rearrangements upon start codon recognition in human 48S translation initiation complex. Nucleic Acids Res. 50, 5282–5298 (2022).
García-García, C., Frieda, K. L., Feoktistova, K., Fraser, C. S. & Block, S. M. Factor-dependent processivity in human eIF4A DEAD-box helicase. Science 348, 1486–1488 (2015).
Sen, N. D., Zhou, F., Harris, M. S., Ingolia, N. T. & Hinnebusch, A. G. eIF4B stimulates translation of long mRNAs with structured 5′ UTRs and low closed-loop potential but weak dependence on eIF4G. Proc. Natl Acad. Sci. USA 113, 10464–10472 (2016).
Shahbazian, D. et al. Control of cell survival and proliferation by mammalian eukaryotic initiation factor 4B. Mol. Cell Biol. 30, 1478–1485 (2010).
Calviello, L. et al. DDX3 depletion represses translation of mRNAs with complex 5′ UTRs. Nucleic Acids Res. 49, 5336–5350 (2021).
Gupta, N., Lorsch, J. R. & Hinnebusch, A. G. Yeast Ded1 promotes 48S translation pre-initiation complex assembly in an mRNA-specific and eIF4F-dependent manner. eLife 7, e38892 (2018).
Pisareva, V. P., Pisarev, A. V., Komar, A. A., Hellen, C. U. T. & Pestova, T. V. Translation initiation on mammalian mRNAs with structured 5′ UTRs requires DExH-box protein DHX29. Cell 135, 1237–1250 (2008).
Huang, B. Y. & Fernández, I. S. Long-range interdomain communications in eIF5B regulate GTP hydrolysis and translation initiation. Proc. Natl Acad. Sci. USA 117, 1429–1437 (2020).
Lapointe, C. P. et al. eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining. Nature 607, 185–190 (2022). This study reveals how eIF5B coordinates with eIF1A to reorient the tRNA and allow joining of the 60S ribosome subunit.
Pestova, T. V. et al. The joining of ribosomal subunits in eukaryotes requires eIF5B. Nature 403, 332–335 (2000). This study reveals that joining of the 60S ribosome subunit requires eIF5B.
Wang, J. et al. eIF5B gates the transition from translation initiation to elongation. Nature 573, 605–608 (2019).
Wang, J. et al. Structural basis for the transition from translation initiation to elongation by an 80S–eIF5B complex. Nat. Commun. 11, 5003 (2020).
Archer, S. K., Shirokikh, N. E., Beilharz, T. H. & Preiss, T. Dynamics of ribosome scanning and recycling revealed by translation complex profiling. Nature 535, 570–574 (2016).
Choe, J. et al. mRNA circularization by METTL3–eIF3h enhances translation and promotes oncogenesis. Nature 561, 556–560 (2018).
Díaz-López, I., Toribio, R., Berlanga, J. J. & Ventoso, I. An mRNA-binding channel in the ES6S region of the translation 48S-PIC promotes RNA unwinding and scanning. eLife 8, e48246 (2019).
Gu, Y., Mao, Y., Jia, L., Dong, L. & Qian, S.-B. Bi-directional ribosome scanning controls the stringency of start codon selection. Nat. Commun. 12, 6604 (2021).
Hayek, H. et al. eIF3 interacts with histone H4 messenger RNA to regulate its translation. J. Biol. Chem. 296, 100578 (2021).
Herrmannová, A. et al. Adapted formaldehyde gradient cross-linking protocol implicates human eIF3d and eIF3c, k and l subunits in the 43S and 48S pre-initiation complex assembly, respectively. Nucleic Acids Res. 48, 1969–1984 (2020).
Lee, A. S., Kranzusch, P. J., Doudna, J. A. & Cate, J. H. D. eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation. Nature 536, 96–99 (2016). This study reveals that eIF3d is a cap-binding protein required for the translation of specific mRNAs.
Robert, F., Cencic, R., Cai, R., Schmeing, T. M. & Pelletier, J. RNA-tethering assay and eIF4G:eIF4A obligate dimer design uncovers multiple eIF4F functional complexes. Nucleic Acids Res. 48, 8562–8575 (2020).
Sokabe, M. & Fraser, C. S. A helicase-independent activity of eIF4A in promoting mRNA recruitment to the human ribosome. Proc. Natl Acad. Sci. USA 114, 6304–6309 (2017).
Yourik, P. et al. Yeast eIF4A enhances recruitment of mRNAs regardless of their structural complexity. eLife 6, e31476 (2017).
Zinshteyn, B., Rojas-Duran, M. F. & Gilbert, W. V. Translation initiation factor eIF4G1 preferentially binds yeast transcript leaders containing conserved oligo-uridine motifs. RNA 23, 1365–1375 (2017).
Malik, I., Kelley, C. P., Wang, E. T. & Todd, P. K. Molecular mechanisms underlying nucleotide repeat expansion disorders. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-021-00382-6 (2021).
Meyer, K. D. et al. 5′ UTR m6A promotes cap-independent translation. Cell 163, 999–1010 (2015).
Zhou, J. et al. Dynamic m6A mRNA methylation directs translational control of heat shock response. Nature 526, 591–594 (2015).
Legnini, I. et al. Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol. Cell 66, 22–37.e9 (2017).
Pamudurti, N. R. et al. Translation of circRNAs. Mol. Cell 66, 9–21.e7 (2017).
Yang, Y. et al. Extensive translation of circular RNAs driven by N6-methyladenosine. Cell Res. 27, 626–641 (2017).
Banerjee, A. K. et al. SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses. Cell 183, 1325–1339.e21 (2020).
Schubert, K. et al. SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation. Nat. Struct. Mol. Biol. 27, 959–966 (2020).
Thoms, M. et al. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science 369, 1249–1255 (2020). This study reveals how nsp1 of SARS-CoV-2 binds to the 40S small ribosomal subunit.
Tidu, A. et al. The viral protein NSP1 acts as a ribosome gatekeeper for shutting down host translation and fostering SARS-CoV-2 translation. RNA https://doi.org/10.1261/rna.078121.120 (2020).
Chang, J. H. et al. Crystal structure of the eIF4A–PDCD4 complex. Proc. Natl Acad. Sci. USA 106, 3148–3153 (2009).
Loh, P. G. et al. Structural basis for translational inhibition by the tumour suppressor Pdcd4. EMBO J. 28, 274–285 (2009).
Suzuki, C. et al. PDCD4 inhibits translation initiation by binding to eIF4A using both its MA3 domains. Proc. Natl Acad. Sci. USA 105, 3274–3279 (2008).
Yang, H.-S. et al. A novel function of the MA-3 domains in transformation and translation suppressor Pdcd4 is essential for its binding to eukaryotic translation initiation factor 4A. Mol. Cell. Biol. 24, 3894–3906 (2004).
Passmore, L. A. et al. The eukaryotic translation initiation factors eIF1 and eIF1A induce an open conformation of the 40S ribosome. Mol. Cell 26, 41–50 (2007).
Sokabe, M. & Fraser, C. S. Human eukaryotic initiation factor 2 (eIF2)–GTP–Met-tRNAi ternary complex and eIF3 stabilize the 43S preinitiation complex. J. Biol. Chem. 289, 31827–31836 (2014).
Bochler, A. et al. Structural differences in translation initiation between pathogenic trypanosomatids and their mammalian hosts. Cell Rep. 33, 108534 (2020).
Elantak, L. et al. The indispensable N-terminal half of eIF3j/HCR1 cooperates with its structurally conserved binding partner eIF3b/PRT1-RRM and with eIF1A in stringent AUG selection. J. Mol. Biol. 396, 1097–1116 (2010).
Fekete, C. A. et al. N- and C-terminal residues of eIF1A have opposing effects on the fidelity of start codon selection. EMBO J. 26, 1602–1614 (2007).
Hussain, T. et al. Structural changes enable start codon recognition by the eukaryotic translation initiation complex. Cell 159, 597–607 (2014). This study identifies some crucial structural rearrangement of the 48S complex upon start-codon selection.
Lomakin, I. B. & Steitz, T. A. The initiation of mammalian protein synthesis and mRNA scanning mechanism. Nature 500, 307–311 (2013).
Nanda, J. S., Saini, A. K., Muñoz, A. M., Hinnebusch, A. G. & Lorsch, J. R. Coordinated movements of eukaryotic translation initiation factors eIF1, eIF1A, and eIF5 trigger phosphate release from eIF2 in response to start codon recognition by the ribosomal preinitiation complex. J. Biol. Chem. 288, 5316–5329 (2013).
Nanda, J. S. et al. eIF1 controls multiple steps in start codon recognition during eukaryotic translation initiation. J. Mol. Biol. 394, 268–285 (2009).
Pestova, T. V., Borukhov, S. I. & Hellen, C. U. Eukaryotic ribosomes require initiation factors 1 and 1A to locate initiation codons. Nature 394, 854–859 (1998).
Thakur, A., Marler, L. & Hinnebusch, A. G. A network of eIF2β interactions with eIF1 and Met-tRNAi promotes accurate start codon selection by the translation preinitiation complex. Nucleic Acids Res. 5, 2574–2593 (2019).
Thakur, A. & Hinnebusch, A. G. eIF1 loop 2 interactions with Met-tRNAi control the accuracy of start codon selection by the scanning preinitiation complex. Proc. Natl Acad. Sci. USA 115, E4159–E4168 (2018).
Valášek, L., Nielsen, K. H., Zhang, F., Fekete, C. A. & Hinnebusch, A. G. Interactions of eukaryotic translation initiation factor 3 (eIF3) subunit NIP1/c with eIF1 and eIF5 promote preinitiation complex assembly and regulate start codon selection. Mol. Cell Biol. 24, 9437–9455 (2004).
Weisser, M., Voigts-Hoffmann, F., Rabl, J., Leibundgut, M. & Ban, N. The crystal structure of the eukaryotic 40S ribosomal subunit in complex with eIF1 and eIF1A. Nat. Struct. Mol. Biol. 20, 1015–1017 (2013).
Zhou, F., Zhang, H., Kulkarni, S. D., Lorsch, J. R. & Hinnebusch, A. G. eIF1 discriminates against suboptimal initiation sites to prevent excessive uORF translation genome-wide. RNA 26, 419–438 (2020).
des Georges, A. et al. Structure of mammalian eIF3 in the context of the 43S preinitiation complex. Nature 525, 491–495 (2015). This study reveals the first complete architecture of mammalian eIF3.
Erzberger, J. P. et al. Molecular architecture of the 40S⋅eIF1⋅eIF3 translation initiation complex. Cell 158, 1123–1135 (2014).
Kratzat, H. et al. A structural inventory of native ribosomal ABCE1–43S pre-initiation complexes. EMBO J. 40, e105179 (2020).
Llácer, J. L. et al. Large-scale movement of eIF3 domains during translation initiation modulate start codon selection. Nucleic Acids Res. 49, 11491–11511 (2021).
Llácer, J. L. et al. Translational initiation factor eIF5 replaces eIF1 on the 40S ribosomal subunit to promote start-codon recognition. eLife 7, e39273 (2018).
Aitken, C. E. et al. Eukaryotic translation initiation factor 3 plays distinct roles at the mRNA entry and exit channels of the ribosomal preinitiation complex. eLife 5, e20934 (2016).
Sun, C. et al. Two RNA-binding motifs in eIF3 direct HCV IRES-dependent translation. Nucleic Acids Res. 41, 7512–7521 (2013).
Cuchalová, L. et al. The RNA recognition motif of eukaryotic translation initiation factor 3g (eIF3g) is required for resumption of scanning of posttermination ribosomes for reinitiation on GCN4 and together with eIF3i stimulates linear scanning. Mol. Cell. Biol. 30, 4671–4686 (2010).
Obayashi, E. et al. Molecular landscape of the ribosome pre-initiation complex during mRNA scanning: structural role for eIF3c and its control by eIF5. Cell Rep. 18, 2651–2663 (2017).
Lamper, A. M., Fleming, R. H., Ladd, K. M. & Lee, A. S. Y. A phosphorylation-regulated eIF3d translation switch mediates cellular adaptation to metabolic stress. Science 370, 853–856 (2020).
Pelletier, J. & Sonenberg, N. The organizing principles of eukaryotic ribosome recruitment. Annu. Rev. Biochem. 88, 307–335 (2019).
Gouridis, G. et al. ABCE1 controls ribosome recycling by an asymmetric dynamic conformational equilibrium. Cell Rep. 28, 723–734.e6 (2019).
Young, D. J. & Guydosh, N. R. Hcr1/eIF3j is a 60S ribosomal subunit recycling accessory factor in vivo. Cell Rep. 28, 39–50.e4 (2019).
Aylett, C. H. S., Boehringer, D., Erzberger, J. P., Schaefer, T. & Ban, N. Structure of a yeast 40S–eIF1–eIF1A–eIF3–eIF3j initiation complex. Nat. Struct. Mol. Biol. 22, 269–271 (2015).
Fraser, C. S., Berry, K. E., Hershey, J. W. B. & Doudna, J. A. eIF3j is located in the decoding center of the human 40S ribosomal subunit. Mol. Cell 26, 811–819 (2007).
Park, E.-H. et al. Multiple elements in the eIF4G1 N-terminus promote assembly of eIF4G1•PABP mRNPs in vivo. EMBO J. 30, 302–316 (2011).
Yanagiya, A. et al. Requirement of RNA binding of mammalian eukaryotic translation initiation factor 4GI (eIF4GI) for efficient interaction of eIF4E with the mRNA cap. Mol. Cell Biol. 29, 1661–1669 (2009).
Haimov, O. et al. Dynamic interaction of eukaryotic initiation factor 4G1 (eIF4G1) with eIF4E and eIF1 underlies scanning-dependent and -independent translation. Mol. Cell Biol. 38, e00139-18 (2018).
Kahvejian, A., Svitkin, Y. V., Sukarieh, R., M’Boutchou, M.-N. & Sonenberg, N. Mammalian poly(A)-binding protein is a eukaryotic translation initiation factor, which acts via multiple mechanisms. Genes Dev. 19, 104–113 (2005).
Amrani, N., Ghosh, S., Mangus, D. A. & Jacobson, A. Translation factors promote the formation of two states of the closed-loop mRNP. Nature 453, 1276–1280 (2008).
Lai, W.-J. C. et al. Intrinsically unstructured sequences in the mRNA 3′ UTR reduce the ability of poly(A) tail to enhance translation. J. Mol. Biol. 434, 167877 (2022).
Wells, S. E., Hillner, P. E., Vale, R. D. & Sachs, A. B. Circularization of mRNA by eukaryotic translation initiation factors. Mol. Cell 2, 135–140 (1998).
Alekhina, O. M., Terenin, I. M., Dmitriev, S. E. & Vassilenko, K. S. Functional cyclization of eukaryotic mRNAs. Int. J. Mol. Sci. 21, 1677 (2020).
Vicens, Q., Kieft, J. S. & Rissland, O. S. Revisiting the closed-loop model and the nature of mRNA 5′–3′ communication. Mol. Cell 72, 805–812 (2018).
Yamanaka, S. et al. Essential role of NAT1/p97/DAP5 in embryonic differentiation and the retinoic acid pathway. EMBO J. 19, 5533–5541 (2000).
Liberman, N. et al. DAP5 associates with eIF2β and eIF4AI to promote internal ribosome entry site driven translation. Nucleic Acids Res. 43, 3764–3775 (2015).
Kulak, N. A., Pichler, G., Paron, I., Nagaraj, N. & Mann, M. Minimal, encapsulated proteomic-sample processing applied to copy-number estimation in eukaryotic cells. Nat. Methods 11, 319–324 (2014).
Tauber, D. et al. Modulation of RNA condensation by the DEAD-Box protein eIF4A. Cell 180, 411–426.e16 (2020).
Çetin, B. & O’Leary, S. E. mRNA- and factor-driven dynamic variability controls eIF4F-cap recognition for translation initiation. Nucleic Acids Res. 50, 8240–8261 (2022).
Feoktistova, K., Tuvshintogs, E., Do, A. & Fraser, C. S. Human eIF4E promotes mRNA restructuring by stimulating eIF4A helicase activity. Proc. Natl Acad. Sci. USA 110, 13339–13344 (2013).
Rozovsky, N., Butterworth, A. C. & Moore, M. J. Interactions between eIF4AI and its accessory factors eIF4B and eIF4H. RNA 14, 2136–2148 (2008).
Andreou, A. Z. & Klostermeier, D. The DEAD-box helicase eIF4A. RNA Biol. 10, 19–32 (2013).
Ma, X. M. & Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 10, 307–318 (2009).
Marcotrigiano, J., Gingras, A. C., Sonenberg, N. & Burley, S. K. Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Mol. Cell 3, 707–716 (1999).
Bartish, M. et al. The role of eIF4F-driven mRNA translation in regulating the tumour microenvironment. Nat. Rev. Cancer https://doi.org/10.1038/s41568-023-00567-5 (2023).
Bhat, M. et al. Targeting the translation machinery in cancer. Nat. Rev. Drug Discov. 14, 261–278 (2015).
Harris, T. E. et al. mTOR-dependent stimulation of the association of eIF4G and eIF3 by insulin. EMBO J. 25, 1659–1668 (2006).
LeFebvre, A. K. et al. Translation initiation factor eIF4G-1 binds to eIF3 through the eIF3e subunit. J. Biol. Chem. 281, 22917–22932 (2006).
Giess, A. et al. Profiling of small ribosomal subunits reveals modes and regulation of translation initiation. Cell Rep. 31, 107534 (2020).
Cheung, Y.-N. et al. Dissociation of eIF1 from the 40S ribosomal subunit is a key step in start codon selection in vivo. Genes Dev. 21, 1217–1230 (2007).
Maag, D., Fekete, C. A., Gryczynski, Z. & Lorsch, J. R. A conformational change in the eukaryotic translation preinitiation complex and release of eIF1 signal recognition of the start codon. Mol. Cell 17, 265–275 (2005).
Martin-Marcos, P. et al. Enhanced eIF1 binding to the 40S ribosome impedes conformational rearrangements of the preinitiation complex and elevates initiation accuracy. RNA 20, 150–167 (2014).
Chen, R. et al. Engineering circular RNA for enhanced protein production. Nat. Biotechnol. 41, 262–272 (2023).
Wen, S., Qadir, J. & Yang, B. B. Circular RNA translation: novel protein isoforms and clinical significance. Trends Mol. Med. https://doi.org/10.1016/j.molmed.2022.03.003 (2022).
Wesselhoeft, R. A., Kowalski, P. S. & Anderson, D. G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9, 2629 (2018).
Chen, C. Y. & Sarnow, P. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science 268, 415–417 (1995).
Mailliot, J. & Martin, F. Viral internal ribosomal entry sites: four classes for one goal. Wiley Interdiscip. Rev. RNA https://doi.org/10.1002/wrna.1458 (2018).
Gallie, D. R. The cap and poly(A) tail function synergistically to regulate mRNA translational efficiency. Genes Dev. 5, 2108–2116 (1991).
Leppek, K., Das, R. & Barna, M. Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat. Rev. Mol. Cell Biol. 19, 158–174 (2018).
Elfakess, R. et al. Unique translation initiation of mRNAs-containing TISU element. Nucleic Acids Res. 39, 7598–7609 (2011).
Elfakess, R. & Dikstein, R. A translation initiation element specific to mRNAs with very short 5′ UTR that also regulates transcription. PLoS ONE 3, e3094 (2008).
Akulich, K. A. et al. Four translation initiation pathways employed by the leaderless mRNA in eukaryotes. Sci. Rep. 6, 37905 (2016).
Andreev, D. E., Terenin, I. M., Dunaevsky, Y. E., Dmitriev, S. E. & Shatsky, I. N. A leaderless mRNA can bind to mammalian 80S ribosomes and direct polypeptide synthesis in the absence of translation initiation factors. Mol. Cell Biol. 26, 3164–3169 (2006).
Cattie, D. J. et al. Mutations in nonessential eIF3k and eIF3l genes confer lifespan extension and enhanced resistance to ER stress in Caenorhabditis elegans. PLoS Genet. 12, e1006326 (2016).
Smith, M. D. et al. Human-like eukaryotic translation initiation factor 3 from Neurospora crassa. PLoS ONE 8, e78715 (2013).
Chapat, C. et al. Cap-binding protein 4EHP effects translation silencing by microRNAs. Proc. Natl Acad. Sci. USA 114, 5425–5430 (2017).
Niederer, R. O., Rojas-Duran, M. F., Zinshteyn, B. & Gilbert, W. V. Direct analysis of ribosome targeting illuminates thousand-fold regulation of translation initiation. Cell Syst. 13, 256–264.e3 (2022).
Asano, K. et al. Multiple roles for the C-terminal domain of eIF5 in translation initiation complex assembly and GTPase activation. EMBO J. 20, 2326–2337 (2001).
He, H. et al. The yeast eukaryotic initiation factor 4G (eIF4G) HEAT domain interacts with eIF1 and eIF5 and is involved in stringent AUG selection. Mol. Cell Biol. 23, 5431–5445 (2003).
Luna, R. E. et al. The C-terminal domain of eukaryotic initiation factor 5 promotes start codon recognition by its dynamic interplay with eIF1 and eIF2β. Cell Rep. 1, 689–702 (2012).
Walker, S. E. et al. Yeast eIF4B binds to the head of the 40S ribosomal subunit and promotes mRNA recruitment through its N-terminal and internal repeat domains. RNA 19, 191–207 (2013).
Eliseev, B. et al. Structure of a human cap-dependent 48S translation pre-initiation complex. Nucleic Acids Res. 46, 2678–2689 (2018).
Padrón, A., Iwasaki, S. & Ingolia, N. T. Proximity RNA labeling by APEX-seq reveals the organization of translation initiation complexes and repressive RNA granules. Mol. Cell 75, 875–887.e5 (2019).
Li, K., Kong, J., Zhang, S., Zhao, T. & Qian, W. Distance-dependent inhibition of translation initiation by downstream out-of-frame AUGs is consistent with a Brownian ratchet process of ribosome scanning. Genome Biol. 23, 254 (2022).
Spirin, A. S. How does a scanning ribosomal particle move along the 5′-untranslated region of eukaryotic mRNA? Brownian ratchet model. Biochemistry 48, 10688–10692 (2009).
Abaeva, I. S., Pestova, T. V. & Hellen, C. U. T. Attachment of ribosomal complexes and retrograde scanning during initiation on the Halastavi árva virus IRES. Nucleic Acids Res. 44, 2362–2377 (2016).
Hashem, Y. et al. Structure of the mammalian ribosomal 43S preinitiation complex bound to the scanning factor DHX29. Cell 153, 1108–1119 (2013).
Sweeney, T. R. et al. Functional role and ribosomal position of the unique N-terminal region of DHX29, a factor required for initiation on structured mammalian mRNAs. Nucleic Acids Res. 49, 12955–12969 (2021).
Gao, Z. et al. Coupling between the DEAD-box RNA helicases Ded1p and eIF4A. eLife 5, e16408 (2016).
Gulay, S., Gupta, N., Lorsch, J. R. & Hinnebusch, A. G. Distinct interactions of eIF4A and eIF4E with RNA helicase Ded1 stimulate translation in vivo. eLife 9, e58243 (2020).
Matsuda, D. & Dreher, T. W. Close spacing of AUG initiation codons confers dicistronic character on a eukaryotic mRNA. RNA 12, 1338–1349 (2006).
Rozen, F. et al. Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F. Mol. Cell. Biol. 10, 1134–1144 (1990).
Kozak, M. Downstream secondary structure facilitates recognition of initiator codons by eukaryotic ribosomes. Proc. Natl Acad. Sci. USA 87, 8301–8305 (1990).
Loughran, G. et al. Unusually efficient CUG initiation of an overlapping reading frame in POLG mRNA yields novel protein POLGARF. Proc. Natl Acad. Sci. USA 117, 24936–24946 (2020).
Guenther, U.-P. et al. The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs. Nature 559, 130–134 (2018).
Filipowicz, W. & Haenni, A. L. Binding of ribosomes to 5′-terminal leader sequences of eukaryotic messenger RNAs. Proc. Natl Acad. Sci. USA 76, 3111–3115 (1979).
Mohammad, M. P., Smirnova, A., Gunišová, S. & Valášek, L. S. eIF4G is retained on ribosomes elongating and terminating on short upstream ORFs to control reinitiation in yeast. Nucleic Acids Res. 49, 8743–8756 (2021).
Sonenberg, N., Shatkin, A. J., Ricciardi, R. P., Rubin, M. & Goodman, R. M. Analysis of terminal structures of RNA from potato virus X. Nucleic Acids Res. 5, 2501–2512 (1978).
Alone, P. V., Cao, C. & Dever, T. E. Translation initiation factor 2γ mutant alters start codon selection independent of Met-tRNA binding. Mol. Cell Biol. 28, 6877–6888 (2008).
Basu, I., Gorai, B., Chandran, T., Maiti, P. K. & Hussain, T. Selection of start codon during mRNA scanning in eukaryotic translation initiation. Commun. Biol. 5, 587 (2022).
Donahue, T. F., Cigan, A. M., Pabich, E. K. & Valavicius, B. C. Mutations at a Zn(II) finger motif in the yeast eIF-2β gene alter ribosomal start-site selection during the scanning process. Cell 54, 621–632 (1988).
Dorris, D. R., Erickson, F. L. & Hannig, E. M. Mutations in GCD11, the structural gene for eIF-2γ in yeast, alter translational regulation of GCN4 and the selection of the start site for protein synthesis. EMBO J. 14, 2239–2249 (1995).
Das, S., Ghosh, R. & Maitra, U. Eukaryotic translation initiation factor 5 functions as a GTPase-activating protein. J. Biol. Chem. 276, 6720–6726 (2001).
Paulin, F. E. M., Campbell, L. E., O’Brien, K., Loughlin, J. & Proud, C. G. Eukaryotic translation initiation factor 5 (eIF5) acts as a classical GTPase-activator protein. Curr. Biol. 11, 55–59 (2001).
Algire, M. A., Maag, D. & Lorsch, J. R. Pi release from eIF2, not GTP hydrolysis, is the step controlled by start-site selection during eukaryotic translation initiation. Mol. Cell 20, 251–262 (2005). This study presents the first evidence that Pi release and not GTP hydrolysis marks the end of scanning.
Simonetti, A. et al. eIF3 peripheral subunits rearrangement after mRNA binding and start-codon recognition. Mol. Cell 63, 206–217 (2016).
Yu, Y. et al. Position of eukaryotic translation initiation factor eIF1A on the 40S ribosomal subunit mapped by directed hydroxyl radical probing. Nucleic Acids Res. 37, 5167–5182 (2009).
Kozak, M. Point mutations close to the AUG initiator codon affect the efficiency of translation of rat preproinsulin in vivo. Nature 308, 241–246 (1984).
Acker, M. G., Shin, B.-S., Dever, T. E. & Lorsch, J. R. Interaction between eukaryotic initiation factors 1A and 5B is required for efficient ribosomal subunit joining. J. Biol. Chem. 281, 8469–8475 (2006).
Brown, Z. P. et al. Molecular architecture of 40S translation initiation complexes on the hepatitis C virus IRES. EMBO J. 41, e110581 (2022).
Fringer, J. M., Acker, M. G., Fekete, C. A., Lorsch, J. R. & Dever, T. E. Coupled release of eukaryotic translation initiation factors 5B and 1A from 80S ribosomes following subunit joining. Mol. Cell Biol. 27, 2384–2397 (2007).
Kazan, R. et al. Role of aIF5B in archaeal translation initiation. Nucleic Acids Res. 50, 6532–6548 (2022).
Lee, J. H. et al. Initiation factor eIF5B catalyzes second GTP-dependent step in eukaryotic translation initiation. Proc. Natl Acad. Sci. USA 99, 16689–16694 (2002).
Acker, M. G. et al. Kinetic analysis of late steps of eukaryotic translation initiation. J. Mol. Biol. 385, 491–506 (2009).
Fernández, I. S. et al. Molecular architecture of a eukaryotic translational initiation complex. Science 342, 1240585 (2013).
Shin, B.-S. et al. Uncoupling of initiation factor eIF5B/IF2 GTPase and translational activities by mutations that lower ribosome affinity. Cell 111, 1015–1025 (2002).
Unbehaun, A., Borukhov, S. I., Hellen, C. U. T. & Pestova, T. V. Release of initiation factors from 48S complexes during ribosomal subunit joining and the link between establishment of codon–anticodon base-pairing and hydrolysis of eIF2-bound GTP. Genes Dev. 18, 3078–3093 (2004).
Wagner, S. et al. Selective translation complex profiling reveals staged initiation and co-translational assembly of initiation factor complexes. Mol. Cell 79, 546–560.e7 (2020).
Lin, Y. et al. eIF3 associates with 80S ribosomes to promote translation elongation, mitochondrial homeostasis, and muscle health. Mol. Cell 79, 575–587.e7 (2020).
Mohammad, M. P., Munzarová Pondelícková, V., Zeman, J., Gunišová, S. & Valášek, L. S. In vivo evidence that eIF3 stays bound to ribosomes elongating and terminating on short upstream ORFs to promote reinitiation. Nucleic Acids Res. 45, 2658–2674 (2017).
Munzarová, V. et al. Translation reinitiation relies on the interaction between eIF3a/TIF32 and progressively folded cis-acting mRNA elements preceding short uORFs. PLoS Genet. 7, e1002137 (2011).
Jang, S. K. et al. A segment of the 5′ nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J. Virol. 62, 2636–2643 (1988).
Pelletier, J. & Sonenberg, N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature 334, 320–325 (1988).
Lee, K.-M., Chen, C.-J. & Shih, S.-R. Regulation mechanisms of viral IRES-driven translation. Trends Microbiol. 25, 546–561 (2017).
Filbin, M. E., Vollmar, B. S., Shi, D., Gonen, T. & Kieft, J. S. HCV IRES manipulates the ribosome to promote the switch from translation initiation to elongation. Nat. Struct. Mol. Biol. 20, 150–158 (2013).
Hashem, Y. et al. Hepatitis-C-virus-like internal ribosome entry sites displace eIF3 to gain access to the 40S subunit. Nature 503, 539–543 (2013).
Murray, J. et al. Structural characterization of ribosome recruitment and translocation by type IV IRES. eLife 5, e13567 (2016).
Neupane, R., Pisareva, V. P., Rodriguez, C. F., Pisarev, A. V. & Fernández, I. S. A complex IRES at the 5′-UTR of a viral mRNA assembles a functional 48S complex via an uAUG intermediate. eLife 9, e54575 (2020).
Quade, N., Boehringer, D., Leibundgut, M., van den Heuvel, J. & Ban, N. Cryo-EM structure of hepatitis C virus IRES bound to the human ribosome at 3.9-Å resolution. Nat. Commun. 6, 7646 (2015).
Schüler, M. et al. Structure of the ribosome-bound cricket paralysis virus IRES RNA. Nat. Struct. Mol. Biol. 13, 1092–1096 (2006).
Yamamoto, H. et al. Structure of the mammalian 80S initiation complex with initiation factor 5B on HCV-IRES RNA. Nat. Struct. Mol. Biol. 21, 721–727 (2014).
Hellen, C. U. & Sarnow, P. Internal ribosome entry sites in eukaryotic mRNA molecules. Genes Dev. 15, 1593–1612 (2001).
Macejak, D. G. & Sarnow, P. Internal initiation of translation mediated by the 5′ leader of a cellular mRNA. Nature 353, 90–94 (1991).
Stoneley, M. & Willis, A. E. Cellular internal ribosome entry segments: structures, trans-acting factors and regulation of gene expression. Oncogene 23, 3200–3207 (2004).
Ivanov, I. P. et al. Evolutionarily conserved inhibitory uORFs sensitize Hox mRNA translation to start codon selection stringency. Proc. Natl Acad. Sci. USA 119, e2117226119 (2022).
Hansen, T. B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013).
Kleaveland, B., Shi, C. Y., Stefano, J. & Bartel, D. P. A network of noncoding regulatory RNAs acts in the mammalian brain. Cell 174, 350–362.e17 (2018).
Memczak, S. et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333–338 (2013).
Di Timoteo, G. et al. Modulation of circRNA Metabolism by m6A modification. Cell Rep. 31, 107641 (2020).
Perry, R. P., Kelley, D. E., Friderici, K. & Rottman, F. The methylated constituents of L cell messenger RNA: evidence for an unusual cluster at the 5′ terminus. Cell 4, 387–394 (1975).
Viegas, I. J. et al. N6-Methyladenosine in poly(A) tails stabilize VSG transcripts. Nature https://doi.org/10.1038/s41586-022-04544-0 (2022).
Wang, X. et al. N6-Methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117–120 (2014).
Su, R. et al. METTL16 exerts an m6A-independent function to facilitate translation and tumorigenesis. Nat. Cell Biol. 24, 205–216 (2022).
Wang, X. et al. Structural basis of N6-adenosine methylation by the METTL3–METTL14 complex. Nature 534, 575–578 (2016).
Li, A. et al. Cytoplasmic m6A reader YTHDF3 promotes mRNA translation. Cell Res. 27, 444–447 (2017).
Takahashi, H., Kato, S., Murata, M. & Carninci, P. CAGE—cap analysis gene expression: a protocol for the detection of promoter and transcriptional networks. Methods Mol. Biol. 786, 181–200 (2012).
Jia, L. & Qian, S.-B. A versatile eIF3d in translational control of stress adaptation. Mol. Cell 81, 10–12 (2021).
de la Parra, C. et al. A widespread alternate form of cap-dependent mRNA translation initiation. Nat. Commun. 9, 3068 (2018).
Volta, V. et al. A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells. Nat. Commun. 12, 6979 (2021).
Haizel, S. A., Bhardwaj, U., Gonzalez, R. L., Mitra, S. & Goss, D. J. 5′-UTR recruitment of the translation initiation factor eIF4GI or DAP5 drives cap-independent translation of a subset of human mRNAs. J. Biol. Chem. 295, 11693–11706 (2020).
Costa-Mattioli, M. & Walter, P. The integrated stress response: from mechanism to disease. Science 368, eaat5314 (2020).
Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).
Hinnebusch, A. G. Translational regulation of GCN4 and the general amino acid control of yeast. Annu. Rev. Microbiol. 59, 407–450 (2005).
Hinnebusch, A. G., Ivanov, I. P. & Sonenberg, N. Translational control by 5′-untranslated regions of eukaryotic mRNAs. Science 352, 1413–1416 (2016).
Bohlen, J. et al. DENR promotes translation reinitiation via ribosome recycling to drive expression of oncogenes including ATF4. Nat. Commun. 11, 4676 (2020).
Skabkin, M. A. et al. Activities of ligatin and MCT-1/DENR in eukaryotic translation initiation and ribosomal recycling. Genes Dev. 24, 1787–1801 (2010).
Lomakin, I. B., Dmitriev, S. E. & Steitz, T. A. Crystal structure of the DENR–MCT-1 complex revealed zinc-binding site essential for heterodimer formation. Proc. Natl Acad. Sci. USA 116, 528–533 (2019).
Weisser, M. et al. Structural and functional insights into human re-initiation complexes. Mol. Cell 67, 447–456.e7 (2017).
Green, K. M., Miller, S. L., Malik, I. & Todd, P. K. Non-canonical initiation factors modulate repeat-associated non-AUG translation. Hum. Mol. Genet. https://doi.org/10.1093/hmg/ddac021 (2022).
Komar, A. A. & Merrick, W. C. A retrospective on eIF2A- and not the α subunit of eIF2. Int. J. Mol. Sci. 21, 2054 (2020).
Tahmasebi, S., Khoutorsky, A., Mathews, M. B. & Sonenberg, N. Translation deregulation in human disease. Nat. Rev. Mol. Cell Biol. 19, 791–807 (2018).
Robichaud, N., Sonenberg, N., Ruggero, D. & Schneider, R. J. Translational control in cancer. Cold Spring Harb. Perspect. Biol. 11, a032896 (2019).
Alvarez, E., Menéndez-Arias, L. & Carrasco, L. The eukaryotic translation initiation factor 4GI is cleaved by different retroviral proteases. J. Virol. 77, 12392–12400 (2003).
Etchison, D., Milburn, S. C., Edery, I., Sonenberg, N. & Hershey, J. W. Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex. J. Biol. Chem. 257, 14806–14810 (1982).
Ventoso, I., Blanco, R., Perales, C. & Carrasco, L. HIV-1 protease cleaves eukaryotic initiation factor 4G and inhibits cap-dependent translation. Proc. Natl Acad. Sci. USA 98, 12966–12971 (2001).
Kamitani, W., Huang, C., Narayanan, K., Lokugamage, K. G. & Makino, S. A two-pronged strategy to suppress host protein synthesis by SARS coronavirus Nsp1 protein. Nat. Struct. Mol. Biol. 16, 1134–1140 (2009).
Kamitani, W. et al. Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation. Proc. Natl Acad. Sci. USA 103, 12885–12890 (2006).
Yuan, S. et al. Nonstructural protein 1 of SARS-CoV-2 is a potent pathogenicity factor redirecting host protein synthesis machinery toward viral RNA. Mol. Cell 80, 1055–1066.e6 (2020).
Lapointe, C. P. et al. Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation. Proc. Natl Acad. Sci. USA 118, e2017715118 (2021).
Mendez, A. S. et al. The N-terminal domain of SARS-CoV-2 nsp1 plays key roles in suppression of cellular gene expression and preservation of viral gene expression. Cell Rep. 37, 109841 (2021).
Rao, S. et al. Genes with 5′ terminal oligopyrimidine tracts preferentially escape global suppression of translation by the SARS-CoV-2 Nsp1 protein. RNA 27, 1025–1045 (2021).
Sosnowski, P., Tidu, A., Eriani, G., Westhof, E. & Martin, F. Correlated sequence signatures are present within the genomic 5′ UTR RNA and NSP1 protein in coronaviruses. RNA https://doi.org/10.1261/rna.078972.121 (2022).
Vora, S. M. et al. Targeting stem-loop 1 of the SARS-CoV-2 5′ UTR to suppress viral translation and Nsp1 evasion. Proc. Natl Acad. Sci. USA 119, e2117198119 (2022).
Tanaka, T., Kamitani, W., DeDiego, M. L., Enjuanes, L. & Matsuura, Y. Severe acute respiratory syndrome coronavirus nsp1 facilitates efficient propagation in cells through a specific translational shutoff of host mRNA. J. Virol. 86, 11128–11137 (2012).
Cleary, J. D., Pattamatta, A. & Ranum, L. P. W. Repeat-associated non-ATG (RAN) translation. J. Biol. Chem. 293, 16127–16141 (2018).
Storkebaum, E., Rosenblum, K. & Sonenberg, N. Messenger RNA translation defects in neurodegenerative diseases. N. Engl. J. Med. 388, 1015–1030 (2023).
Ash, P. E. A. et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639–646 (2013).
Green, K. M. et al. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nat. Commun. 8, 2005 (2017).
Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335–1338 (2013).
Tabet, R. et al. CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts. Nat. Commun. 9, 152 (2018).
Zu, T. et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl Acad. Sci. USA 108, 260–265 (2011).
Afonja, O., Juste, D., Das, S., Matsuhashi, S. & Samuels, H. H. Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosis. Oncogene 23, 8135–8145 (2004).
Chen, Y. et al. Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis. J. Pathol. 200, 640–646 (2003).
Zhang, H. et al. Involvement of programmed cell death 4 in transforming growth factor-β1-induced apoptosis in human hepatocellular carcinoma. Oncogene 25, 6101–6112 (2006).
Biyanee, A., Ohnheiser, J., Singh, P. & Klempnauer, K.-H. A novel mechanism for the control of translation of specific mRNAs by tumor suppressor protein Pdcd4: inhibition of translation elongation. Oncogene 34, 1384–1392 (2015).
Singh, P., Wedeken, L., Waters, L. C., Carr, M. D. & Klempnauer, K.-H. Pdcd4 directly binds the coding region of c-myb mRNA and suppresses its translation. Oncogene 30, 4864–4873 (2011).
Safaee, N. et al. Interdomain allostery promotes assembly of the poly(A) mRNA complex with PABP and eIF4G. Mol. Cell 48, 375–386 (2012).
Grüner, S. et al. The structures of eIF4E–eIF4G complexes reveal an extended interface to regulate translation initiation. Mol. Cell 64, 467–479 (2016).
Schütz, P. et al. Crystal structure of the yeast eIF4A–eIF4G complex: an RNA-helicase controlled by protein–protein interactions. Proc. Natl Acad. Sci. USA 105, 9564–9569 (2008).
Yang, M., Lu, Y., Piao, W. & Jin, H. The translational regulation in mTOR pathway. Biomolecules 12, 802 (2022).
Hernández, G. The versatile relationships between eIF4E and eIF4E-interacting proteins. Trends Genet. 38, 801–804 (2022).
Berman, A. J. et al. Controversies around the function of LARP1. RNA Biol. 18, 207–217 (2021).
Meyuhas, O. & Kahan, T. The race to decipher the top secrets of TOP mRNAs. Biochim. Biophys. Acta 1849, 801–811 (2015).
Christie, M. & Igreja, C. eIF4E-homologous protein (4EHP): a multifarious cap-binding protein. FEBS J. https://doi.org/10.1111/febs.16275 (2021).
Adomavicius, T. et al. The structural basis of translational control by eIF2 phosphorylation. Nat. Commun. 10, 2136 (2019).
Gordiyenko, Y., Llácer, J. L. & Ramakrishnan, V. Structural basis for the inhibition of translation through eIF2α phosphorylation. Nat. Commun. 10, 2640 (2019).
Kashiwagi, K. et al. Structural basis for eIF2B inhibition in integrated stress response. Science 364, 495–499 (2019).
Kenner, L. R. et al. eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response. Science 364, 491–495 (2019).
Krishnamoorthy, T., Pavitt, G. D., Zhang, F., Dever, T. E. & Hinnebusch, A. G. Tight binding of the phosphorylated α subunit of initiation factor 2 (eIF2α) to the regulatory subunits of guanine nucleotide exchange factor eIF2B is required for inhibition of translation initiation. Mol. Cell Biol. 21, 5018–5030 (2001).
Tsai, J. C. et al. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule. Science 359, eaaq0939 (2018).
Zyryanova, A. F. et al. Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science 359, 1533–1536 (2018).
Acknowledgements
The authors thank T. Dever, A. Hinnebusch, J. Lorsch, C. S. Fraser, N. Sonenberg, J. Pelletier and W. Filipowicz for feedback on the manuscript. J.B.Q. was supported by a Federation of European Biochemical Societies long-term fellowship; I.D.-L. was supported by an EMBO Postdoctoral Fellowship; and V.R. was supported by the UK Medical Research Council (MC_U105184332), a Wellcome Trust Investigator award (WT096570) and the Louis-Jeantet Foundation.
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Glossary
- DEAD-box RNA helicase
-
A member of a large family of conserved RNA-binding proteins that contain the amino acid sequence DEAD in motif II and an upstream Q motif, and present ATP-dependent RNA helicase activity.
- Decoding centre
-
A conserved region in the ribosomal RNA that forms the platform for codon–anticodon selection during mRNA translation.
- Kissing loops
-
RNA secondary structures that form when the unpaired nucleotides present in one hairpin loop form base pairs with the unpaired nucleotides of another hairpin loop in the same RNA molecule.
- mRNA channel
-
A groove located between the head and the body of the small ribosomal subunit (40S) that accommodates mRNA during all of the translation process. The decoding centre is in the mRNA channel.
- Pseudoknots
-
RNA secondary structures comprising two or more stem–loop structures, wherein one stem’s half is inserted between the two halves of another stem.
- Toeprinting
-
(Also known as primer extension inhibition assay). A method utilizing the pause of reverse transcriptase when encountering ribosomal complexes to identify the position of the ribosome along the mRNA.
- Translation initiator of short 5′ UTR
-
(TISU). A motif flanking the AUG start codon that allows an alternative mechanism of initiation and selection of start codons located near the mRNA 5’ end.
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Brito Querido, J., Díaz-López, I. & Ramakrishnan, V. The molecular basis of translation initiation and its regulation in eukaryotes. Nat Rev Mol Cell Biol 25, 168–186 (2024). https://doi.org/10.1038/s41580-023-00624-9
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DOI: https://doi.org/10.1038/s41580-023-00624-9
