A Versatile eIF3d in Translational Control of Stress Adaptation

Lamper et al., 2020Lamper 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. 2020; 370: 853-856Crossref Scopus (10) Google Scholar reported that eIF3d-mediated cap-dependent is subject regulation by phosphorylation during chronic glucose deprivation, providing a mechanism underlying selective of stress genes essential for cell survival. remarkable feature all living organisms the ability sense fluctuations environmental cues and respond adverse conditions adjusting activities. Protein synthesis consumes lion’s share energy. Not surprisingly, many suppress global protein as part response. However, certain mRNAs needs be maintained or even upregulated sustain vital functions. Given diverse types stressors, how stress-specific are selected has been an area great interest. Even same type stress, acute induce different translational regulation. Stress cells restore homeostasis, but mechanisms remain incompletely understood. unique program in mammalian prolonged starvation. In eukaryotic cells, mRNA typically begins with binding eIF4F 7-methylguanylate (m7G) cap found on 5? end mRNAs. heterotrimeric complex consisting eIF4E (cap-binding), eIF4G (scaffold), eIF4A (RNA helicase) (Hershey 2019Hershey J.W.B. Sonenberg N. Mathews M.B. Principles Translational Control.Cold Spring Harb. Perspect. Biol. 2019; 11: a032607Crossref (49) Scholar). Under normal growth condition, activated mTORC1 phosphorylates eIF4E-binding proteins (4E-BPs), permitting translation. multitude stresses inhibit activity, resulting hypophosphorylated 4E-BPs sequester (Shu 2020Shu X.E. Swanda R.V. Qian S.B. Nutrient Control Translation.Annu. Rev. Nutr. 40: 51-75Crossref (2) Upon inhibition, however, overall reduced only ?60% (An 2020An H. Ordureau A. Körner M. Paulo J.A. Harper J.W. Systematic quantitative analysis ribosome inventory nutrient stress.Nature. 583: 303-309Crossref (15) This does not necessarily mean remaining 40% solely relies cap-independent mechanisms. Notably, most still capped when canonical inhibited. Although widely believed driven through eIF4F, alternative likely exist mediate absence functional eIF4F. Indeed, previous study uncovered another cap-binding (Lee 2016Lee A.S. Kranzusch P.J. Doudna Cate J.H. required specialized initiation.Nature. 2016; 536: 96-99Crossref PubMed (139) subunit eIF3, largest initiation factor binds solvent-exposed side 40S ribosome. eIF3 involved nearly every step initiation, including loading, scanning, start codon selection (Valášek 2017Valášek L.S. Zeman J. Wagner S. Beznosková P. Pavlíková Z. Mohammad M.P. Hronová V. Herrmannová Hashem Y. Gunišová Embraced eIF3: structural insights into roles across cycle.Nucleic Acids Res. 2017; 45: 10948-10968Crossref (54) Surprisingly, shown regulate mRNA-specific manner 2015Lee targets cell-proliferation messenger RNAs activation repression.Nature. 2015; 522: 111-114Crossref (192) It appears activity defines role general versus specific Importantly, eIF3d-targeted mRNAs, exemplified Jun, possess stem loop structure UTR block binding. whether was unclear until now (Figure 1). The first clue came from observation deprivation increased Jun. measured endogenous separating domain entire complex. possible because contains natural HIV-1 protease cleavage site. Remarkably, starvation led 10-fold. Since common signaling pathways, authors confirmed nutrient-dependent eIF3d. Using biochemical genetic approaches, they mapped sites also identified CK2 responsible kinase phosphorylation. During limitation, inhibited leads dephosphorylation subsequent enhanced Jun indicate tight eIF3d-specialized via broad range substrates eIF3b, whose coordination merits further investigation. Apparently, one preferentially bound it challenging determine scope under integral developed elegant approach introducing TEV site proximal After removing undergoing translation, protected were enriched followed deep sequencing. total 668 transcripts deprived HEK293T suggesting spectrum eIF3d-programmed Gene ontology revealed eIF3d-specific metabolism pathways. One interesting target Raptor, which encodes component mTORC1. Like Raptor bears conserved secondary structures evidenced SHAPE, RNA analysis. disruption abolished control quite essentially controls eIF4F-mediated transient inhibition might beneficial requires reactivation. phenomenon initially documented endoplasmic reticulum (Guan 2017Guan B.J. van Hoef Jobava R. Elroy-Stein O. Valasek Cargnello Gao X.H. Krokowski D. Merrick W.C. Kimball S.R. al.A Unique ISR Program Determines Cellular Responses Chronic Stress.Mol. Cell. 68: 885-900.e6Abstract Full Text PDF (59) conceivable acts phosphorylation, restoration eIF4F-dependent reprogramming corresponds transition response adaptation. Failure such switch, case phosphomimetic eIF3d, causes death deprivation. discovery stress-induced expands diversity eIF3. Composed 13 subunits, 800-kDa long viewed static entity recruiting interaction Accumulating evidence suggests participates non-canonical mediated internal entry (IRES) well m6A (Meyer 2015Meyer K.D. Patil D.P. Zhou Zinoviev Skabkin M.A. Elemento Pestova T.V. Jaffrey 5’UTR m(6)A Promotes Cap-Independent Translation.Cell. 163: 999-1010Abstract (785) reshapes our current concept clear no longer equated deployment enables reprogram their translatome, confer adaptive benefits synthesized. As this new paradigm translatome remodeling emerges, number outstanding questions remain. For instance, require presence UTR. those Structural studies Scholar), recognizes remains obscure. Another fundamental question distinct stimuli. serum glutamine Does have other switches produce stimulus-specific translatome? hypoxia, use variants output (Uniacke 2012Uniacke Holterman C.E. Lachance G. Franovic Jacob M.D. Fabian M.R. Payette Holcik Pause An oxygen-regulated machinery.Nature. 2012; 486: 126-129Crossref (189) Blocking theme re-direct Future will uncover pathways critical proteome depending physiological cell. multiple factors, RNA-binding proteins, rich sequence elements, interactions represent regulatory nexus determines priorities research about laboratory supported US National Institutes Health ( R01GM1222814 DP1GM142101 ) HHMI Faculty 55108556 S.-B.Q.