Versatility of the translational machinery during stress: changing partners to keep dancing

Abstract

Cap-dependent translation is initiated by the binding of eIF4E to the cap structure at the 5′ end of mRNAs. During hypoxic stress, global translation decreases because eIF4E is inactivated. In a recent article in Nature, Lee and colleagues show that residual hypoxic translation is maintained by a specialized isoform of eIF4E, which binds to target mRNAs in complex with a hypoxia-induced RNP.Translation of most messenger RNAs in the cell is initiated by binding of eukaryotic initiation factor (eIF) 4E to the m 7 GpppN cap structure at the mRNA 5′ end. Multiple eIF4E isoforms have been described in a variety of organisms along the evolutionary scale, but their functions remain for the most part obscure [1]. Translation is drastically reduced upon low oxygen tension (hypoxia) by mechanisms that inhibit the function of eIF4E. Cell function under hypoxia, however, is maintained by a significant degree of "residual" translation. In a recent article in Nature, Lee and colleagues show that the eIF4E homologue 4E2, in complex with the transcription factor HIF-2α and the RNA-binding protein RBM4, sustains cap-dependent translation during hy-. Thus, by using a specialized isoform of eIF4E in complex with a hypoxia-induced RNP, the translational machinery preserves selective protein synthesis during stress (Figure 1).The hypoxia inducible factor (HIF) family of transcription factors maintain cellular oxygen homeostasis. HIF-2α is induced under hypoxia and activates the expression of epidermal growth factor receptor (EGFR), a factor that confers growth advantage to hypoxic tumor cells. Lee and colleagues first show that the accumulation of EGFR is independent of the transcriptional activity of HIF-2α. First, EGFR protein accumulates in cells treated with transcription inhibitors; second, no changes in the steady state amounts of EGFR mRNA are detected upon hypoxia; and third, depletion of HIF-1β, a factor required for HIF transcriptional activity, has no effect on EGFR expression. These results pointed to a surprising direct role of HIF-2α in EGFR mRNA translation, a notion reinforced by the finding that HIF-2α associates with polysomes.The authors further show that HIF-2α associates to a region of EGFR 3′ UTR that is necessary and sufficient to drive translation of reporters in a HIF-2α-dependent manner. HIF-2α does not contain discernible RNA-binding motifs, raising the possibility that RNA binding is mediated by interactions with bridge RNA-binding proteins. An unbiased search for HIF-2α interactors identified RBM4, a protein involved in translational control [3,4]. RBM4 interacts with the HIF-2α-responsive region of EGFR 3′ UTR, and its depletion results in dissociation of HIF-2α from EGFR mRNA, indicating that RBM4 recruits HIF-2α to the 3′ UTR of the EGFR transcript. Furthermore, depletion of RBM4 abrogates the hypoxic translation of endogenous EGFR or EGFR reporters without affecting the levels of HIF-2α. Thus, RBM4 mediates the effects of HIF-2α in hypoxic translation of EGFR mRNA.But the HIF-2α/RBM4 complex regulate...

Hypoxia re-programs 2′-O-Me modifications on ribosomal RNA

“…Hypoxia represses cap-mediated translation by promoting sequestration of eIF4E, as a result of increased binding of eIF4E with 4E-BP1. This causes disruption of the eIF4F-containing translation initiation complex ( Gebauer, 2012 ; van den Beucken et al., 2006 ). In hypoxic conditions, some genes, such as vascular endothelial growth factor (VEGF-C), utilize an alternative mode of protein translation that engages the internal ribosome entry site (IRES) ( Braunstein et al., 2007 ; Morfoisse et al., 2014 ).…”

Translational Control of Canonical and Non-Canonical Translation Initiation Factors at the Sea Urchin Egg to Embryo Transition

“…eIF4E1 is the canonical cap-binding protein implicated in translation initiation, whereas eIF4E2 and eIF4E3 are involved in mRNA-specific translation regulation [18,19,20,21]. In some specific physiological or physio-pathological cases, alternative cap- and/or eIF4E1-independent translation can occur, in which non-canonical translation factors take control [22]. DAP5 is a protein homologous to the C-terminal end of eIF4G that is unable to interact with eIF4E or PABP but still retains the capacity to bind eIF3 and eIF4A.…”