Abstract
The multi-subunit eukaryotic translation initiation factor eIF3 is thought to assist in the recruitment of ribosomes to mRNA. The expression of eIF3 subunits is frequently disrupted in human cancers, but the specific roles of individual subunits in mRNA translation and cancer remain elusive. Using global transcriptomic, proteomic, and metabolomic profiling, we found a striking failure of Schizosaccharomyces pombe cells lacking eIF3e and eIF3d to synthesize components of the mitochondrial electron transport chain, leading to a defect in respiration, endogenous oxidative stress, and premature aging. Energy balance was maintained, however, by a switch to glycolysis with increased glucose uptake, upregulation of glycolytic enzymes, and strict dependence on a fermentable carbon source. This metabolic regulatory function appears to be conserved in human cells where eIF3e binds metabolic mRNAs and promotes their translation. Thus, via its eIF3d-eIF3e module, eIF3 orchestrates an mRNA-specific translational mechanism controlling energy metabolism that may be disrupted in cancer.
Highlights
Protein synthesis through mRNA translation is the dominant determinant of cellular protein levels (Schwanhausser et al, 2011)
Translation initiation is considered a rate-limiting step in protein synthesis that is governed by the availability and activity of eukaryotic translation initiation factors (Sonenberg and Hinnebusch, 2009). eIF3 is the most complex translation initiation factor (Hinnebusch, 2006), comprising 13 subunits in mammals (Damoc et al, 2007; Querol-Audi et al, 2013) and 11 subunits in the fission yeast Schizosaccharomyces pombe (Sha et al, 2009; Zhou et al, 2005). eIF3 appears to encircle the 40S ribosome to serve as a scaffold orchestrating the recruitment of other eIFs involved in mRNA binding, scanning, and AUG recognition (Erzberger et al, 2014; des Georges et al, 2015; Querol-Audi et al, 2013)
We show here that eIF3e and eIF3d form a specificity module for the efficient synthesis of components of the mitochondrial electron transport chain (ETC) and that lack of eIF3d and eIF3e leads to a metabolic switch from respiration to glycolysis, similar to what is frequently observed in cancer cells undergoing the Warburg effect
Summary
Protein synthesis through mRNA translation is the dominant determinant of cellular protein levels (Schwanhausser et al, 2011). EIF3 is the most complex translation initiation factor (Hinnebusch, 2006), comprising 13 subunits in mammals (Damoc et al, 2007; Querol-Audi et al, 2013) and 11 subunits in the fission yeast Schizosaccharomyces pombe (Sha et al, 2009; Zhou et al, 2005). For certain mRNAs, the eIF3-dependent initiation mechanism involves direct interactions with RNA stem-loop structures or methylated adenosines within the 50 UTR (Lee et al, 2015; Meyer et al, 2015). Overexpression of some subunits can drive de novo holo-complex formation and modest increases in protein synthesis along with cell transformation (Zhang et al, 2007), the specific mechanisms leading to transformation remain unknown. A recent study suggested that eIF3 promotes the synthesis of proteins related to cell proliferation and demonstrated that eIF3-mediated synthesis of c-JUN promotes cell migration (Lee et al, 2015)
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