Translational Control during Endoplasmic Reticulum Stress beyond Phosphorylation of the Translation Initiation Factor eIF2{alpha} [Gene Regulation]
March 19th, 2014 by Guan, B.-J., Krokowski, D., Majumder, M., Schmotzer, C. L., Kimball, S. R., Merrick, W. C., Koromilas, A. E., Hatzoglou, M.
The accumulation of unfolded/mis-folded proteins in the endoplasmic reticulum (ER) causes stress, to which an unfolded protein response (UPR) is activated to render cell survival or apoptosis (chronic stress). Transcriptional and translational reprogramming is tightly regulated during the UPR to ensure specific gene expression. The master regulator of this response is the PERK/eIF2α/ATF4 signaling, where eIF2α is phosphorylated (eIF2α-P) by the kinase PERK. This signal leads to global translational shutdown, but it also enables translation of the transcription factor ATF4 mRNA. We showed recently that ATF4 induces an anabolic program through the up-regulation of selected amino acid transporters and aminoacyl-tRNA synthetases. Paradoxically, this anabolic program led cells to apoptosis during chronic ER stress in a manner that involved recovery from stress-induced protein synthesis inhibition. By using eIF2α-P deficient cells as an experimental system, we identified a communicating network of signaling pathways that contribute to the inhibition of protein synthesis during chronic ER stress. This eIF2α-P-independent network includes: (i) inhibition of mTORC1-targeted protein phosphorylation, (ii) inhibited translation of a selective group of TOP mRNAs (encoding proteins involved in the translation machinery and translationally controlled by mTORC1 signaling), and (iii) inhibited translation of non-TOP ribosomal protein mRNAs and ribosomal RNA biogenesis. We propose that the PERK/eIF2α-P/ATF4 signaling acts as a brake in the decline of protein synthesis during chronic ER stress, by positively regulating signaling downstream of the mTORC1 activity. These studies advance our knowledge on the complexity of the communicating signaling pathways in controlling protein synthesis rates during chronic stress.