RRC ID 62097
Author Guan BJ, Krokowski D, Majumder M, Schmotzer CL, Kimball SR, Merrick WC, Koromilas AE, Hatzoglou M.
Title Translational control during endoplasmic reticulum stress beyond phosphorylation of the translation initiation factor eIF2α.
Journal J Biol Chem
Abstract The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes stress to which an unfolded protein response is activated to render cell survival or apoptosis (chronic stress). Transcriptional and translational reprogramming is tightly regulated during the unfolded protein response 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 mammalian target of rapamycin kinase protein complex 1 (mTORC1)-targeted protein phosphorylation, (ii) inhibited translation of a selective group of 5'-terminal oligopyrimidine mRNAs (encoding proteins involved in the translation machinery and translationally controlled by mTORC1 signaling), and (iii) inhibited translation of non-5'-terminal oligopyrimidine 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.
Volume 289(18)
Pages 12593-611
Published 2014-5-2
DOI 10.1074/jbc.M113.543215
PII S0021-9258(20)41445-0
PMID 24648524
PMC PMC4007450
MeSH Activating Transcription Factor 4 / genetics Activating Transcription Factor 4 / metabolism Amino Acids / metabolism Amino Acyl-tRNA Synthetases / metabolism Animals Autophagy-Related Protein 5 Blotting, Western Calcium-Transporting ATPases / antagonists & inhibitors Calcium-Transporting ATPases / metabolism Cells, Cultured Embryo, Mammalian / cytology Endoplasmic Reticulum Stress* Eukaryotic Initiation Factor-2 / genetics Eukaryotic Initiation Factor-2 / metabolism* Fibroblasts / cytology Fibroblasts / drug effects Fibroblasts / metabolism* Mechanistic Target of Rapamycin Complex 1 Mice Mice, Knockout Microtubule-Associated Proteins / deficiency Microtubule-Associated Proteins / genetics Multiprotein Complexes / genetics Multiprotein Complexes / metabolism Phosphorylation Polyribosomes / metabolism Protein Biosynthesis* RNA Interference RNA, Messenger / genetics RNA, Messenger / metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects TOR Serine-Threonine Kinases / genetics TOR Serine-Threonine Kinases / metabolism Thapsigargin / pharmacology Time Factors eIF-2 Kinase / metabolism
IF 4.238
Human and Animal Cells Atg5^(+/+)MEF(RCB2710) Atg5^(-/-)MEF(RCB2711)