title: Translational control during endoplasmic reticulum stress beyond phosphorylation of the translation initiation factor eIF2α.
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.
authors.affiliation: From the Department of Pharmacology.
authors.forename: Bo-Jhih
authors.initials: BJ
authors.lastname: Guan
authors.forename: Dawid
authors.initials: D
authors.lastname: Krokowski
authors.forename: Mithu
authors.initials: M
authors.lastname: Majumder
authors.forename: Christine L
authors.initials: CL
authors.lastname: Schmotzer
authors.forename: Scot R
authors.initials: SR
authors.lastname: Kimball
authors.forename: William C
authors.initials: WC
authors.lastname: Merrick
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism; D000818:Animals; D000071187:Autophagy-Related Protein 5; D015153:Blotting, Western; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D000596:Amino Acids; D000604:Amino Acyl-tRNA Synthetases; D000071187:Autophagy-Related Protein 5; D000252:Calcium-Transporting ATPases; D015852:Eukaryotic Initiation Factor-2; D000076222:Mechanistic Target of Rapamycin Complex 1; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; D019284:Thapsigargin; D019892:eIF-2 Kinase; C081452:Atf4 protein, mouse; C495773:Atg5 protein, mouse
keywords: ATF4; Amino Acid Transport; Autophagy; Endoplasmic Reticulum Stress; Gene Expression; Integrated Stress Response; Sequestosome; Translation Control; Unfolded Protein Response; eIF2α; p62