| 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
|
| Resource |
| Human and Animal Cells |
Atg5^(+/+)MEF(RCB2710)
Atg5^(-/-)MEF(RCB2711) |
