Journal ArticleDOI
Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase
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TLDR
The cloning of perk is described, a gene encoding a type I transmembrane ER-resident protein that contains a protein-kinase domain most similar to that of the known eIF2α kinases, PKR and HRI that implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.Abstract:
Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2alpha (eIF2alpha) in response to a stress signal from the endoplasmic reticulum (ER). Activation of this process leads to reduced rates of initiation of protein translation during ER stress. Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. PERK has a lumenal domain that is similar to the ER-stress-sensing lumenal domain of the ER-resident kinase Ire1, and a cytoplasmic portion that contains a protein-kinase domain most similar to that of the known eIF2alpha kinases, PKR and HRI. ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. These properties implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.read more
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Phosphorylation of eukaryotic initiation factor 2 by heme-regulated inhibitor kinase-related protein kinases in Schizosaccharomyces pombe is important for resistance to environmental stresses
TL;DR: Results demonstrate that HRI-related enzymes are not unique to vertebrates and suggest that these eIF2α kinases are important participants in diverse stress response pathways in some lower eukaryotes.
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Causes and consequences of endoplasmic reticulum stress in rheumatic disease
Fatemeh Navid,Robert A. Colbert +1 more
TL;DR: This Review discusses several settings in which ER stress contributes to the pathogenesis of rheumatic diseases and considers some of the therapeutic opportunities that these discoveries provide.
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A PERK–miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival
Yiwen Bu,Akihiro Yoshida,Nilesh Chitnis,Brian J. Altman,Feven Tameire,Amanda R. Oran,Victoria J. Gennaro,Kent Armeson,Steven B. McMahon,Gerald Wertheim,Chi V. Dang,Davide Ruggero,Constantinos Koumenis,Serge Y. Fuchs,J. Alan Diehl +14 more
TL;DR: It is demonstrated that c-Myc-dependent activation of the UPR inhibits Bmal1 in Burkitt’s lymphoma, thereby suppressing both circadian oscillation and ongoing protein synthesis to facilitate tumour progression.
Journal ArticleDOI
Bioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene expression
Heather P. Harding,Yuhong Zhang,Sonya M. Khersonsky,Stefan J. Marciniak,Donalyn Scheuner,Randal J. Kaufman,Norman B. Javitt,Young-Tae Chang,David Ron +8 more
TL;DR: Interestingly, compound-mediated activation of sterol-regulated genes was enhanced in cells with an ISR-blocking mutation in the regulatory phosphorylation site of eIF2alpha, suggesting a mechanism by which interactions between sterol metabolism, the ISR, and the SREBP pathway affect lipid metabolism during ER stress.
Journal ArticleDOI
Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins.
Ryan J Paxman,Lars Plate,Erik A Blackwood,Chris C Glembotski,Evan T. Powers,R. Luke Wiseman,Jeffery W. Kelly +6 more
TL;DR: 147 is a pro-drug that preferentially activates ATF6 signaling through a mechanism involving localized metabolic activation and selective covalent modification of ER resident proteins that regulate ATF6 activity.
References
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Journal ArticleDOI
Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.
Caroline E. Shamu,Peter Walter +1 more
TL;DR: Molecular genetic and biochemical studies described here suggest that, as in the case of growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by otherIre1p molecules as a result of oligomerization.
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Protein folding in the cell.
TL;DR: Folding and assembly of polypeptides in vivo involves other proteins, many of which belong to families that have been highly conserved during evolution.
Journal ArticleDOI
The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins
TL;DR: Testing the hypothesis that the presence of malfolded proteins may be the primary signal for induction of GRPs by expressing wild-type and mutant forms of influenza virus haemagglutinin in simian cells shows that malfoldingper se, rather than abnormal glycosylation1, is the proximal inducer of this family of stress proteins.
Journal ArticleDOI
Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase
TL;DR: IRE1 encodes a transmembrane serine/threonine kinase that it is proposed transmits the unfolded protein signal across the ER or inner nuclear membrane, suggesting that the induction of ER resident proteins is coupled to the biogenesis of new ER membrane.
Journal ArticleDOI
A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells
TL;DR: HIre1p is an essential proximal sensor of the unfolded protein response pathway in mammalian cells and is demonstrated to be highly conserved to the yeast counterpart having a Ser/Thr protein kinase domain and a domain homologous to RNase L.