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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Journal ArticleDOI
Reovirus Induces and Benefits from an Integrated Cellular Stress Response
Jennifer A. Smith,Stephen C. Schmechel,Arvind Raghavan,Michelle Abelson,Cavan S. Reilly,Michael G. Katze,Randal J. Kaufman,Paul R. Bohjanen,Leslie A. Schiff +8 more
TL;DR: It is hypothesized that eIF2α phosphorylation facilitates reovirus replication in two ways—first, by inducing ATF4 synthesis, and second, by creating an environment that places abundant reov virus transcripts at a competitive advantage for limited translational components.
Journal ArticleDOI
Quality and quantity control at the endoplasmic reticulum.
TL;DR: Current concepts underlying the pathways that mediate protein degradation from the ER and their deployment under physiologic and pathologic conditions are synthesized.
Journal ArticleDOI
Ubiquitin fold modifier 1 (UFM1) and its target UFBP1 protect pancreatic beta cells from ER stress-induced apoptosis.
Katleen Lemaire,Rodrigo Ferreira de Moura,Mikaela Granvik,Mariana Igoillo-Esteve,Mariana Igoillo-Esteve,Hans E. Hohmeier,Nico Hendrickx,Christopher B. Newgard,Etienne Waelkens,Miriam Cnop,Miriam Cnop,Frans Schuit +11 more
TL;DR: It is shown that ER stress, which is common in secretory cells, induces expression of UFM1, Ufbp1 and Ufl1 in the beta-cell line INS-1E, suggesting that U FM1-UFBP1 conjugation is required to prevent ER stress-induced apoptosis.
Journal ArticleDOI
ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation
Adam K. Walker,Adam K. Walker,Kai Y. Soo,Vinod Sundaramoorthy,Sonam Parakh,Yi Ma,Manal A. Farg,Robyn H. Wallace,Peter J. Crouch,Peter J. Crouch,Bradley J. Turner,Malcolm K. Horne,Malcolm K. Horne,Julie D. Atkin,Julie D. Atkin +14 more
TL;DR: It is demonstrated that pharmacological induction of ER stress causes TAR DNA binding protein 43 to accumulate in the cytoplasm, where TDP-43 also associates with stress granules (SGs) and forms large inclusions, providing evidence for ER stress as a pathogenic pathway in T DP-43-mediated disease.
Journal ArticleDOI
Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities
Toru Hosoi,Koichiro Ozawa +1 more
TL;DR: The importance of ER stress under pathological conditions in mammals is considered and the therapeutic potential for treatment targeting ER stress is discussed.
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.
Journal ArticleDOI
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.