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Journal ArticleDOI

Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase

Heather P. Harding, +2 more
- 21 Jan 1999 - 
- Vol. 397, Iss: 6716, pp 271-274
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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.

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Citations
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Journal ArticleDOI

Role of endoplasmic reticulum stress in cystic fibrosis-related airway inflammatory responses.

TL;DR: The functional role of the UPR in airway inflammation is described, how expansion of the ER Ca(2+) stores in inflamed airway epithelia contributes toAirway inflammation, and how UPR activation might be relevant for CF airways inflammatory disease are discussed.
Journal ArticleDOI

mRNA translation is compartmentalized to the endoplasmic reticulum following physiological inhibition of cap-dependent translation.

TL;DR: Data demonstrate that ribosome and mRNA release from the ER is regulated independent of translation termination and identify the ER as a privileged site for protein synthesis.
Journal ArticleDOI

Regulation of the unfolded protein response via S-nitrosylation of sensors of endoplasmic reticulum stress

TL;DR: It is demonstrated that nitric oxide (NO) can S-nitrosylate the ER stress sensors IRE1α and PERK and shows that nitrosative stress leads to dysfunctional ER stress signaling, thus contributing to neuronal cell death.
Journal ArticleDOI

Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini.

TL;DR: TUDCA prevented the CCK-8-induced BiP upregulation, diminished PERK and JNK phosphorylation, and prohibited the expression of CHOP, caspase 3 activation and apoptosis, and XBP-1 splicing was not altered.
References
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Journal ArticleDOI

Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.

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.
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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.
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