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
Citations
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Journal ArticleDOI
Redox signaling loops in the unfolded protein response.
TL;DR: Redox dependent activation (ER) and amplification (cytosol) loops that control the UPR are described and the consequences these regulatory loops have on cell fate and physiology are described.
Journal ArticleDOI
Suppressive effects of 4‐phenylbutyrate on the aggregation of Pael receptors and endoplasmic reticulum stress
Kyoko Kubota,Yoshifumi Niinuma,Masayuki Kaneko,Masayuki Kaneko,Yasunobu Okuma,Mami Sugai,Tomohiro Omura,Mai Uesugi,Takashi Uehara,Toru Hosoi,Toru Hosoi,Yasuyuki Nomura,Yasuyuki Nomura +12 more
TL;DR: Results suggest that 4‐PBA suppresses ER stress by directly reducing the amount of misfolded protein, including Pael‐R accumulated in the ER.
Journal ArticleDOI
Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties.
Daisuke Ito,John R. Walker,Charlie S. Thompson,Isabella Moroz,William Lin,Margaret Veselits,Antoine M. Hakim,Allen A. Fienberg,Gopal Thinakaran +8 more
TL;DR: Stanniocalcin 2 (STC2), a mammalian homologue of a calcium- and phosphate-regulating hormone first identified in fish, is described as a novel target of the unfolded-protein response (UPR) and induced STC2 expression is an essential feature of survival component of the UPR.
Journal ArticleDOI
Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with other cellular stress pathways.
TL;DR: It is demonstrated that the ER-localized protein Herp represents a second target, in addition to CHOP, that is dually regulated by both the shared and the ER stress-specific branches of the UPR during UPR activation.
Journal ArticleDOI
Dilated Cardiomyopathy Caused by Aberrant Endoplasmic Reticulum Quality Control in Mutant KDEL Receptor Transgenic Mice
Hiromichi Hamada,Masashi Suzuki,Shigeki Yuasa,Naoya Mimura,Norihiro Shinozuka,Yuki Takada,Misao Suzuki,Takashi Nishino,Haruaki Nakaya,Haruhiko Koseki,Tomohiko Aoe +10 more
TL;DR: It is suggested that impairment of the KDEL receptor disturbs ER quality control, resulting in accumulation of misfolded proteins in the ER in an in vivo system, and that the dilated cardiomyopathy found in the mutant KD EL receptor transgenic mice is associated with ER stress.
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.