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
Intersection of the unfolded protein response and hepatic lipid metabolism.
Ann-Hwee Lee,Laurie H. Glimcher +1 more
TL;DR: The unfolded protein response (UPR) was identified as a signal transduction system that is activated by ER stress and its contribution to human metabolic disorders such as hepatic steatosis, atherosclerosis and type 2 diabetes that are associated with dysregulation of lipid homeostasis are warranted.
Journal ArticleDOI
Ire1-mediated decay in mammalian cells relies on mRNA sequence, structure, and translational status
Kristin A. Moore,Julie Hollien +1 more
TL;DR: Endoplasmic reticulum (ER) stress induces the degradation of mRNAs by Ire1, but this process depends on specific stem-loop structures in the targetmRNAs and on Perk, a second sensor of ER stress, which appears to be required to translationally attenuate the stem- loop regions of target m RNAs.
Journal ArticleDOI
Cadmium-induced teratogenicity: association with ROS-mediated endoplasmic reticulum stress in placenta.
Zhen Wang,Hua Wang,Zhong Mei Xu,Yan-Li Ji,Yuan-Hua Chen,Zhi-Hui Zhang,Cheng Zhang,Xiu-Hong Meng,Mei Zhao,De-Xiang Xu +9 more
TL;DR: Antioxidants may be used as pharmacological agents to protect against Cd-induced fetal malformation and growth restriction and alpha-phenyl-N-t-butylnitrone, a free radical spin-trapping agent, significantly alleviated C d-induced placental ER stress and UPR.
Journal ArticleDOI
Non-alcoholic fatty liver disease and insulin resistance: from bench to bedside.
TL;DR: Lipid accumulation, particularly of diacylglycerol, appears to be of major importance in this process and Mitochondrial dysfunction, through decreased mitochondrial biogenesis, increases oxidative stress, and ageing also plays an important role.
Journal ArticleDOI
Sarco/endoplasmic reticulum calcium ATPase-2 expression is regulated by ATF6 during the endoplasmic reticulum stress response: intracellular signaling of calcium stress in a cardiac myocyte model system.
Donna J. Thuerauf,Holly Hoover,Julia Meller,Jessica Hernandez,Leo Y. Su,Catherine Andrews,Wolfgang H. Dillmann,Patrick M. McDonough,Christopher C. Glembotski +8 more
TL;DR: In this article, the authors investigated the role of the transcription factor, ATF6, in the activation of SERCA2 promoter in the presence of calcium depletion in the sarcoplasmic reticulum (SR).
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.