Journal ArticleDOI
Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase
Reads0
Chats0
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
More filters
Journal ArticleDOI
The UPR and cell fate at a glance.
TL;DR: In eukaryotic cells, secreted and resident proteins of the endomembrane system fold into their native structures within the endoplasmic reticulum (ER), whose lumenal environment is crowded with molecular chaperones and protein-modification enzymes.
Journal ArticleDOI
Apolipoprotein B100 acts as a molecular link between lipid‐induced endoplasmic reticulum stress and hepatic insulin resistance
TL;DR: Evidence is provided for a molecular link between hepatic apolipoprotein B100 (apoB100), induction of ER stress, and attenuated insulin signaling and small interfering (si)RNA‐mediated attenuation of elevated apoB level in the ApoB50‐expressing cells rescued cells from lipid‐induced ER stress and reversed insulin insensitivity.
Journal ArticleDOI
Protein-Folding Homeostasis in the Endoplasmic Reticulum and Nutritional Regulation
David Ron,Heather P. Harding +1 more
TL;DR: PerK, its downstream effectors, and the allied branches of the unfolded protein response intersect broadly with signaling pathways that regulate nutrient assimilation, and ER stress and the response to it have been implicated in the development of the metabolic syndrome accompanying obesity in mammals.
Journal ArticleDOI
Phosphorylation of eIF2α at serine 51 is an important determinant of cell survival and adaptation to glucose deficiency.
Hala Muaddi,Hala Muaddi,Mithu Majumder,Philippos Peidis,Philippos Peidis,Andreas I. Papadakis,Andreas I. Papadakis,Martin Holcik,Donalyn Scheuner,Randal J. Kaufman,Maria Hatzoglou,Antonis E. Koromilas,Antonis E. Koromilas +12 more
TL;DR: Phosphorylation of eIF2α is an adaptive process that establishes a cytoprotective state in glucose-deficient cells, with possible implications in biological responses that interfere with glucose metabolism.
Journal ArticleDOI
Activation of the unfolded protein response by Listeria monocytogenes.
TL;DR: It is demonstrated that the facultative intracellular pathogen Listeria monocytogenes (Lm) induces ER expansion and UPR prior to host cell entry and suggests that UPR plays an important role in the cell autonomous defence responses to bacterial infection.
References
More filters
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.