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
Endoplasmic reticulum stress mediates radiation-induced autophagy by perk-eIF2α in caspase-3/7-deficient cells
TL;DR: The mechanism by which radiation triggers autophagy in caspase-3/7-deficient cells is investigated, and the involvement of endoplasmic reticulum (ER) stress is found, revealing ER stress as a novel potential mechanism of radiation-induced autophileagy and as a potential strategy to maximize efficiency of radiation therapy in breast cancer.
Journal ArticleDOI
Endoplasmic reticulum stress signal mediators are targets of selenium action.
TL;DR: Treatment of PC-3 human prostate cancer cells with MSA was found to induce a number of signature ER stress markers, providing strong evidence to support an important role of ER stress response in mediating the anticancer effect of selenium.
Journal ArticleDOI
Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression
Alisson C. Cardoso,Nicholas T. Lam,Jainy J. Savla,Yuji Nakada,Ana Helena Macedo Pereira,Abdallah Elnwasany,Ivan Menendez-Montes,Emily L Ensley,Ursa Bezan Petric,Gaurav Sharma,A. Dean Sherry,A. Dean Sherry,Craig R. Malloy,Chalermchai Khemtong,Michael Kinter,Wilson Lek Wen Tan,Chukwuemeka George Anene-Nzelu,Roger Foo,Ngoc Uyen Nhi Nguyen,Shujuan Li,Shujuan Li,Mahmoud S. Ahmed,Waleed M. Elhelaly,Salim Abdisalaam,Aroumougame Asaithamby,Chao Xing,Mohammed Kanchwala,Gonçalo Vale,Kaitlyn M. Eckert,Matthew A. Mitsche,Jeffrey G. McDonald,Joseph A. Hill,Linzhang Huang,Philip W. Shaul,Luke I. Szweda,Hesham A. Sadek +35 more
TL;DR: It is shown that decreasing fatty-acid oxidation extends the perinatal cardiomyocyte proliferative window and can reintroduce cell-cycle activity in adult cardiomers, and may be a viable target for cardiac regenerative therapies.
Journal ArticleDOI
Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways.
TL;DR: There is evidence that expression of VWM mutant eIF2B may enhance the translation of specific mRNAs, and the variability of the clinical phenotype in VWM may reflect the multiple ways in which VWM mutations affect eif2B function.
Journal ArticleDOI
The structure of the PERK kinase domain suggests the mechanism for its activation
TL;DR: The crystal structure of PERK's kinase domain suggests conservation in the mode of activation of eIF2α kinases and is consistent with a `line-up' model for PERK activation triggered by oligomerization of its luminal domain.
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.
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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.