Inhibition of translational initiation by activators of the glucose-regulated stress protein and heat shock protein stress response systems: Role of the interferon-inducible double-stranded RNA-activated eukaryotic initiation factor 2 alpha kinase
Depletion of endoplasmic reticulum (ER) Ca super(2+) perturbs protein folding and processing within the organelle while inhibiting translational initiation through activation of the double-stranded RNA-activated eukaryotic initiation factor (eIF)-2 alpha kinase (PKR). The glucose-regulated stress pr...
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Veröffentlicht in: | The Journal of biological chemistry 1996, Vol.271 (40), p.24995-25002 |
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Hauptverfasser: | , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Depletion of endoplasmic reticulum (ER) Ca super(2+) perturbs protein folding and processing within the organelle while inhibiting translational initiation through activation of the double-stranded RNA-activated eukaryotic initiation factor (eIF)-2 alpha kinase (PKR). The glucose-regulated stress protein (GRP) chaperones are subsequently induced. We now report that sodium arsenite, a prototype for stressors fostering cytoplasmic protein misfolding, also inhibits translational initiation through activation of PKR while subsequently inducing the heat shock protein (HSP) chaperones. Arsenite neither mobilized ER-associated Ca super(2+) nor slowed peptide chain elongation. Various HSP-inducing chemicals caused rapid phosphorylation of eIF-2 alpha . When incubated with double-stranded RNA, extracts derived from arsenite-treated cells displayed greater degrees of phosphorylation of PKR and eIF-2 alpha than did control extracts. Cells overexpressing a dominant negative PKR mutation resisted translational inhibition and eIF-2 alpha phosphorylation in response to ER or cytoplasmic stressors. Induction of either the HSP or GRP chaperones was accompanied by development of translational tolerance to either Ca super(2+)-mobilizing agents or arsenite. Following induction of the HSPs by arsenite, cells remained susceptible to induction of the GRPs by Ca super(2+)-mobilizing agents. Conversely, cells possessing induced GRP contents in response to Ca super(2+)-mobilizing agents readily induced the HSPs in response to arsenite. It is concluded that the two chaperone systems function independently except for their mutual suppression of PKR. |
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ISSN: | 0021-9258 |
DOI: | 10.1074/jbc.271.40.24995 |