Inhibition of Translational Initiation by Activators of the Glucose-regulated Stress Protein and Heat Shock Protein Stress Response Systems
Depletion of endoplasmic reticulum (ER) Ca 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)-2α kinase (PKR) (Prostko, C. R., Dholakia, J. N., Brostrom,...
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Veröffentlicht in: | The Journal of biological chemistry 1996-10, Vol.271 (40), p.24995-25002 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Depletion of endoplasmic reticulum (ER) Ca 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)-2α kinase (PKR) (Prostko, C. R., Dholakia, J. N.,
Brostrom, M. A., and Brostrom, C. O. (1995) J. Biol. Chem. 270, 6211-6215). 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 2+ nor slowed peptide chain elongation. Various HSP-inducing chemicals caused rapid phosphorylation of eIF-2α. When incubated
with double-stranded RNA, extracts derived from arsenite-treated cells displayed greater degrees of phosphorylation of PKR
and eIF-2α than did control extracts. Cells overexpressing a dominant negative PKR mutation resisted translational inhibition
and eIF-2α 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 2+ -mobilizing agents or arsenite. Following induction of the HSPs by arsenite, cells remained susceptible to induction of the
GRPs by Ca 2+ -mobilizing agents. Conversely, cells possessing induced GRP contents in response to Ca 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 1083-351X |
DOI: | 10.1074/jbc.271.40.24995 |