Control of PERK eIF2α kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK
- Wei Yan*,†,‡,
- Christopher L. Frank*,†,
- Marcus J. Korth*,†,
- Bryce L. Sopher§,
- Isabel Novoa¶,
- David Ron¶, and
- Michael G. Katze*,†
- From the Departments of *Microbiology and §Laboratory Medicine, School of Medicine, and †Washington National Primate Research Center, University of Washington, Seattle, WA 98195; and ¶Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016
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Edited by Carol A. Gross, University of California, San Francisco, CA, and approved October 17, 2002 (received for review June 6, 2002)
Abstract
P58IPK is an Hsp40 family member known to inhibit the interferon (IFN)-induced, double-stranded RNA-activated, eukaryotic initiation factor 2α (eIF2α) protein kinase R (PKR) by binding to its kinase domain. We find that the stress of unfolded proteins in the endoplasmic reticulum (ER) activates P58IPK gene transcription through an ER stress-response element in its promoter region. P58IPK interacts with and inhibits the PKR-like ER-localized eIF2α kinase PERK, which is normally activated during the ER-stress response to protect cells from ER stress by attenuating protein synthesis and reducing ER client protein load. Levels of phosphorylated eIF2α were lower in ER-stressed P58IPK-overexpressing cells and were enhanced in P58IPK mutant cells. In the ER-stress response, PKR-like ER kinase (PERK)-mediated translational repression is transient and is followed by translational recovery and enhanced expression of genes that increase the capacity of the ER to process client proteins. The absence of P58IPK resulted in increased expression levels of two ER stress-inducible genes, BiP and Chop, consistent with the enhanced eIF2α phosphorylation in the P58IPK deletion cells. Our studies suggest that P58IPK induction during the ER-stress response represses PERK activity and plays a functional role in the expression of downstream markers of PERK activity in the later phase of the ER-stress response.
Footnotes
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↵ ‡ To whom correspondence should be addressed at: Department of Microbiology, University of Washington, Box 358070, Seattle, WA 98195-8070. E-mail: wyan96{at}u.washington.edu.
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This paper was submitted directly (Track II) to the PNAS office.
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Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. ).
- Abbreviations:
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eIF2α, eukaryotic initiation factor 2α
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PKR, protein kinase R
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ER, endoplasmic reticulum
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PERK, PKR-like ER kinase
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UPR, unfolded protein response
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ERSE, ER stress-response element
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HA, hemagglutinin
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ES, embryonic stem
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- Copyright © 2002, The National Academy of Sciences
