Control of PERK eIF2α kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58 IPK
Open Access
- 22 November 2002
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 99 (25) , 15920-15925
- https://doi.org/10.1073/pnas.252341799
Abstract
P58 IPK 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 P58 IPK gene transcription through an ER stress-response element in its promoter region. P58 IPK 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 P58 IPK -overexpressing cells and were enhanced in P58 IPK 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 P58 IPK resulted in increased expression levels of two ER stress-inducible genes, BiP and Chop , consistent with the enhanced eIF2α phosphorylation in the P58 IPK deletion cells. Our studies suggest that P58 IPK 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.Keywords
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