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Vol. 18, Issue 9, 3681-3691, September 2007

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The Role of p58^IPK in Protecting the Stressed Endoplasmic Reticulum

D. Thomas Rutkowski^*,, Sang-Wook Kang^,, Alan G. Goodman, Jennifer L. Garrison^||, Jack Taunton^||, Michael G. Katze, Randal J. Kaufman^*,¶,#, and Ramanujan S. Hegde^,#

*Howard Hughes Medical Institute and ^¶Departments of Biological Chemistry and Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-0650; Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; Department of Microbiology, University of Washington, Seattle, WA 98195; and ^||Department of Pharmacology, University of California, San Francisco, San Francisco, CA 94143

Submitted March 23, 2007; Revised May 23, 2007; Accepted June 4, 2007
Monitoring Editor: Reid Gilmore

The preemptive quality control (pQC) pathway protects cells from acute endoplasmic reticulum (ER) stress by attenuating translocation of nascent proteins despite their targeting to translocons at the ER membrane. Here, we investigate the hypothesis that the DnaJ protein p58^IPK plays an essential role in this process via HSP70 recruitment to the cytosolic face of translocons for extraction of translocationally attenuated nascent chains. Our analyses revealed that the heightened stress sensitivity of p58–/– cells was not due to an impairment of the pQC pathway or elevated ER substrate burden during acute stress. Instead, the lesion was in the protein processing capacity of the ER lumen, where p58^IPK was found to normally reside in association with BiP. ER lumenal p58^IPK could be coimmunoprecipitated with a newly synthesized secretory protein in vitro and stimulated protein maturation upon overexpression in cells. These results identify a previously unanticipated location for p58^IPK in the ER lumen where its putative function as a cochaperone explains the stress-sensitivity phenotype of knockout cells and mice.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

^# The laboratories of R.S.H. and R.J.K. contributed equally to this study.

Address correspondence to: Randal J. Kaufman (kaufmanr{at}umich.edu) or Ramanujan S. Hegde (hegder{at}mail.nih.gov).

Abbreviations used: GCR, glycoprotein to cytosolic protein ratio; pQC, preemptive quality control; TG, thapsigargin; TM, tunicamycin; UPR, unfolded protein response.

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