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MBC in Press, published online ahead of print June 13, 2007
Mol. Biol. Cell 10.1091/mbc.E07-03-0272

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Submitted on March 23, 2007
Revised on May 23, 2007
Accepted on June 4, 2007

The Role of p58IPK in Protecting the Stressed Endoplasmic Reticulum

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

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

Monitoring Editor: Reid Gilmore

The pre-emptive quality control (pQC) pathway protects cells from acute 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 p58IPK 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 p58IPK was found to normally reside in association with BiP. ER lumenal p58IPK 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 p58IPK in the ER lumen where its putative function as a cochaperone explains the stress-sensitivity phenotype of knockout cells and mice.

{dagger}These authors contributed equally to this work.

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




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