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Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11291-11298. doi: 10.1073/pnas.1904516116. Epub 2019 May 17.

Chaperone-mediated reflux of secretory proteins to the cytosol during endoplasmic reticulum stress.

Author information

1
Department of Medicine, University of California, San Francisco, CA 94143.
2
Diabetes Center, University of California, San Francisco, CA 94143.
3
Quantitative Biosciences Institute, University of California, San Francisco, CA 94143.
4
Gladstone Institute of Virology and Immunology, San Francisco, CA 94158.
5
Center for Models of Life, Niels Bohr Institute, University of Copenhagen, DK 2100 Copenhagen, Denmark.
6
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143.
7
Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
8
Department of Medicine, University of California, San Francisco, CA 94143; frpapa@medicine.ucsf.edu.

Abstract

Diverse perturbations to endoplasmic reticulum (ER) functions compromise the proper folding and structural maturation of secretory proteins. To study secretory pathway physiology during such "ER stress," we employed an ER-targeted, redox-responsive, green fluorescent protein-eroGFP-that reports on ambient changes in oxidizing potential. Here we find that diverse ER stress regimes cause properly folded, ER-resident eroGFP (and other ER luminal proteins) to "reflux" back to the reducing environment of the cytosol as intact, folded proteins. By utilizing eroGFP in a comprehensive genetic screen in Saccharomyces cerevisiae, we show that ER protein reflux during ER stress requires specific chaperones and cochaperones residing in both the ER and the cytosol. Chaperone-mediated ER protein reflux does not require E3 ligase activity, and proceeds even more vigorously when these ER-associated degradation (ERAD) factors are crippled, suggesting that reflux may work in parallel with ERAD. In summary, chaperone-mediated ER protein reflux may be a conserved protein quality control process that evolved to maintain secretory pathway homeostasis during ER protein-folding stress.

KEYWORDS:

ERAD; UPR; endoplasmic reticulum stress; reflux

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