期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 23, 页码 11291-11298出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1904516116
关键词
reflux; UPR; ERAD; endoplasmic reticulum stress
资金
- JDRF postdoctoral fellowship
- National Science Foundation Graduate Research Fellowship
- Ruth L. Kirschstein National Research Service Award
- NIH (Director's New Innovator Award) [DP2 OD001925, R01DK095306]
- Career Award in the Biomedical Sciences from the Burroughs Wellcome Foundation
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.
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