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

TY - JOUR

T1 - Chaperone-mediated reflux of secretory proteins to the cytosol during endoplasmic reticulum stress

AU - Igbaria, Aeid

AU - Merksamer, Philip I.

AU - Trusina, Ala

AU - Tilahun, Firehiwot

AU - Johnson, Jeffrey R.

AU - Brandman, Onn

AU - Krogan, Nevan J.

AU - Weissman, Jonathan S.

AU - Papa, Feroz R.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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. Chaperonemediated 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.

AB - 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. Chaperonemediated 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.

KW - Endoplasmic reticulum stress

KW - ERAD

KW - Reflux

KW - UPR

UR - http://www.scopus.com/inward/record.url?scp=85066797912&partnerID=8YFLogxK

U2 - 10.1073/pnas.1904516116

DO - 10.1073/pnas.1904516116

M3 - Journal article

C2 - 31101715

AN - SCOPUS:85066797912

SN - 0027-8424

VL - 166

SP - 11291

EP - 11298

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 23

ER -