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

Aeid Igbaria, Philip I. Merksamer, Ala Trusina, Firehiwot Tilahun, Jeffrey R. Johnson, Onn Brandman, Nevan J. Krogan, Jonathan S. Weissman, Feroz R. Papa

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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. 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.

Original languageEnglish
Pages (from-to)11291-11298
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume166
Issue number23
DOIs
StatePublished - 1 Jan 2019
Externally publishedYes

Keywords

  • ERAD
  • Endoplasmic reticulum stress
  • Reflux
  • UPR

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