期刊
JOURNAL OF CELL SCIENCE
卷 127, 期 14, 页码 3017-3023出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.144386
关键词
Doa10; ERAD; GPI-anchored protein SRP-independent substrate; Quality control; Translocation
类别
资金
- Miel du Botton Aynsley fund
- Minerva Foundation
- European Research Council Starting Grant (ERC-StG) [260395]
- Adams Fellowship Program of the Israel Academy of Sciences and Humanities
- EMBO Young Investigator programme grant
- Israeli Ministry of Science
The endoplasmic reticulum (ER) identifies and disposes of misfolded secretory pathway proteins through the actions of ER-associated degradation (ERAD) pathways. It is becoming evident that a substantial fraction of the secretome transiently resides in the cytosol before translocating into the ER, both in yeast and in higher eukaryotes. To uncover factors that monitor this transient cytosolic protein pool, we carried out a genetic screen in Saccharomyces cerevisiae. Our findings highlighted a pre-insertional degradation mechanism at the cytosolic leaflet of the ER, which we term prERAD. prERAD relies on the concurrent action of the ER-localized ubiquitylation and deubiquitylation machineries Doa10 and Ubp1. By recognizing C-terminal hydrophobic motifs, prERAD tags for degradation pre-inserted proteins that have remained on the cytosolic leaflet of the ER for too long. Our discoveries delineate a new cellular safeguard, which ensures that every stage of secretory pathway protein biogenesis is scrutinized and regulated.
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