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A cytosolic degradation pathway, prERAD, monitors pre-inserted secretory pathway proteins
Tslil Ast, Naama Aviram, Silvia Gabriela Chuartzman, Maya Schuldiner


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.


  • Competing interests

    The authors declare no competing interests.

  • Author contributions

    M.S., T.A., N.A. and S.G.C. designed and performed the experiments as well as analyzed the data. M.S. and T.A. wrote the manuscript.

  • Funding

    This study was supported by the Miel du Botton Aynsley fund; the Minerva Foundation; and the European Research Council Starting Grant (ERC-StG [grant number 260395]. T.A. is supported by the Adams Fellowship Program of the Israel Academy of Sciences and Humanities. M.S. is supported by an EMBO Young Investigator programme grant and the Israeli Ministry of Science.

  • Supplementary material available online at

  • Received October 21, 2013.
  • Accepted April 22, 2014.
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