A cytosolic degradation pathway, prERAD, monitors pre-inserted secretory pathway proteins.
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.
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
Tslil
T
Ast
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
Naama
N
Aviram
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
Silvia Gabriela
SG
Chuartzman
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel maya.schuldiner@weizmann.ac.il.
Maya
M
Schuldiner
D003600:Cytosol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D006801:Humans; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D055571:Secretory Pathway
D029701:Saccharomyces cerevisiae Proteins
Doa10; ERAD; GPI-anchored protein; Quality control; SRP-independent substrate; Translocation