A cytosolic degradation pathway, prERAD, monitors pre-inserted secretory pathway proteins

Abstract

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 preinsertional degradation mechanism at the cytosolic leaflet of the ER, which we termed prERAD. prERAD relies on the concurrent action of ER localized ubiquitination and deubiquitination 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 novel cellular safeguard, which ensures that every stage of secretory pathway protein biogenesis is scrutinized and regulated.