Abstract
The secretory pathway provides a physical route through which only correctly folded gene products are delivered to the eukaryotic cell surface. The efficiency of endoplasmic reticulum (ER)-associated degradation (ERAD), which orchestrates the clearance of structurally aberrant proteins under basal conditions, is boosted by the unfolded protein response (UPR) as one of several means to relieve ER stress. However, the underlying mechanism that links the two systems in higher eukaryotes has remained elusive. Herein, the results of transient expression, RNAi-mediated knockdown and functional studies demonstrate that the transcriptional elevation of EDEM1 boosts the efficiency of glycoprotein ERAD through the formation of a complex that suppresses the proteolytic downregulation of ER mannosidase I (ERManI). The results of site-directed mutagenesis indicate that this capacity does not require that EDEM1 possess inherent mannosidase activity. A model is proposed in which ERManI, by functioning as a downstream effector target of EDEM1, represents a checkpoint activation paradigm by which the mammalian UPR coordinates the boosting of ERAD.
Highlights
The secretory pathway provides a physical route through which newly synthesized proteins are eventually delivered to the eukaryotic cell surface (Ellgaard and Helenius, 2001)
We recently reported that human ER mannosidase I (ERManI) is subject to proteolytic downregulation under basal conditions (Wu et al, 2007) in a manner that is operationally similar to the regulation of checkpoint proteins that monitor DNA damage, except that lysosomal hydrolases contribute to proteolysis
endoplasmic reticulum (ER) mannosidase I is stabilized as part of the mammalian unfolded protein response (UPR) Our immediate objective was to test the prediction that the proteolytic downregulation of human ERManI is impaired as a component of the mammalian UPR
Summary
The secretory pathway provides a physical route through which newly synthesized proteins are eventually delivered to the eukaryotic cell surface (Ellgaard and Helenius, 2001). Misfolded proteins and unassembled complexes are eliminated by a conformation-based quality control system designated ‘ER-associated degradation’ (ERAD) (Brodsky and McCracken, 1999) This series of requisite events that orchestrate the dislocation of ERAD substrates into the cytosol for degradation by 26S proteasomes (Bonifacino and Weissman, 1998; Plemper and Wolf, 1999) operationally expands the surveillance of eukaryotic genome expression beyond the nucleus. Post-translational reassembly is driven by UDPglucose:glycoprotein glucosyltransferase (UGGT), which is capable of catalyzing the regeneration of the monoglucosylated appendage. This arrangement has been coined the ‘calnexin cycle’ (Zapun et al, 1997)
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