title: A shared endoplasmic reticulum-associated degradation pathway involving the EDEM1 protein for glycosylated and nonglycosylated proteins.
abstract: Studies of misfolded protein targeting to endoplasmic reticulum-associated degradation (ERAD) have largely focused on glycoproteins, which include the bulk of the secretory proteins. Mechanisms of targeting of nonglycosylated proteins are less clear. Here, we studied three nonglycosylated proteins and analyzed their use of known glycoprotein quality control and ERAD components. Similar to an established glycosylated ERAD substrate, the uncleaved precursor of asialoglycoprotein receptor H2a, its nonglycosylated mutant, makes use of calnexin, EDEM1, and HRD1, but only glycosylated H2a is a substrate for the cytosolic SCF(Fbs2) E3 ubiquitin ligase with lectin activity. Two nonglycosylated BiP substrates, NS-1κ light chain and truncated Igγ heavy chain, interact with the ERAD complex lectins OS-9 and XTP3-B and require EDEM1 for degradation. EDEM1 associates through a region outside of its mannosidase-like domain with the nonglycosylated proteins. Similar to glycosylated substrates, proteasomal inhibition induced accumulation of the nonglycosylated proteins and ERAD machinery in the endoplasmic reticulum-derived quality control compartment. Our results suggest a shared ERAD pathway for glycosylated and nonglycosylated proteins composed of luminal lectin machinery components also capable of protein-protein interactions.
authors.affiliation: Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Shenkman
authors.forename: Bella
authors.initials: B
authors.lastname: Groisman
authors.forename: Efrat
authors.initials: E
authors.lastname: Ron
authors.forename: Edward
authors.initials: E
authors.lastname: Avezov
authors.forename: Linda M
authors.initials: LM
authors.lastname: Hendershot
authors.forename: Gerardo Z
authors.initials: GZ
authors.lastname: Lederkremer
mesh_terms: D000818:Animals; D018833:Chaperonins / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation; D005786:Gene Expression Regulation; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry; D037102:Lectins / Q000737:chemistry; D008361:Mannosidases / Q000737:chemistry; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D011134:Polysaccharides / Q000737:chemistry; D011489:Protein Denaturation; D017510:Protein Folding
chemical_list: C486654:EDEM1 protein, human; C434526:Edem1 protein, mouse; D007145:Immunoglobulin kappa-Chains; D037102:Lectins; D008565:Membrane Proteins; D011134:Polysaccharides; D008361:Mannosidases; D018833:Chaperonins