title: Bypass of glycan-dependent glycoprotein delivery to ERAD by up-regulated EDEM1.
abstract: Trimming of mannose residues from the N-linked oligosaccharide precursor is a stringent requirement for glycoprotein endoplasmic reticulum (ER)-associated degradation (ERAD). In this paper, we show that, surprisingly, overexpression of ER degradation-enhancing α-mannosidase-like protein 1 (EDEM1) or its up-regulation by IRE1, as occurs in the unfolded protein response, overrides this requirement and renders unnecessary the expression of ER mannosidase I. An EDEM1 deletion mutant lacking most of the carbohydrate-recognition domain also accelerated ERAD, delivering the substrate to XTP3-B and OS9. EDEM1 overexpression also accelerated the degradation of a mutant nonglycosylated substrate. Upon proteasomal inhibition, EDEM1 concentrated together with the ERAD substrate in the pericentriolar ER-derived quality control compartment (ERQC), where ER mannosidase I and ERAD machinery components are localized, including, as we show here, OS9. We suggest that a nascent glycoprotein can normally dissociate from EDEM1 and be rescued from ERAD by reentering calnexin-refolding cycles, a condition terminated by mannose trimming. At high EDEM1 levels, glycoprotein release is prevented and glycan interactions are no longer required, canceling the otherwise mandatory ERAD timing by mannose trimming and accelerating the targeting to degradation.
authors.affiliation: Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Ron
authors.forename: Marina
authors.initials: M
authors.lastname: Shenkman
authors.forename: Bella
authors.initials: B
authors.lastname: Groisman
authors.forename: Yana
authors.initials: Y
authors.lastname: Izenshtein
authors.forename: Julia
authors.initials: J
authors.lastname: Leitman
authors.forename: Gerardo Z
authors.initials: GZ
authors.lastname: Lederkremer
mesh_terms: D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000378:metabolism*; D001665:Binding Sites; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D037102:Lectins / Q000378:metabolism; D008358:Mannose / Q000378:metabolism; D008361:Mannosidases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D056811:Unfolded Protein Response; D015854:Up-Regulation
chemical_list: D037263:Asialoglycoprotein Receptor; C486654:EDEM1 protein, human; C531192:ERLEC1 protein, human; D037102:Lectins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C098898:OS9 protein, human; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C568343:MAN1B1 protein, human; D008361:Mannosidases; D008358:Mannose