title: Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+channel, ENaC.
abstract: Ubiquitylation of the epithelial Na+channel (ENaC) plays a critical role in cellular functions, including transmembrane transport of Na+, Na+and water balance, and blood pressure stabilization. Published studies have suggested that ENaC subunits are targets of ER-related degradation (ERAD) in yeast systems. However, the molecular mechanism underlying proteasome-mediated degradation of ENaC subunits remains to be established. Derlin-1, an E3 ligase mediator, links recognized target proteins to ubiquitin-mediated proteasomal degradation in the cytosol. In the present study, we found that derlin-1 suppressed the expression of ENaC at the protein level and that the subunit α-ENaC (also known as SCNN1A) physically interacted with derlin-1 at the membrane-anchored domains or the loop regions, and that derlin-1 initiated α-ENaC retrotranslocation. In addition, HUWE1, an endoplasmic reticulum (ER)-resident E3 ubiquitin ligase, was recruited and promoted K11-linked polyubiquitylation of α-ENaC and, hence, formation of an α-ENaC ubiquitin-mediated degradation complex. These findings suggest that derlin-1 promotes ENaC ubiquitylation and enhances ENaC ubiquitin- mediated proteasome degradation. The derlin-1 pathway therefore may represent a significant early checkpoint in the recognition and degradation of ENaC in mammalian cells.
authors.affiliation: Renal Division, Sir Run Run Hospital, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, 211166, China.|Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tong-Ji University, Shanghai, 200072, China.
authors.forename: Hui
authors.identifier: 0000-0002-6545-7787
authors.initials: H
authors.lastname: You
authors.affiliation: Renal Division, Sir Run Run Hospital, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, 211166, China.
authors.forename: Yamei
authors.identifier: 0000-0002-8739-8773
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Renal Division, Sir Run Run Hospital, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, 211166, China.
authors.forename: Jian
authors.identifier: 0000-0003-4779-0786
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Renal Division, Sir Run Run Hospital, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, 211166, China.
authors.forename: Yizhi
authors.identifier: 0000-0001-6469-5962
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Renal Division, Sir Run Run Hospital, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, 211166, China.
authors.forename: Jing
authors.identifier: 0000-0003-3397-0655
authors.initials: J
authors.lastname: Xing
authors.affiliation: Center of Pathology and Clinical Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, 211166, China.
authors.forename: Dongming
authors.initials: D
authors.lastname: Su
authors.affiliation: Renal Division, Sir Run Run Hospital, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, 211166, China.
authors.forename: Yujie
authors.identifier: 0000-0002-4430-0158
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Renal Division, Sir Run Run Hospital, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, 211166, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tong-Ji University, Shanghai, 200072, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Qu
authors.affiliation: Department of Physiology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: Renal Division, Sir Run Run Hospital, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, 211166, China liangxiubin@njmu.edu.cn.
authors.forename: Xiubin
authors.identifier: 0000-0001-9169-0390
authors.initials: X
authors.lastname: Liang
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D059748:Proteolysis; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C487709:DERL1 protein, human; D053503:Epithelial Sodium Channels; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; C530424:derlin-1 protein, mouse; D025821:Polyubiquitin; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D008239:Lysine
keywords: Derlin-1; Epithelial Na+ channel; Protein–protein interaction; Ubiquitin-mediated proteasome degradation; Ubiquitylation