title: A systematic search for endoplasmic reticulum (ER) membrane-associated RING finger proteins identifies Nixin/ZNRF4 as a regulator of calnexin stability and ER homeostasis.
abstract: To identify novel regulators of endoplasmic reticulum (ER)-linked protein degradation and ER function, we determined the entire inventory of membrane-spanning RING finger E3 ubiquitin ligases localized to the ER. We identified 24 ER membrane-anchored ubiquitin ligases and found Nixin/ZNRF4 to be central for the regulation of calnexin turnover. Ectopic expression of wild type Nixin induced a dramatic down-regulation of the ER-localized chaperone calnexin that was prevented by inactivation of the Nixin RING domain. Importantly, Nixin physically interacts with calnexin in a glycosylation-independent manner, induces calnexin ubiquitination, and p97-dependent degradation, indicating an ER-associated degradation-like mechanism of calnexin turnover.
authors.affiliation: From the Biochemistry Section, Surgical Neurological Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892,; the Department of Biomedicine, and the University Eye Clinic, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland,. Electronic address: albert.neutzner@unibas.ch.
authors.forename: Albert
authors.initials: A
authors.lastname: Neutzner
authors.affiliation: the Department of Biomedicine, and the University Eye Clinic, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland,; the Department of Neuropathology, Institute of Pathology, University of Basel, Schönbeinstrasse 40, 4031 Basel, Switzerland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Neutzner
authors.affiliation: the Department of Biomedicine, and the University Eye Clinic, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Benischke
authors.affiliation: From the Biochemistry Section, Surgical Neurological Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892,; the Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea, and.
authors.forename: Seung-Wook
authors.initials: SW
authors.lastname: Ryu
authors.affiliation: the Department of Neuropathology, Institute of Pathology, University of Basel, Schönbeinstrasse 40, 4031 Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.affiliation: From the Biochemistry Section, Surgical Neurological Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
authors.affiliation: From the Biochemistry Section, Surgical Neurological Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892,; the Center for Biomedical Engineering and Technology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201. Electronic address: mkarbowski@umaryland.edu.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Karbowski
mesh_terms: D037281:Calnexin / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D006367:HeLa Cells; D006801:Humans; D055550:Protein Stability
chemical_list: D004268:DNA-Binding Proteins; C558097:ZNRF4 protein, human; D037281:Calnexin