2. Academic Validation
  3. A systematic search for endoplasmic reticulum (ER) membrane-associated RING finger proteins identifies Nixin/ZNRF4 as a regulator of calnexin stability and ER homeostasis

A systematic search for endoplasmic reticulum (ER) membrane-associated RING finger proteins identifies Nixin/ZNRF4 as a regulator of calnexin stability and ER homeostasis

  • J Biol Chem. 2011 Mar 11;286(10):8633-8643. doi: 10.1074/jbc.M110.197459.
Albert Neutzner 1,  Melanie Neutzner 2,  Anne-Sophie Benischke 3,  Seung-Wook Ryu 4,  Stephan Frank 5,  Richard J Youle 6,  Mariusz Karbowski 7
Affiliations

Affiliations

  • 1 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: [email protected].
  • 2 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.
  • 3 the Department of Biomedicine, and the University Eye Clinic, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
  • 4 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.
  • 5 the Department of Neuropathology, Institute of Pathology, University of Basel, Schönbeinstrasse 40, 4031 Basel, Switzerland.
  • 6 From the Biochemistry Section, Surgical Neurological Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892.
  • 7 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: [email protected].
PMID: 21205830 DOI: 10.1074/jbc.M110.197459
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.

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