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A systematic search for endoplasmic reticulum (ER) membrane-associated RING finger proteins identifies Nixin/ZNRF4 as a regulator of calnexin stability and ER homeostasis
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
A systematic search for endoplasmic reticulum (ER) membrane-associated RING finger proteins identifies Nixin/ZNRF4 as a regulator of calnexin stability and ER homeostasis
Journal
Journal of biological chemistry
Volume
286
Number
10
Pages / Article-Number
8633-43
Keywords
Calnexin/genetics/*metabolism; DNA-Binding Proteins/genetics/*metabolism; Down-Regulation/*physiology; Endoplasmic Reticulum/genetics/*metabolism; Glycosylation; HeLa Cells; Humans; Protein Stability
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.
