系统搜索内质网（ER）膜相关的环指蛋白，鉴定出 Nixin/ZNRF4 是钙连蛋白稳定性和 ER 动态平衡的调节剂。
A systematic search for endoplasmic reticulum (ER) membrane-associated RING finger proteins identifies Nixin/ZNRF4 as a regulator of calnexin stability and ER homeostasis.
机构信息
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,.
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.
出版信息
J Biol Chem. 2011 Mar 11;286(10):8633-8643. doi: 10.1074/jbc.M110.197459. Epub 2011 Jan 4.
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.
摘要
为了鉴定内质网（ER）相关蛋白降解和 ER 功能的新调节因子，我们确定了定位于 ER 的所有跨膜环指 E3 泛素连接酶。我们鉴定了 24 个 ER 膜锚定的泛素连接酶，并发现 Nixin/ZNRF4 是调节 calnexin 周转的核心。野生型 Nixin 的异位表达会导致 ER 定位的伴侣 calnexin 的急剧下调，而 Nixin RING 结构域的失活则可以防止这种下调。重要的是，Nixin 以一种不依赖于糖基化的方式与 calnexin 发生物理相互作用，诱导 calnexin 的泛素化和 p97 依赖性降解，表明 calnexin 周转存在 ER 相关降解样机制。
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