Oda Yukako, Okada Tetsuya, Yoshida Hiderou, Kaufman Randal J, Nagata Kazuhiro, Mori Kazutoshi
Department of Molecular and Cellular Biology Institute for Frontier Medical Sciences, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
J Cell Biol. 2006 Jan 30;172(3):383-93. doi: 10.1083/jcb.200507057.
Proteins that are unfolded or misfolded in the endoplasmic reticulum (ER) must be refolded or degraded to maintain the homeostasis of the ER. Components of both productive folding and ER-associated degradation (ERAD) mechanisms are known to be up-regulated by the unfolded protein response (UPR). We describe two novel components of mammalian ERAD, Derlin-2 and -3, which show weak homology to Der1p, a transmembrane protein involved in yeast ERAD. Both Derlin-2 and -3 are up-regulated by the UPR, and at least Derlin-2 is a target of the IRE1 branch of the response, which is known to up-regulate ER degradation enhancing alpha-mannosidase-like protein (EDEM) and EDEM2, receptor-like molecules for misfolded glycoprotein. Overexpression of Derlin-2 or -3 accelerated degradation of misfolded glycoprotein, whereas their knockdown blocked degradation. Derlin-2 and -3 are associated with EDEM and p97, a cytosolic ATPase responsible for extraction of ERAD substrates. These findings indicate that Derlin-2 and -3 provide the missing link between EDEM and p97 in the process of degrading misfolded glycoproteins.
在内质网（ER）中发生错误折叠或未折叠的蛋白质必须重新折叠或降解，以维持内质网的稳态。已知有效的折叠机制和内质网相关降解（ERAD）机制的组成部分都会因未折叠蛋白反应（UPR）而上调。我们描述了哺乳动物ERAD的两个新组分，Derlin-2和Derlin-3，它们与参与酵母ERAD的跨膜蛋白Der1p具有微弱的同源性。Derlin-2和Derlin-3均受UPR上调，并且至少Derlin-2是该反应中IRE1分支的靶点，已知该分支会上调内质网降解增强α-甘露糖苷酶样蛋白（EDEM）和EDEM2，即错误折叠糖蛋白的受体样分子。Derlin-2或Derlin-3的过表达加速了错误折叠糖蛋白的降解，而它们的敲低则阻断了降解。Derlin-2和Derlin-3与EDEM以及p97相关，p97是一种负责提取ERAD底物的胞质ATP酶。这些发现表明，Derlin-2和Derlin-3在错误折叠糖蛋白的降解过程中提供了EDEM和p97之间缺失的联系。
