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 α-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.
Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation
Y. Oda and T. Okada contributed equally to this paper.
Abbreviations used in this paper: α1-PI, α1-proteinase inhibitor; BiP, binding protein; DIG, digoxigenin; EDEM, ER degradation enhancing α-mannosidase–like protein; ERAD, ER-associated degradation; GAPDH, glyceraldehyde- 3-phosphate dehydrogenase; HC, heavy chain; HEK, human embryonic kidney; MEF, mouse embryonic fibroblast; NHK, null Hong Kong; shRNA, short hairpin RNA; tv, transcriptional variant; UPR, unfolded protein response; VCP, vasolin-containing protein.
Yukako Oda, Tetsuya Okada, Hiderou Yoshida, Randal J. Kaufman, Kazuhiro Nagata, Kazutoshi Mori; Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation . J Cell Biol 30 January 2006; 172 (3): 383–393. doi: https://doi.org/10.1083/jcb.200507057
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