Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation

TLDR

Unfolded or misfolded proteins in the ER must be refolded or degraded to maintain ER homeostasis, and the unfolded protein response upregulates both folding and ER‑associated degradation components. This study identifies Derlin‑2 and Derlin‑3 as novel mammalian ERAD components homologous to yeast Der1p. Derlin‑2 and Derlin‑3 associate with the ERAD factors EDEM and the cytosolic ATPase p97, linking substrate recognition to extraction. They are induced by the UPR (Derlin‑2 via IRE1), and overexpression accelerates, while knockdown blocks, misfolded glycoprotein degradation, establishing them as the missing link between EDEM and p97.

Abstract

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.