EDEM As an Acceptor of Terminally Misfolded Glycoproteins Released from Calnexin

TLDR

Terminally misfolded proteins in the ER are retrotranslocated to the cytoplasm and degraded by proteasomes via ER‑associated degradation, a process accelerated by the Man8B‑binding protein EDEM. Both binding of substrates to calnexin and their release from calnexin are required for ERAD to occur. EDEM interacts with calnexin through its transmembrane region and, when overexpressed, accelerates ERAD by promoting release of terminally misfolded proteins, thereby acting as an acceptor of substrates from calnexin.

Abstract

Terminally misfolded proteins in the endoplasmic reticulum (ER) are retrotranslocated to the cytoplasm and degraded by proteasomes through a mechanism known as ER-associated degradation (ERAD). EDEM, a postulated Man8B-binding protein, accelerates the degradation of misfolded proteins in the ER. Here, EDEM was shown to interact with calnexin, but not with calreticulin, through its transmembrane region. Both binding of substrates to calnexin and their release from calnexin were required for ERAD to occur. Overexpression of EDEM accelerated ERAD by promoting the release of terminally misfolded proteins from calnexin. Thus, EDEM appeared to function in the ERAD pathway by accepting substrates from calnexin.