ERdj5 is required as a disulfide reductase for degradation of misfolded proteins in the ER

Membrane and secretory proteins cotranslationally enter and are folded in the endoplasmic reticulum ( ER). Misfolded or unassembled proteins are discarded by a process known as ER- associated degradation ( ERAD), which involves their retrotranslocation into the cytosol. ERAD substrates frequently contain disulfide bonds that must be cleaved before their retrotranslocation. Here, we found that an ER- resident protein ERdj5 had a reductase activity, cleaved the disulfide bonds of misfolded proteins, and accelerated ERAD through its physical and functional associations with EDEM ( ER degradation- enhancing alpha-mannosidase-like protein) and an ER- resident chaperone BiP. Thus, ERdj5 is a member of a supramolecular ERAD complex that recognizes and unfolds misfolded proteins for their efficient retrotranslocation.