Misfolded proteins are extracted from the endoplasmic reticulum (ER) and eliminated through ER-associated degradation (ERAD), in which the E3 ubiquitin ligase gp78 and the p97/VCP ATPase play central roles. The chaperone Bag6 helps maintain substrate solubility and may hand over substrates from p97 to the proteasome. Ye and colleagues find that the de-ubiquitylase USP13 cooperates with gp78 in ERAD by maintaining a functional Bag6 complex (eLife 3, e01369; 2014).

Several de-ubiquitylation enzymes interact with p97 but their role in ERAD remains unclear. In a screen for p97-interacting proteins that increase the p97–USP13 interaction, the authors find gp78 and demonstrate that it directly interacts with USP13. Depletion of USP13 prevents ERAD of a model substrate, and further analyses indicate that USP13 acts at a step downstream of retrotranslocation. Specifically, the authors find that USP13 also interacts with the Bag6 complex and prevents accumulation of ubiquitylated Ubl4A, a Bag6 cofactor. Hyper-ubiquitylation of Ubl14 is associated with cleavage of a fraction of the Bag6 pool and with inhibition of ERAD. Lys48 is identified as the residue in Ubl4A targeted by ubiquitylation (which is mediated by gp78 and other ligases). The authors had shown previously that Ubl4A promotes the interaction of Bag6 with the co-chaperone SGTA, and they now discover that USP13 knockdown reduces this interaction. They suggest that USP13 is required to antagonize promiscuous gp78-mediated ubiquitylation of Ubl4A, to prevent Bag6 cleavage and promote the interaction between Bag6 and SGTA.