The HERCulean task of recognizing, ubiquitinating, and shielding misfolded integral membrane proteins

Abstract

During ER-associated decay, unfolded membrane-resident proteins are targeted for removal and degradation by ubiquitin ligases whose identities and precise operations remain unclear. In this issue, Guerriero and Brodsky discuss new results from Kamada et al. (https://doi.org/10.1083/jcb.202308003) showing the clearance of misfolded CFTR by the E3 ligase HERC3.

Figure 1.

HERC3 joins the cast of E3s that coordinate CFTR degradation. (A) CFTR is depicted with transmembrane domains in blue, NBD1 (N1) in yellow, the regulatory domain (R) in red, and NBD2 (N2) in green. Also shown are two ER-resident E3 ubiquitin ligases, RNF185 (orange) and RNF5 (brown), which might recognize MSDs. (B) CHIP (blue oval) ubiquitinates NBD1 and potentially shorter cytosol resident loops after recognition by molecular chaperones (not shown). (C) HERC3 (red star) plays several roles in F508del-CFTR turnover, including ubiquitination and potentially binding to exposed MSDs to promote retrotranslocation and/or help maintain solubility. Created with https://BioRender.com.