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.