The RNF185/Membralin ubiquitin ligase complex is a new ERAD branch involved in the degradation of a distinct subset of integral membrane proteins.

The endoplasmic reticulum-associated degradation (ERAD) pathway is responsible for ubiquitin-mediated quality control of secretory and ER-resident proteins. In the present study, two short-lived ER integral membrane model proteins were used to screen a genome-wide CRISPR-Cas9 library, resulting in the identification of a new ERAD branch consisting of the RNF185/Membralin ubiquitin ligase complex. Biochemical and affinity pull-down studies followed by mass spectrometry revealed that the ubiquitin-like domain containing proteins TMUB-1 and -2 are also part of the core complex being specifically enriched by RNF185/Membralin but not by other known ERAD factors like HRD1. Genetic studies showed that the RNF185/Membralin complex control the degradation of endogenous integral membrane proteins, including TMUB2 itself and CYP51A1 from which the initial recombinant model protein was derived.