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Misfolded proteins in the endoplasmic reticulum (ER) are degraded by ER-associated degradation (ERAD). Although ERAD components involved in degradation of luminal substrates are well characterized, much less is known about quality control of membrane proteins. Here, we analyzed the degradation pathways of two short-lived ER membrane model proteins in mammalian cells. Using a CRISPR-Cas9 genome-wide library screen, we identified an ERAD branch required for quality control of a subset of membrane proteins. Using biochemical and mass spectrometry approaches, we showed that this ERAD branch is defined by an ER membrane complex consisting of the ubiquitin ligase RNF185, the ubiquitin-like domain containing proteins TMUB1/2 and TMEM259/Membralin, a poorly characterized protein. This complex cooperates with cytosolic ubiquitin ligase UBE3C and p97 ATPase in degrading their membrane substrates. Our data reveal that ERAD branches have remarkable specificity for their membrane substrates, suggesting that multiple, perhaps combinatorial, determinants are involved in substrate selection.

Original publication




Journal article


Mol Cell

Publication Date





768 - 781.e7


ER-associated degradation, ERAD, RNF185, TEB4/MARCH6, TMEM259, TMUB1/TMUB2, UBE3C, endoplasmic reticulum, membralin, protein quality control, CRISPR-Cas Systems, Cell Line, Cytochrome P-450 Enzyme System, Endoplasmic Reticulum, HEK293 Cells, HeLa Cells, Humans, Membrane Proteins, Mitochondrial Proteins, Nerve Tissue Proteins, Protein Domains, Protein Folding, Proteolysis, Saccharomyces cerevisiae Proteins, Sterol 14-Demethylase, Ubiquitin-Protein Ligases