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bioRxiv · 10.64898/2026.09.23.753758

RNF185 destabilizes specific membrane proteins that span all ERAD branches

Chino, H.·Ruiz, I. M.·Corbo, J. H.·Paulo, J. A.·Shao, S.
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Abstract

The endoplasmic reticulum (ER) is the primary site of eukaryotic membrane protein synthesis and quality control, which largely relies on ER-associated degradation (ERAD) to eliminate aberrant nascent proteins. In yeast, two ubiquitin ligases target proteins for ERAD based on aberrancies in substrate transmembrane (ERAD-M), lumenal (ERAD-L), or cytosolic (ERAD-C) domains. How an expanded repertoire of mammalian ERAD factors selects substrates across these classifications is unclear. Here, we show that the human ER-resident RNF185 ubiquitin ligase complex destabilizes a small but specific set of membrane proteins that span all three ERAD branches. Comparisons of three single-pass membrane proteins destabilized by RNF185 identify ERAD-M features in misoriented CHST10, ERAD-C features in unassembled SRPRB, and N-linked glycosylation-dependent ERAD-L features in ATP1B2. Our findings identify RNF185-destabilized membrane proteins with distinct aberrancies that collectively encompass all canonical ERAD substrate classifications and unexpectedly diverse quality control defects.

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Chino, H., Ruiz, I. M., Corbo, J. H., Paulo, J. A., Shao, S.. 2026-09-24. RNF185 destabilizes specific membrane proteins that span all ERAD branches. https://doi.org/10.64898/2026.09.23.753758

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