RNF185 destabilizes specific membrane proteins that span all ERAD branches
- 1Harvard Medical School
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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BibTeX
@misc{chino2026rnf185,
title = {{RNF185 destabilizes specific membrane proteins that span all ERAD branches}},
author = {H. Chino and I. M. Ruiz and J. H. Corbo and J. A. Paulo and S. Shao},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.753758},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.753758v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - RNF185 destabilizes specific membrane proteins that span all ERAD branches
AU - H. Chino
AU - I. M. Ruiz
AU - J. H. Corbo
AU - J. A. Paulo
AU - S. Shao
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.753758
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.753758v1
AB - 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.
ER -