Year: 2026
Type: preprint
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.
Institutions: Harvard University, Howard Hughes Medical Institute
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214231259