RNF185 is an E3 ubiquitin ligase that plays critical roles in multiple cellular processes through its ubiquitination activity. The protein functions as a key component of the endoplasmic reticulum-associated degradation (ERAD) pathway, where it forms a complex with Membralin and other proteins to degrade misfolded membrane proteins 1. RNF185 specifically recognizes and ubiquitinates ER membrane substrates, including CFTR and Tapasin, with the latter regulating MHC-I surface expression and antigen presentation 2. Beyond ERAD, RNF185 catalyzes K27-linked polyubiquitination of various substrates, including TUFM during viral-induced mitophagy 3 and BAK1 to maintain mitochondrial integrity 4. The protein also regulates innate immune responses by modulating the cGAS-STING pathway through substrate ubiquitination 5. Mechanistically, RNF185 preferentially associates with E2 enzymes UBE2J1 and UBE2J2 and recognizes exposed membrane-spanning domains of substrates. Clinically, RNF185 expression correlates with cancer progression, showing both tumor-suppressive roles in prostate cancer through COL3A1 regulation 6 and oncogenic functions in esophageal squamous cell carcinoma by preventing apoptosis 4, suggesting context-dependent therapeutic implications.