RNF213 encodes a large 591-kDa cytosolic protein that functions as an atypical E3 ubiquitin ligase with dual roles in cell-autonomous immunity and vascular development 1. The protein contains both Walker motif ATPase activity and RING finger ubiquitin ligase domains, along with an RZ-type zinc finger that enables unique lipid ubiquitination 12. RNF213 acts as a key immune sensor by catalyzing ubiquitination of bacterial lipopolysaccharide (LPS), specifically targeting the lipid A moiety to generate ubiquitin coats on cytosolic bacteria like Salmonella 2. This ubiquitination triggers antibacterial autophagy and restricts bacterial proliferation through both direct LPS ubiquitination and indirect recruitment of the LUBAC complex 2. In vascular biology, RNF213 regulates angiogenesis through the Hippo pathway, where loss-of-function mutations lead to pathological vessel formation by activating YAP/TAZ signaling and promoting VEGFR2 overexpression 3. RNF213 is the major susceptibility gene for Moyamoya disease, particularly the R4810K variant in East Asian populations, though with low penetrance suggesting additional environmental factors are required 41. Recent evidence indicates Moyamoya disease may represent an immune-related angiopathy, with RNF213's antimicrobial functions potentially contributing to disease pathogenesis when combined with infectious or autoimmune triggers 5.