Mysterin, also known as RNF213, is a unique ubiquitin ligase with a huge molecular size (591 kDa), dynein-like motor ATPase activity, and lipid-directed ubiquitylation activity. It plays a central role in cell-autonomous immunity by tagging various intracellular pathogens, including Salmonella, for clearance via autophagy and inflammatory pathways (Otten et al., Nature, 2021). We originally identified and cloned mysterin as the causative gene for moyamoya disease (MMD), a rare cerebrovascular disorder (#Liu, #Morito et al., PLOS ONE, 2011). Despite this genetic link, the mechanistic connection between mysterin’s physiological function in host defense and its role in MMD pathogenesis has remained unknown. We recently found that MMD-associated mysterin mutant aberrantly targets mitochondria, mistaking them for cell-invading pathogens. In the presentation, I will detail these findings and discuss the potential cause of MMD that has long been considered cryptogenic.