RNF213 regulates palmitate signaling through AAA+ and RZ-finger domains, a process enhanced by gain-of-function moyamoya disease-associated mutations.

RNF213 was originally identified as a susceptibility gene for Moyamoya disease (MMD), and its variants are also associated with other vascular occlusive disorders, including pulmonary arterial hypertension and large-artery atherosclerosis. RNF213 encodes a large protein with AAA+ ATPase and E3 ubiquitin ligase activities and has been implicated in vasculopathy as well as cellular responses to microbial infection and lipid stress. However, the precise biological functions of RNF213 and the pathogenic mechanisms underlying disease-associated mutations remain poorly understood. Recent studies have suggested lipid-induced stress may play a key role in MMD pathogenesis. Therefore, we performed temporal transcriptomic analyses to identify RNF213-regulated signaling pathways in response to palmitate, the most common saturated fatty acid. Our results demonstrate that RNF213 is required for activation of apoptosis, the unfolded protein response, and NFκB signaling, as well as for the regulation of autophagy and oxidative stress responses following palmitate exposure. These functions were dependent on both the AAA+ ATPase and RZ-finger domains of RNF213 while MMD-associated RNF213 mutations enhanced palmitate-induced signaling responses. Together, these findings suggest that gain-of-function RNF213 mutations, combined with dysregulated lipid metabolism, contribute to the pathogenesis of RNF213-associated vasculopathies.