Succinate drives gut inflammation by promoting FoxP3 degradation through a molecular switch 2492

Abstract Description Succinate is elevated in patients with inflammatory bowel diseases (IBD), but its pathogenic role remains unknown. Herein, we show that succinate administration dramatically reduced FoxP3 but increased IL-17 expression, promoting colitis pathogenesis in mice. Succinate selectively impedes the expression of 2-oxoglutarate dehydrogenase complex (OGDHc), the enzyme for succinyl-CoA synthesis. Therefore, succinate inhibits succinyl-CoA production, which reduces FoxP3 succinylation, making the lysine residues available for ubiquitination-mediated FoxP3 degradation. Genetic OGDHc disruption in Tregs triggers severe gut inflammation, with reduced FoxP3 expression and impaired immune suppressive functions that can be fully mitigated by succinyl-CoA supplementation. Tregs from IBD patients show reduced FoxP3 and OGDHc expression, which negatively correlated the elevated succinate and inflammatory severity. During the IBD remission phase, blood and gut succinate levels decrease with restored FoxP3 expression. Our study reveals a novel succinate-mediated molecular switch from succinylation to ubiquitination of FoxP3, leading to impaired Treg suppressive functions during gut inflammation. Funding Sources R01DK120330, R01CA257520 Topic Categories Mucosal and Regional Immunology (MUC)