A20's linear ubiquitin-binding motif restrains pathogenic activation of Th17 cells and IL-22-driven enteritis.

ABSTRACT: A20, encoded by the TNFAIP3 gene, is a protein linked to Crohn's disease and celiac disease in humans. We now find that mice expressing point mutations in A20's M1-ubiquitin-binding zinc finger 7 (ZF7) motif spontaneously develop proximal enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveals expansion of Th17 cells and exuberant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7 mice. While deletion of IL-17A from A20ZF7/ZF7 mice exacerbates enteritis, deletion of IL-22 abrogates intestinal epithelial cell hyperproliferation, barrier dysfunction, and alarmin expression. Colonization of adult germ-free mice with microbiota from adult WT specific pathogen-free mice drives duodenal IL-22 expression and duodenitis. A20ZF7/ZF

SUBMITTER: Bowman CJ 

PROVIDER: S-EPMC12404748 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature