{"doi":"10.1172/jci187499","title":"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/ZF7 Th17 cells autonomously express more RORγt and IL-22 after differentiation in vitro. ATAC sequencing identified an enhancer region upstream of the Il22 gene, and this enhancer demonstrated increased activating histone acetylation coupled with exaggerated Il22 transcription in A20ZF7/ZF7 T cells. Acute inhibition of RORγt normalized histone acetylation at this enhancer. Finally, CRISPR/Cas9-mediated ablation of A20ZF7 in human T cells increases RORγt expression and IL22 transcription. These studies link A20's M1-ubiquitin binding function with RORγt expression, expansion of Th17 cells, and epigenetic activation of IL-22-driven enteritis.","journal":"Journal of Clinical Investigation","year":2025,"id":526734,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9439,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1400354,"name":"Dorothea Stibor","orcid":"0000-0003-2019-5856","position":1,"is_corresponding":false},{"id":769067,"name":"Xiaofei Sun","orcid":"0000-0002-4835-9309","position":2,"is_corresponding":false},{"id":1400788,"name":"Nika Lenci","orcid":null,"position":3,"is_corresponding":false},{"id":1402843,"name":"Hiromichi Shimizu","orcid":"0000-0003-3268-0613","position":4,"is_corresponding":false},{"id":1403373,"name":"Emily F. Yamashita","orcid":null,"position":5,"is_corresponding":false},{"id":769753,"name":"Rommel Advincula","orcid":null,"position":6,"is_corresponding":false},{"id":986272,"name":"Min Cheol Kim","orcid":"0000-0002-2234-8070","position":7,"is_corresponding":false},{"id":623133,"name":"Jessie A. Turnbaugh","orcid":"0000-0003-3933-1985","position":8,"is_corresponding":false},{"id":2816,"name":"Yang Sun","orcid":"0000-0002-9344-8060","position":9,"is_corresponding":false},{"id":832018,"name":"Bahram Razani","orcid":"0000-0003-4069-8178","position":10,"is_corresponding":false},{"id":36356,"name":"Peter J. Turnbaugh","orcid":"0000-0002-0888-2875","position":11,"is_corresponding":false},{"id":2802,"name":"Chun Jimmie Ye","orcid":"0000-0001-6560-3783","position":12,"is_corresponding":false},{"id":832019,"name":"Barbara A. Malynn","orcid":"0000-0001-6986-1261","position":13,"is_corresponding":false},{"id":511664,"name":"Averil Ma","orcid":"0000-0003-4817-1258","position":14,"is_corresponding":false},{"id":1400355,"name":"Christopher Bowman","orcid":"0000-0002-4107-4116","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:50:34.851930Z","pmid":"40892518","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}