{"doi":"10.1172/jci138103","title":"Epithelial-derived gasdermin D mediates nonlytic IL-1β release during experimental colitis","abstract":"Gasdermin D (GSDMD) induces pyroptosis via the pore-forming activity of its N-terminal domain, cleaved by activated caspases associated with the release of IL-1β. Here, we report a nonpyroptotic role of full-length GSDMD in guiding the release of IL-1β-containing small extracellular vesicles (sEVs) from intestinal epithelial cells (IECs). In response to caspase-8 inflammasome activation, GSDMD, chaperoned by Cdc37/Hsp90, recruits the E3 ligase, NEDD4, to catalyze polyubiquitination of pro-IL-1β, serving as a signal for cargo loading into secretory vesicles. GSDMD and IL-1β colocalize with the exosome markers CD63 and ALIX intracellularly, and GSDMD and NEDD4 are required for release of CD63+ sEVs containing IL-1β, GSDMD, NEDD4, and caspase-8. Importantly, increased expression of epithelial-derived GSDMD is observed both in patients with inflammatory bowel disease (IBD) and those with experimental colitis. While GSDMD-dependent release of IL-1β-containing sEVs is detected in cultured colonic explants from colitic mice, GSDMD deficiency substantially attenuates disease severity, implicating GSDMD-mediated release of IL-1β sEVs in the pathogenesis of intestinal inflammation, such as that observed in IBD.","journal":"Journal of Clinical Investigation","year":2020,"id":51381,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":158,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":256156,"name":"Junjie Zhao","orcid":"0000-0002-4285-9986","position":1,"is_corresponding":false},{"id":240319,"name":"Yun Liao","orcid":"0000-0002-0829-8986","position":2,"is_corresponding":false},{"id":256157,"name":"Nitish Rana","orcid":"0000-0002-6412-5983","position":3,"is_corresponding":false},{"id":256158,"name":"Daniele Corridoni","orcid":"0000-0003-0251-2248","position":4,"is_corresponding":false},{"id":256159,"name":"Agne Antanaviciute","orcid":"0000-0002-9019-2215","position":5,"is_corresponding":false},{"id":27363,"name":"Xing Chen","orcid":"0000-0001-9727-3598","position":6,"is_corresponding":false},{"id":256160,"name":"Han Wang","orcid":"0000-0002-1442-4539","position":7,"is_corresponding":false},{"id":256161,"name":"Qian Wen","orcid":"0000-0001-5935-6237","position":8,"is_corresponding":false},{"id":257298,"name":"William A. Miller-Little","orcid":null,"position":9,"is_corresponding":false},{"id":256162,"name":"Shadi Swaidani","orcid":"0000-0003-1506-4472","position":10,"is_corresponding":false},{"id":243565,"name":"Fangqiang Tang","orcid":null,"position":11,"is_corresponding":false},{"id":256163,"name":"Belinda Willard","orcid":"0000-0001-6884-6369","position":12,"is_corresponding":false},{"id":256164,"name":"Keith R. McCrae","orcid":"0000-0001-7340-475X","position":13,"is_corresponding":false},{"id":256165,"name":"Zizhen Kang","orcid":"0000-0002-0809-2638","position":14,"is_corresponding":false},{"id":256166,"name":"George Dubyak","orcid":"0000-0001-9720-4226","position":15,"is_corresponding":false},{"id":256167,"name":"Fabio Cominelli","orcid":"0000-0002-1571-1548","position":16,"is_corresponding":false},{"id":60565,"name":"Alison Simmons","orcid":"0000-0003-3454-0710","position":17,"is_corresponding":false},{"id":240325,"name":"Theresa T. Pizarro","orcid":"0000-0003-3163-915X","position":18,"is_corresponding":false},{"id":240331,"name":"Xiaoxia Li","orcid":"0000-0002-4872-9525","position":19,"is_corresponding":false},{"id":240321,"name":"Katarzyna Bulek","orcid":"0000-0001-8064-7047","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-18T20:40:28.278215Z","pmid":"32597834","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":[]}