{"doi":"10.1126/sciimmunol.adg3196","title":"Alternative splicing of <i>GSDMB</i> modulates killer lymphocyte–triggered pyroptosis","abstract":"Granzyme A from killer lymphocytes cleaves gasdermin B (GSDMB) and triggers pyroptosis in targeted human tumor cells, eliciting antitumor immunity. However, GSDMB has a controversial role in pyroptosis and has been linked to both anti- and protumor functions. Here, we found that GSDMB splicing variants are functionally distinct. Cleaved N-terminal (NT) fragments of GSDMB isoforms 3 and 4 caused pyroptosis, but isoforms 1, 2, and 5 did not. The nonfunctional isoforms have a deleted or modified exon 6 and therefore lack a stable belt motif. The belt likely contributes to the insertion of oligomeric GSDMB-NTs into the membrane. Consistently, noncytotoxic GSDMB-NTs blocked pyroptosis caused by cytotoxic GSDMB-NTs in a dominant-negative manner. Upon natural killer (NK) cell attack, GSDMB3-expressing cells died by pyroptosis, whereas GSDMB4-expressing cells died by mixed pyroptosis and apoptosis, and GSDMB1/2-expressing cells died only by apoptosis. GSDMB4 partially resisted NK cell-triggered cleavage, suggesting that only GSDMB3 is fully functional. GSDMB1-3 were the most abundant isoforms in the tested tumor cell lines and were similarly induced by interferon-γ and the chemotherapy drug methotrexate. Expression of cytotoxic GSDMB3/4 isoforms, but not GSDMB1/2 isoforms that are frequently up-regulated in tumors, was associated with better outcomes in bladder and cervical cancers, suggesting that GSDMB3/4-mediated pyroptosis was protective in those tumors. Our study indicates that tumors may block and evade killer cell-triggered pyroptosis by generating noncytotoxic GSDMB isoforms. Therefore, therapeutics that favor the production of cytotoxic GSDMB isoforms by alternative splicing may improve antitumor immunity.","journal":"Science Immunology","year":2023,"id":316888,"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":89,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":461280,"name":"Shiyu Xia","orcid":"0000-0001-9024-0689","position":1,"is_corresponding":false},{"id":875109,"name":"Xingxin Pan","orcid":"0000-0002-4429-4878","position":2,"is_corresponding":false},{"id":361139,"name":"Kaixiong Ye","orcid":"0000-0003-4658-7292","position":3,"is_corresponding":false},{"id":379741,"name":"Zhouyihan Li","orcid":null,"position":4,"is_corresponding":false},{"id":274884,"name":"Jiexi Li","orcid":"0000-0002-6786-0705","position":5,"is_corresponding":false},{"id":1021356,"name":"Xiaoqiang Tang","orcid":"0000-0002-3434-267X","position":6,"is_corresponding":false},{"id":56377,"name":"Nidhi Sahni","orcid":"0000-0002-9155-5882","position":7,"is_corresponding":false},{"id":56383,"name":"S. Stephen Yi","orcid":"0000-0003-0047-8103","position":8,"is_corresponding":false},{"id":277212,"name":"Xing Liu","orcid":"0000-0002-6277-3856","position":9,"is_corresponding":false},{"id":228831,"name":"Hao Wu","orcid":"0000-0002-7281-8579","position":10,"is_corresponding":false},{"id":73903,"name":"Michael B. Elowitz","orcid":"0000-0002-1221-0967","position":11,"is_corresponding":false},{"id":253642,"name":"Judy Lieberman","orcid":"0000-0002-6200-4715","position":12,"is_corresponding":false},{"id":517633,"name":"Zhibin Zhang","orcid":"0000-0003-1349-2713","position":13,"is_corresponding":false},{"id":602056,"name":"Qing Kong","orcid":"0000-0002-3902-243X","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T01:06:44.698773Z","pmid":"37115914","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":[]}