{"doi":"10.1101/2021.01.06.425634","title":"Activation of GSDME compensates for GSDMD deficiency in a mouse model of NLRP3 inflammasomopathy","abstract":"Abstract The D301N NLRP3 mutation in mice (D303N in humans) causes severe multi-organ damage and early death driven by the constitutively activated NLRP3 (NLRP3 ca ) inflammasome. Triggered inflammasomes activate caspase-1 to process IL-1 family cytokines and gasdermin D (GSDMD), generating N-terminal fragments, which oligomerize within the plasma membrane to form pores, which cause inflammatory cell death (pyroptosis) and through which IL-1β and IL-18 are secreted. GSDMD activation is central to disease symptoms since spontaneous inflammation in Nlrp3 ca ; Gsdmd -/- mice is negligible. Unexpectedly, when Nlrp3 ca ; Gsdmd -/- mice were challenged with LPS or TNF-α, they secreted high amounts of IL-1β and IL-18, suggesting an alternative GSDMD-independent inflammatory pathway. Here we show that GSDMD deficient macrophages subjected to inflammatory stimuli activate caspase-8, -3 and GSDME-dependent cytokine release and pyroptosis. Caspase-8, -3 and GSDME also activated pyroptosis when NLRP3 was stimulated in caspase-1 deficient macrophages. Thus, a salvage caspase-8, -3-GSDME inflammatory pathway is activated following NLRP3 activation when the canonical NLRP3-caspase-1-GSDMD is blocked. Surprisingly, the active metabolite of the GSDMD-inhibitor disulfiram, inhibited not only GSDMD but also GSDME-mediated inflammation in vitro and suppressed severe inflammatory disease symptoms in Nlrp3 ca mice, a model for severe neonatal multisystem inflammatory disease. Although disulfiram did not directly inhibit GSDME, it suppressed inflammasome activation in GSDMD-deficient cells. Thus, the combination of inflammatory signals and NLRP3 ca overwhelmed the protection provided by GSDMD deficiency, rewiring signaling cascades through caspase-8, -3 and GSDME to propagate inflammation. This functional redundancy suggests that concomitant inhibition of GSDMD and GSDME may be necessary to suppress disease in inflammasomopathy patients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":213369,"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":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":311713,"name":"Tong Yang","orcid":"0000-0001-5304-9308","position":1,"is_corresponding":false},{"id":311709,"name":"Jianqiu Xiao","orcid":"0000-0002-8896-9187","position":2,"is_corresponding":false},{"id":805299,"name":"Canxin Xu","orcid":"0000-0002-5153-2424","position":3,"is_corresponding":false},{"id":311712,"name":"Yael Alippe","orcid":"0000-0003-2760-7155","position":4,"is_corresponding":false},{"id":311714,"name":"Kai Sun","orcid":"0000-0001-9619-9007","position":5,"is_corresponding":false},{"id":105446,"name":"Thirumala‐Devi Kanneganti","orcid":"0000-0002-6395-6443","position":6,"is_corresponding":false},{"id":311716,"name":"Joseph B. Monahan","orcid":"0000-0002-5433-4001","position":7,"is_corresponding":false},{"id":230168,"name":"Yousef Abu‐Amer","orcid":"0000-0002-5890-5086","position":8,"is_corresponding":false},{"id":253642,"name":"Judy Lieberman","orcid":"0000-0002-6200-4715","position":9,"is_corresponding":false},{"id":230166,"name":"Gabriel Mbalaviele","orcid":"0000-0003-4660-0952","position":10,"is_corresponding":false},{"id":311710,"name":"Chun Wang","orcid":"0000-0002-8167-0043","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-18T23:52:36.886828Z","pmid":null,"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":[]}