{"doi":"10.1016/j.jbc.2021.101379","title":"Caspase-6 promotes activation of the caspase-11-NLRP3 inflammasome during gram-negative bacterial infections","abstract":"The innate immune system acts as the first line of defense against infection. One key component of the innate immune response to gram-negative bacterial infections is inflammasome activation. The caspase-11 (CASP11)-nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is activated by cytosolic lipopolysaccharide, a gram-negative bacterial cell wall component, to trigger pyroptosis and host defense during infection. Although several cellular signaling pathways have been shown to regulate CASP11-NLRP3 inflammasome activation in response to lipopolysaccharide, the upstream molecules regulating CASP11 activation during infection with live pathogens remain unclear. Here, we report that the understudied caspase-6 (CASP6) contributes to the activation of the CASP11-NLRP3 inflammasome in response to infections with gram-negative bacteria. Using in vitro cellular systems with bone marrow-derived macrophages and 293T cells, we found that CASP6 can directly process CASP11 by cleaving at Asp59 and Asp285, the CASP11 auto-cleavage sites, which could contribute to the activation of CASP11 during gram-negative bacterial infection. Thus, the loss of CASP6 led to impaired CASP11-NLRP3 inflammasome activation in response to gram-negative bacteria. These results demonstrate that CASP6 potentiates activation of the CASP11-NLRP3 inflammasome to produce inflammatory cytokines during gram-negative bacterial infections.","journal":"Journal of Biological Chemistry","year":2021,"id":174905,"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":0.95,"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":105431,"name":"Rajendra Karki","orcid":"0000-0003-4436-9128","position":1,"is_corresponding":false},{"id":244989,"name":"Balabhaskararao Kancharana","orcid":"0000-0002-1362-4942","position":2,"is_corresponding":false},{"id":715065,"name":"Hartmut Berns","orcid":"0000-0002-0882-3541","position":3,"is_corresponding":false},{"id":250571,"name":"Shondra M. Pruett‐Miller","orcid":"0000-0002-3793-585X","position":4,"is_corresponding":false},{"id":105446,"name":"Thirumala‐Devi Kanneganti","orcid":"0000-0002-6395-6443","position":5,"is_corresponding":false},{"id":105437,"name":"Min Zheng","orcid":"0009-0003-9811-4937","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":null,"created_at":"2026-07-18T23:47:11.249697Z","pmid":"34740613","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":[]}