{"doi":"10.1101/2023.09.14.557714","title":"Sequentially activated death complexes regulate pyroptosis and IL-1β release in response to <i>Yersinia</i> blockade of immune signaling","abstract":"Abstract The Yersinia virulence factor YopJ potently inhibits immune signaling in macrophages by blocking activation of the signaling kinases TAK1 and IKK. In response, macrophages trigger a backup pathway of host defense that mediates cell death via the apoptotic enzyme caspase-8 and pyroptotic enzyme caspase-1. While caspase-1 is normally activated within multiprotein inflammasome complexes that contain the adaptor ASC and NLRs, which act as sensors of pathogen virulence, caspase-1 activation following Yersinia blockade of TAK1/IKK surprisingly requires caspase-8 and is independent of all known inflammasome components. Here, we report that caspase-1 activation by caspase-8 requires both caspase-8 catalytic and auto-processing activity. Intriguingly, while caspase-8 serves as an essential initiator of caspase-1 activation, caspase-1 amplifies its own activation through a feed-forward loop involving auto-processing, caspase-1-dependent cleavage of the pore-forming protein GSDMD, and subsequent activation of the canonical NLRP3 inflammasome. Notably, while caspase-1 activation and cell death are independent of inflammasomes during Yersinia infection, IL-1β release requires the canonical NLPR3 inflammasome. Critically, activation of caspase-8 and activation of the canonical inflammasome are kinetically and spatially separable events, as rapid capase-8 activation occurs within multiple foci throughout the cell, followed by delayed subsequent assembly of a single canonical inflammasome. Importantly, caspase-8 auto-processing normally serves to prevent RIPK3/MLKL-mediated necroptosis, and in caspase-8’s absence, MLKL triggers NLPR3 inflammasome activation and IL-1β release. Altogether, our findings reveal that functionally interconnected but temporally and spatially distinct death complexes differentially mediate pyroptosis and IL-1β release to ensure robust host defense against pathogen blockade of TAK1 and IKK. One Sentence Summary Yersinia -induced cell death and IL-1β release are driven by spatially and temporally distinct but functionally connected death complexes.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":397291,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"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":502641,"name":"Christina Go","orcid":"0000-0002-7716-8720","position":1,"is_corresponding":false},{"id":259710,"name":"Benedikt S. Saller","orcid":"0000-0003-0790-2720","position":2,"is_corresponding":false},{"id":65708,"name":"Olaf Groß","orcid":"0000-0001-8660-3619","position":3,"is_corresponding":false},{"id":58045,"name":"Phillip Scott","orcid":"0000-0001-8732-0653","position":4,"is_corresponding":false},{"id":239930,"name":"Igor E. Brodsky","orcid":"0000-0001-7970-872X","position":5,"is_corresponding":false},{"id":907961,"name":"Ronit Schwartz Wertman","orcid":"0000-0003-4297-3495","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T01:19:35.497854Z","pmid":"37745613","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":[]}