{"doi":"10.1101/2020.08.14.246132","title":"DPP9 directly sequesters the NLRP1 C-terminus to repress inflammasome activation","abstract":"Abstract NLRP1 is a cytosolic inflammasome sensor that mediates activation of caspase-1, which in turn induces cytokine maturation and pyroptotic cell death 1-6 . Gain-of-function NLPR1 mutations cause skin inflammatory diseases including carcinoma, keratosis, and papillomatosis 7-14 . NLRP1 contains a unique function-to-find domain (FIIND) that autoproteolyzes into noncovalently associated subdomains 15-18 . Proteasomal degradation of the autoinhibitory N-terminal fragment (NT) activates NLRP1 by releasing the inflammatory C-terminal fragment (CT) 19,20 . Cytosolic dipeptidyl peptidases 8 and 9 (DPP8/9) interact with NLRP1, and small-molecule DPP8/9 inhibitors activate NLRP1 by poorly characterized mechanisms 11,19,21 . Here, we report cryo-EM structures of the human NLRP1-DPP9 complex, alone and in complex with the DPP8/9 inhibitor Val-boroPro (VbP). Surprisingly, the NLRP1-DPP9 complex is a ternary complex comprised of DPP9, one intact FIIND of a non-degraded full-length NLRP1 (NLRP1-FL) and one NLRP1-CT freed by NT degradation. The N-terminus of the NLRP1-CT unfolds and inserts into the DPP9 active site but is not cleaved by DPP9, and this binding is disrupted by VbP. Structure-based mutagenesis reveals that the binding of NLRP1-CT to DPP9 requires NLRP1-FL and vice versa, and inflammasome activation by ectopic NLRP1-CT expression is rescued by co-expressing autoproteolysis-deficient NLRP1-FL. Collectively, these data indicate that DPP9 functions as a “bomb-diffuser” to prevent NLRP1-CTs from inducing inflammation during homeostatic protein turnover.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":121703,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"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":230564,"name":"Humayun Sharif","orcid":"0000-0003-1308-3442","position":1,"is_corresponding":false},{"id":260797,"name":"Andrew R. Griswold","orcid":"0000-0003-2957-2355","position":2,"is_corresponding":false},{"id":550806,"name":"Pietro Fontana","orcid":"0000-0003-3215-3784","position":3,"is_corresponding":false},{"id":352068,"name":"Julian Mintseris","orcid":null,"position":4,"is_corresponding":false},{"id":561743,"name":"Kevin B. Dagbay","orcid":"0000-0001-7002-7207","position":5,"is_corresponding":false},{"id":136624,"name":"Joao A. Paulo","orcid":"0000-0002-4291-413X","position":6,"is_corresponding":false},{"id":107041,"name":"Steven P. Gygi","orcid":"0000-0001-7626-0034","position":7,"is_corresponding":false},{"id":260803,"name":"Daniel A. Bachovchin","orcid":"0000-0001-8210-1662","position":8,"is_corresponding":false},{"id":228831,"name":"Hao Wu","orcid":"0000-0002-7281-8579","position":9,"is_corresponding":false},{"id":561742,"name":"Louis Hollingsworth","orcid":"0000-0002-4130-3580","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-18T23:14:46.979435Z","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":[]}