{"doi":"10.1016/j.celrep.2020.108264","title":"Activation of the CARD8 Inflammasome Requires a Disordered Region","abstract":"Several cytosolic pattern-recognition receptors (PRRs) form multiprotein complexes called canonical inflammasomes in response to intracellular danger signals. Canonical inflammasomes recruit and activate caspase-1 (CASP1), which in turn cleaves and activates inflammatory cytokines and gasdermin D (GSDMD), inducing pyroptotic cell death. Inhibitors of the dipeptidyl peptidases DPP8 and DPP9 (DPP8/9) activate both the human NLRP1 and CARD8 inflammasomes. NLRP1 and CARD8 have different N-terminal regions but have similar C-terminal regions that undergo autoproteolysis to generate two non-covalently associated fragments. Here, we show that DPP8/9 inhibition activates a proteasomal degradation pathway that targets disordered and misfolded proteins for destruction. CARD8's N terminus contains a disordered region of ∼160 amino acids that is recognized and destroyed by this degradation pathway, thereby freeing its C-terminal fragment to activate CASP1 and induce pyroptosis. Thus, CARD8 serves as an alarm to signal the activation of a degradation pathway for disordered and misfolded proteins.","journal":"Cell Reports","year":2020,"id":61431,"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":57,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"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":260797,"name":"Andrew R. Griswold","orcid":"0000-0003-2957-2355","position":1,"is_corresponding":false},{"id":260796,"name":"Cornelius Y. Taabazuing","orcid":"0000-0003-2361-5457","position":2,"is_corresponding":false},{"id":260798,"name":"Elizabeth L. Orth-He","orcid":"0000-0002-8180-1330","position":3,"is_corresponding":false},{"id":324257,"name":"Kuo Gai","orcid":"0000-0001-8469-5935","position":4,"is_corresponding":false},{"id":260799,"name":"Sahana D. Rao","orcid":"0000-0003-4592-8921","position":5,"is_corresponding":false},{"id":260795,"name":"Daniel P. Ball","orcid":"0000-0003-0693-7614","position":6,"is_corresponding":false},{"id":324258,"name":"Jeffrey C. Hsiao","orcid":"0000-0002-4363-9467","position":7,"is_corresponding":false},{"id":260803,"name":"Daniel A. Bachovchin","orcid":"0000-0001-8210-1662","position":8,"is_corresponding":false},{"id":324256,"name":"Ashley J. Chui","orcid":"0000-0003-0037-5761","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-18T21:09:27.985420Z","pmid":"33053349","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":[]}