{"doi":"10.1101/2022.06.26.497666","title":"CARD8 negatively regulates NLRP1 inflammasome activation level by interaction with NLRP1","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>NLRP1 inflammasome functions as canonical cytosolic sensor in response to intracellular infections and is implicated in auto-inflammatory diseases. But the regulation and signal transduction mechanisms of NLRP1 are incompletely understood. Here, we show that the T60 variant of CARD8, but not the canonical T48 isoform, negatively regulates NLRP1 inflammasome activation by directly interacting with the receptor molecule NLRP1 and inhibiting inflammasome assembly. Furthermore, our results suggest that the different ASC preference in three types of inflammasomes, namely ASC-indispensable NLRP1 inflammasome, ASC-dispensable mNLRP1b inflammasome and ASC-independent CARD8 inflammasome, is mainly caused by the CARD domain, not the UPA subdomain. Based on the systematic site-directed mutagenesis and structural analysis, we find that the signal transduction of NLRP1 inflammasome relies on multiple interaction surfaces on its death domain superfamily member CARD domain. Finally, our results partly explain the mechanism of the NLRP1 mutation-derived auto-inflammatory diseases caused by the overactivation of the NLRP1 inflammasome. In conclusion, our study not only reveals how CARD8 downregulates NLRP1 inflammasome activation, but also provides insights into the mechanisms of CARD-containing inflammasome assembly.</jats:p>","journal":null,"year":null,"id":621693,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1605559,"name":"Shasha Deng","orcid":null,"position":1,"is_corresponding":false},{"id":1605560,"name":"Yuluo Huang","orcid":null,"position":2,"is_corresponding":false},{"id":1188258,"name":"Yunru Yang","orcid":null,"position":3,"is_corresponding":false},{"id":1605561,"name":"Liangqi Sun","orcid":null,"position":4,"is_corresponding":false},{"id":1605562,"name":"Hanyuan Liu","orcid":null,"position":5,"is_corresponding":false},{"id":304631,"name":"Dan Zhao","orcid":"0000-0002-5749-1467","position":6,"is_corresponding":false},{"id":1300280,"name":"Weihong Zeng","orcid":"0000-0003-3853-3630","position":7,"is_corresponding":false},{"id":1605563,"name":"Xueying Yin","orcid":null,"position":8,"is_corresponding":false},{"id":1605564,"name":"Peiyi Zheng","orcid":null,"position":9,"is_corresponding":false},{"id":1187818,"name":"Muziying Liu","orcid":"0000-0002-3084-2431","position":10,"is_corresponding":false},{"id":1540947,"name":"Weidong Zhao","orcid":null,"position":11,"is_corresponding":false},{"id":419626,"name":"Ying Zhou","orcid":"0000-0003-0408-3731","position":12,"is_corresponding":false},{"id":288499,"name":"Tengchuan Jin","orcid":"0000-0002-1395-188X","position":13,"is_corresponding":false},{"id":1373022,"name":"Zhihao Xu","orcid":"0000-0003-2368-7661","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"CARD8 negatively regulates NLRP1 inflammasome activation level by interaction with NLRP1","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>NLRP1 inflammasome functions as canonical cytosolic sensor in response to intracellular infections and is implicated in auto-inflammatory diseases. But the regulation and signal transduction mechanisms of NLRP1 are incompletely understood. Here, we show that the T60 variant of CARD8, but not the canonical T48 isoform, negatively regulates NLRP1 inflammasome activation by directly interacting with the receptor molecule NLRP1 and inhibiting inflammasome assembly. Furthermore, our results suggest that the different ASC preference in three types of inflammasomes, namely ASC-indispensable NLRP1 inflammasome, ASC-dispensable mNLRP1b inflammasome and ASC-independent CARD8 inflammasome, is mainly caused by the CARD domain, not the UPA subdomain. Based on the systematic site-directed mutagenesis and structural analysis, we find that the signal transduction of NLRP1 inflammasome relies on multiple interaction surfaces on its death domain superfamily member CARD domain. Finally, our results partly explain the mechanism of the NLRP1 mutation-derived auto-inflammatory diseases caused by the overactivation of the NLRP1 inflammasome. In conclusion, our study not only reveals how CARD8 downregulates NLRP1 inflammasome activation, but also provides insights into the mechanisms of CARD-containing inflammasome assembly.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19910364","pmcid":null,"openalex_id":"https://openalex.org/W4283731141","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"cc-by-nc-nd","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2022/06/28/2022.06.26.497666.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2022/06/28/2022.06.26.497666.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2022.06.26.497666","host_type":"publisher"},{"url":"https://doi.org/10.1101/2022.06.26.497666","host_type":"repository"}],"fields_of_study":["Inflammasome and immune disorders","Kawasaki Disease and Coronary Complications","interferon and immune responses"],"mesh_terms":[],"keywords":["Inflammasome","NLRP1","Pyrin domain","Cell biology","Signal transduction","Receptor","Caspase 1","AIM2","Chemistry","Biology","Genetics","Caspase","Programmed cell death","Apoptosis"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T15:37:36.311107Z","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":[]}