{"doi":"10.1101/2020.04.05.026542","title":"Zα2 domain of ZBP1 is a molecular switch regulating Influenza-induced PANoptosis and perinatal lethality during development","abstract":"ABSTRACT Z-DNA-binding protein 1 (ZBP1) is an innate nucleic acid sensor which regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating RIPK3, caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we have generated Zbp1 Δ Z α2/Δ Z α2 mice that lack the Zα2 domain of ZBP1 and demonstrate that this domain is critical for influenza A virus (IAV)-induced PANoptosis and perinatal lethality in RIPK1-RHIM mutated ( Ripk1 RHIM/RHIM ) mice. Deletion of the Zα2 domain in ZBP1 abolished IAV-induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1 RHIM/RHIM mice from the perinatal lethality which is caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in physiological functions and establish a link between sensing of Z-RNAs via the Zα2 domain and the promotion of influenza-induced PANoptosis and perinatal lethality.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":120112,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"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":105440,"name":"R. K. Subbarao Malireddi","orcid":"0000-0001-8855-9447","position":1,"is_corresponding":false},{"id":229286,"name":"Amanda R. Burton","orcid":null,"position":2,"is_corresponding":false},{"id":252949,"name":"Shaina N. Porter","orcid":null,"position":3,"is_corresponding":false},{"id":105443,"name":"Peter Vogel","orcid":"0000-0002-7535-0545","position":4,"is_corresponding":false},{"id":250571,"name":"Shondra M. Pruett‐Miller","orcid":"0000-0002-3793-585X","position":5,"is_corresponding":false},{"id":105446,"name":"Thirumala‐Devi Kanneganti","orcid":"0000-0002-6395-6443","position":6,"is_corresponding":false},{"id":107636,"name":"Sannula Kesavardhana","orcid":"0000-0002-9536-8830","position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-18T23:14:33.640077Z","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":[]}