biostudies-literatureUjevic ABundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)Bundesministerium für Bildung und ForschungAkademie Věd České Republiky (Academy of Sciences of the Czech Republic)Grantová Agentura České RepublikyGrantová Agentura České Republiky (Grant Agency of the Czech Republic)Univerzita Karlova v Praze (Charles University)European Molecular Biology Organization (EMBO)EC | Horizon 2020 Framework ProgrammeGrantová Agentura, Univerzita Karlova (Charles University Grant Agency)Ministerstvo Školství, Mládeže a Tělovýchovy (Ministry of Education, Youth and Sports)Grantová Agentura, Univerzita KarlovaEuropean Molecular Biology OrganizationUniverzita Karlova v PrazeAkademie Věd České RepublikyDeutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft (German Research Foundation)Ministerstvo Školství, Mládeže a TělovýchovyEC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)10013https://www.ebi.ac.uk/biostudies/studies/S-EPMC11576971biostudies-literatureUnknown15(1)The cytokine TNF can trigger highly proinflammatory RIPK1-dependent cell death. Here, we show that the two adapter proteins, TANK and AZI2, suppress TNF-induced cell death by regulating the activation of TBK1 kinase. Mice lacking either TANK or AZI2 do not show an overt phenotype. Conversely, animals deficient in both adapters are born in a sub-Mendelian ratio and suffer from severe multi-organ inflammation, excessive antibody production, male sterility, and early mortality, which can be rescued by TNFR1 deficiency and significantly improved by expressing a kinase-dead form of RIPK1. Mechanistically, TANK and AZI2 both recruit TBK1 to the TNF receptor signaling complex, but with distinct kinetics due to interaction with different complex components. While TANK binds directly to the adapterNature communicationsTBK1-associated adapters TANK and AZI2 protect mice against TNF-induced cell death and severe autoinflammatory diseases.PMC11576971UNCE/MED/016SVV 2606374063224420PRIMUS/20/MED/00316LW0213Programme EXCELES, LX22NPO5102SFB1403 (414786233)Programme EXCELES, LX22NPO510321-25251S802878LM2023036RVO 68378050CooperatioUjevic ADe Guia RFedosieieva OPribikova MRoeck BFDalinskaya AMihola OStepanek OKnizkova DProchazka JSynackova ALabaj JNiederlova VKasparek PPaprckova DTrachtulec ZSedlacek RTrivic TDrobek ADraber PfalseTBK1-associated adapters TANK and AZI2 protect mice against TNF-induced cell death and severe autoinflammatory diseases.The cytokine TNF can trigger highly proinflammatory RIPK1-dependent cell death. Here, we show that the two adapter proteins, TANK and AZI2, suppress TNF-induced cell death by regulating the activation of TBK1 kinase. Mice lacking either TANK or AZI2 do not show an overt phenotype. Conversely, animals deficient in both adapters are born in a sub-Mendelian ratio and suffer from severe multi-organ inflammation, excessive antibody production, male sterility, and early mortality, which can be rescued by TNFR1 deficiency and significantly improved by expressing a kinase-dead form of RIPK1. Mechanistically, TANK and AZI2 both recruit TBK1 to the TNF receptor signaling complex, but with distinct kinetics due to interaction with different complex components. While TANK binds directly to the adapter2024-01-01T00:00:00Z2024 Nov2025-04-04T01:19:00.377Z2025-04-04T01:19:00.377ZS-EPMC115769713956278810.1038/s41467-024-54399-4