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 adapter NEMO, AZI2 is recruited later via deubiquitinase A20. In summary, our data show that TANK and AZI2 cooperatively sustain TBK1 activity during different stages of TNF receptor assembly to protect against autoinflammation.

Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

Department of Immunobiology University of Lausanne Epalinges Switzerland

Institute for Genetics CECAD Cluster of Excellence University of Cologne Cologne Germany

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Germ Cell Development Division BIOCEV Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Immunity and Cell Communication Division BIOCEV 1st Faculty of Medicine Charles University Vestec Czech Republic

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