TBK1-associated adapters TANK and AZI2 protect mice against TNF-induced cell death and severe autoinflammatory diseases

Andrea Ujevic, Daniela Knizkova, Alzbeta Synackova, Michaela Pribikova, Tijana Trivic, Anna Dalinskaya, Ales Drobek, Veronika Niederlova, Darina Paprckova, Roldan Guia, Petr Kasparek, Jan Prochazka, Juraj Labaj, Olha Fedosieieva, Bernhard Florian Roeck, Ondrej Mihola, Zdenek Trachtulec, Radislav Sedlacek, Ondrej Stepanek and Peter Draber ()
Additional contact information
Andrea Ujevic: Charles University
Daniela Knizkova: Charles University
Alzbeta Synackova: Charles University
Michaela Pribikova: Charles University
Tijana Trivic: Charles University
Anna Dalinskaya: Charles University
Ales Drobek: Institute of Molecular Genetics of the Czech Academy of Sciences
Veronika Niederlova: Institute of Molecular Genetics of the Czech Academy of Sciences
Darina Paprckova: Institute of Molecular Genetics of the Czech Academy of Sciences
Roldan Guia: Institute of Molecular Genetics of the Czech Academy of Sciences
Petr Kasparek: Institute of Molecular Genetics of the Czech Academy of Sciences
Jan Prochazka: Institute of Molecular Genetics of the Czech Academy of Sciences
Juraj Labaj: Institute of Molecular Genetics of the Czech Academy of Sciences
Olha Fedosieieva: Institute of Molecular Genetics of the Czech Academy of Sciences
Bernhard Florian Roeck: University of Cologne
Ondrej Mihola: Institute of Molecular Genetics of the Czech Academy of Sciences
Zdenek Trachtulec: Institute of Molecular Genetics of the Czech Academy of Sciences
Radislav Sedlacek: Institute of Molecular Genetics of the Czech Academy of Sciences
Ondrej Stepanek: Institute of Molecular Genetics of the Czech Academy of Sciences
Peter Draber: Charles University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54399-4

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