TBK1-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 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.
Authors
- Andrea Ujevic (ORCID: https://orcid.org/0000-0002-2176-5585)
- Tijana Trivić (ORCID: https://orcid.org/0000-0003-2566-253X)
- Roldan M. de Guia (ORCID: https://orcid.org/0000-0002-4239-2407)
- Daniela Knizkova (ORCID: https://orcid.org/0000-0001-8816-1594)
- Jan Procházka (ORCID: https://orcid.org/0000-0003-4675-8995)
- Ondřej Štěpánek (ORCID: https://orcid.org/0000-0002-2735-3311)
- Radislav Sedláček (ORCID: https://orcid.org/0000-0002-3352-392X)
- Peter Dráber (ORCID: https://orcid.org/0000-0001-8658-4614)
- Veronika Niederlová (ORCID: https://orcid.org/0000-0001-8768-9039)
- Michaela Přibíková (ORCID: https://orcid.org/0000-0001-5105-9609)
- Zdeněk Trachtulec (ORCID: https://orcid.org/0000-0001-5772-9394)
- Juraj Lábaj (ORCID: https://orcid.org/0009-0002-6434-872X)
- Petr Kašpárek (ORCID: https://orcid.org/0000-0001-6047-7538)
- Ondřej Mihola (ORCID: https://orcid.org/0000-0003-3243-0825)
- Bernhard F. Roeck (ORCID: https://orcid.org/0009-0002-2306-8481)
- Ales Drobek (ORCID: https://orcid.org/0000-0003-1066-9413)
- Darina Paprčková (ORCID: https://orcid.org/0000-0002-0151-4797)
- Alzbeta Synackova (ORCID: https://orcid.org/0000-0002-6854-4405)
- Olha Fedosieieva
- Anna Dalinskaya
Institutions
- University of Cologne (DE)
- Charles University (CZ)
- Institute of Molecular Genetics (RU)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University of Lausanne (CH)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1038/s41467-024-54399-4
- Citations
- 3
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.72
Funders
- European Molecular Biology Organization
- Univerzita Karlova v Praze
- Grantová Agentura, Univerzita Karlova
- European Commission
- Deutsche Forschungsgemeinschaft
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Grantová Agentura České Republiky
- Bundesministerium für Bildung und Forschung
- Akademie Věd České Republiky
- Ústav Molekulární Genetiky, Akademie Věd České Republiky
- Horizon 2020 Framework Programme
- Advanced Scientific Computing Research