TBK1-associated adapters TANK and AZI2 protect mice against TNF-induced cell death and severe autoinflammatory diseases
Jazyk angličtina Země Anglie, Velká Británie Médium electronic
Typ dokumentu časopisecké články
Grantová podpora
21-25251S
Grantová Agentura České Republiky (Grant Agency of the Czech Republic)
4420
European Molecular Biology Organization (EMBO)
PRIMUS/20/MED/003
Grantová Agentura, Univerzita Karlova (Charles University Grant Agency)
406322
Grantová Agentura, Univerzita Karlova (Charles University Grant Agency)
Cooperatio
Univerzita Karlova v Praze (Charles University)
UNCE/MED/016
Univerzita Karlova v Praze (Charles University)
SVV 260637
Ministerstvo Školství, Mládeže a Tělovýchovy (Ministry of Education, Youth and Sports)
LM2023036
Ministerstvo Školství, Mládeže a Tělovýchovy (Ministry of Education, Youth and Sports)
Programme EXCELES, LX22NPO5102
EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
802878
EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
Programme EXCELES, LX22NPO5103
EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
RVO 68378050
Akademie Věd České Republiky (Academy of Sciences of the Czech Republic)
SFB1403 (414786233)
Deutsche Forschungsgemeinschaft (German Research Foundation)
16LW0213
Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
PubMed
39562788
PubMed Central
PMC11576971
DOI
10.1038/s41467-024-54399-4
PII: 10.1038/s41467-024-54399-4
Knihovny.cz E-zdroje
- MeSH
- adaptorové proteiny signální transdukční * metabolismus genetika MeSH
- buněčná smrt MeSH
- endopeptidasy MeSH
- intracelulární signální peptidy a proteiny metabolismus genetika MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši knockoutované * MeSH
- myši MeSH
- protein-serin-threoninkinasy interagující s receptory * metabolismus genetika MeSH
- protein-serin-threoninkinasy * metabolismus genetika MeSH
- receptory TNF - typ I * metabolismus genetika MeSH
- signální transdukce MeSH
- TNF-alfa * metabolismus MeSH
- TNFAIP3 metabolismus genetika MeSH
- zánět metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adaptorové proteiny signální transdukční * MeSH
- endopeptidasy MeSH
- gumby protein, mouse MeSH Prohlížeč
- intracelulární signální peptidy a proteiny MeSH
- NEMO protein, mouse MeSH Prohlížeč
- protein-serin-threoninkinasy interagující s receptory * MeSH
- protein-serin-threoninkinasy * MeSH
- receptory TNF - typ I * MeSH
- Ripk1 protein, mouse MeSH Prohlížeč
- Tbk1 protein, mouse MeSH Prohlížeč
- TNF-alfa * MeSH
- Tnfaip3 protein, mouse MeSH Prohlížeč
- TNFAIP3 MeSH
- Tnfrsf1a protein, mouse MeSH Prohlížeč
- Tnip2 protein, mouse MeSH Prohlížeč
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.
Department of Immunobiology University of Lausanne Epalinges Switzerland
Institute for Genetics CECAD Cluster of Excellence University of Cologne Cologne Germany
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