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Systematic analysis of the IL-17 receptor signalosome reveals a robust regulatory feedback loop

H. Draberova, S. Janusova, D. Knizkova, T. Semberova, M. Pribikova, A. Ujevic, K. Harant, S. Knapkova, M. Hrdinka, V. Fanfani, G. Stracquadanio, A. Drobek, K. Ruppova, O. Stepanek, P. Draber

. 2020 ; 39 (17) : e104202. [pub] 20200721

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21020170

Grantová podpora
SGS01/LF/2018-2019 Ministerstvo Školství, Mládeže a Tělovýchovy (MEYS)
UNCE/MED/016 Univerzita Karlova v Praze (UK)
FunDiT EC | H2020 | H2020 Priority Excellent Science | H2020 European Research Council (ERC)
18-24070Y Grantová Agentura České Republiky (GACR)
207769/A/17/Z Wellcome Trust (WT)
Wellcome Trust - United Kingdom
IZ11Z0_166538 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
PRIMUS/20/MED/003 Univerzita Karlova v Praze (UK)
IRP03_2018-2020 Ostravská Univerzita v Ostravě (University of Ostrava)
17-27355Y Grantová Agentura České Republiky (GACR)
SGS02/LF/2017-2018 Ministerstvo Školství, Mládeže a Tělovýchovy (MEYS)
4420 European Molecular Biology Organization (EMBO)

IL-17 mediates immune protection from fungi and bacteria, as well as it promotes autoimmune pathologies. However, the regulation of the signal transduction from the IL-17 receptor (IL-17R) remained elusive. We developed a novel mass spectrometry-based approach to identify components of the IL-17R complex followed by analysis of their roles using reverse genetics. Besides the identification of linear ubiquitin chain assembly complex (LUBAC) as an important signal transducing component of IL-17R, we established that IL-17 signaling is regulated by a robust negative feedback loop mediated by TBK1 and IKKε. These kinases terminate IL-17 signaling by phosphorylating the adaptor ACT1 leading to the release of the essential ubiquitin ligase TRAF6 from the complex. NEMO recruits both kinases to the IL-17R complex, documenting that NEMO has an unprecedented negative function in IL-17 signaling, distinct from its role in NF-κB activation. Our study provides a comprehensive view of the molecular events of the IL-17 signal transduction and its regulation.

Citace poskytuje Crossref.org

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