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.

• 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

Interleukin-17A (IL-17A) is a key mediator of protective immunity to yeast and bacterial infections but also drives the pathogenesis of several autoimmune diseases, such as psoriasis or psoriatic arthritis. Here we show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor (IL-17R). CMTM4 constitutively associated with IL-17R subunit C to mediate its stability, glycosylation and plasma membrane localization. Both mouse and human cell lines deficient in CMTM4 were largely unresponsive to IL-17A, due to their inability to assemble the IL-17R signaling complex. Accordingly, CMTM4-deficient mice had a severe defect in the recruitment of immune cells following IL-17A administration and were largely resistant to experimental psoriasis, but not to experimental autoimmune encephalomyelitis. Collectively, our data identified CMTM4 as an essential component of IL-17R and a potential therapeutic target for treating IL-17-mediated autoimmune diseases.

• MeSH
• encefalomyelitida autoimunitní experimentální * genetika   MeSH
• interleukin-17 metabolismus   MeSH
• lidé MeSH
• myši MeSH
• proteiny obsahující MARVEL doménu genetika   MeSH
• psoriatická artritida * MeSH
• psoriáza * MeSH
• receptory interleukinu-17 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• HeLa buňky MeSH
• kinasa I-kappa B genetika   metabolismus   MeSH
• lidé MeSH
• protein-serin-threoninkinasy genetika   metabolismus   MeSH
• receptory interleukinu-17 genetika   metabolismus   MeSH
• signální transdukce * MeSH
• zpětná vazba fyziologická * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH