Systematic analysis of the IL‐17 receptor signalosome reveals a robust regulatory feedback loop. (21st July 2020)

• Record Type: Journal Article
• Authors: Draberova, Helena; Janusova, Sarka; Knizkova, Daniela; Semberova, Tereza; Pribikova, Michaela; Ujevic, Andrea; Harant, Karel; Knapkova, Sofija; Hrdinka, Matous; Fanfani, Viola; Stracquadanio, Giovanni; Drobek, Ales; Ruppova, Klara; Stepanek, Ondrej; Draber, Peter
• Is Part Of: EMBO journal. Volume 39:Number 17(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-07-21
• Subjects: IKKε -- IL‐17 -- LUBAC -- NEMO -- TBK1; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2019104202
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. Synopsis: We resolved the hierarchy of IL‐17 receptor signalosome formation using a novel mass‐spectrometry approach. We identified that LUBAC functions as a new positive regulator of IL‐17 signaling, while NEMO‐recruited kinases TBK1/IKKε provide very potent inhibitory feedback loop. Recruitment of approximately six Act1 molecules to a triggered IL‐17 receptor creates a docking site for trimeric K63‐polyubiquitin ligase TRAF6. TRAF6 promotes recruitment of linear ubiquitin chain assembly complex (LUBAC) and combined activity of these two ubiquitin ligases creates docking sites for activators of downstream signaling. NEMO promotes recruitment of TBK1 and IKKε kinases via adaptors TANK and NAP1, independently of its role in NF‐κB activation. TBK1 and IKKε phosphorylate ACT1 leading to the release of TRAF6 from the complex, explaining the relatively weak cellular response to IL‐17 stimulation. Abstract : Mass‐spectrometric investigation of the IL‐17 cytokine receptor signaling complex reveals a new role for the linear ubiquitin chain assembly complex (LUBAC) as a positive regulator of the IL‐17 pathway, and an inhibitory feedback loop involving NEMO‐recruited kinases TBK1 and IKKε.