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

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.

HOIL1 regulates group 2 innate lymphoid cell numbers and type 2 inflammation in the small intestine

“…One possibility is that HOIL1 plays a cell-intrinsic role in regulating ILC2, and this would be consistent with a requirement for HOIL1 in radiation-resistant, non-bone marrow-derived cells, since some ILC2 are thought to self-renew in tissues 40 . A recent study identified LUBAC as a component of the IL17RA/IL17RC receptor signaling complex (RSC) required for efficient signal transduction and NFκB activation 41 . The same study identified a negative feedback loop for the IL-17RSC, although LUBAC did not appear to be involved.…”

IL‐17 signaling induces iNOS+ microglia activation in retinal vascular diseases

“…The microglia are a subtype of glial-immune sentinel cells in retina and highly express receptor for IL-17 in STZ-injected or OIR mice. Among the five receptors for IL-17 (IL17RA to IL-17RE), IL-17 has been shown to bind IL-17RA with high affinity and IL-17RA receptor has been shown to associate with other receptor such as IL-17RC, forming a IL-17R complex (Draberova et al, 2020). In the retina, IL-17RA and IL-17RC could be found to express on microglia, Muller cells, and astrocytes (Ke et al, 2009).…”

IL-17-induced dimerization of IL-17RA drives the formation of the IL-17 signalosome to potentiate signaling

“…Act1 controls both the transcriptional as well as the post-transcriptional regulation of IL-17 responsive genes, by recruiting and activating different TRAF proteins (TRAF6, TRAF2), and also by directly interacting with RNAs ( Li et al, 2019 ). According to a recent study, the IL-17A/IL-17RA/IL-17RC heterotrimeric receptor recruits approximately six ACT1 molecules, which provide high-avidity docking sites for TRAF6 homotrimers ( Draberova et al, 2020 ). Non-degradative K63-linked polyubiquitination of TRAF6 by Act1 leads to the recruitment of downstream adaptor (ABIN1, TAX1BP1, TANK, NAP1), effector (TAK1, LUBAC, NEMO/IKKα/IKKβ), and regulatory proteins (IKKε, TBK1, A20, Cullin1, β-TrCP1/2) and ultimately to the activation of the NF-κB and MAP kinase pathways ( Amatya et al, 2017 ; Li et al, 2019 ; Draberova et al, 2020 ).…”