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

Sarka Janusova,Ales Drobek,Giovanni Stracquadanio,Michaela Pribikova,Peter Draber,Daniela Knizkova,Tereza Semberova,Viola Fanfani,Karel Harant,Matous Hrdinka,Klara Ruppova,Helena Draberova,Andrea Ujevic,Sofija Knapkova,Ondrej Stepanek

doi:10.15252/embj.2019104202

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.

Highlights

The interleukin 17 (IL-17) is a major proinflammatory cytokine produced by Th17 cell lineage and several innate immune cell types (Harrington et al, 2005; Park et al, 2005; Cua & Tato, 2010)
Because linear ubiquitin chain assembly complex (LUBAC) subunits and TAB/TAK1 complex were detected in IL-17RSC upon ablation of TBK1/IKKe, we addressed their potential roles in the IL-17 signaling
We demonstrated that these kinases are very strongly activated upon IL-17 stimulation, to levels comparable with strongly proinflammatory cytokines IL-1a or tumor necrosis factor (TNF)

Summary

Introduction

The interleukin 17 (IL-17) is a major proinflammatory cytokine produced by Th17 cell lineage and several innate immune cell types (Harrington et al, 2005; Park et al, 2005; Cua & Tato, 2010). Binding of dimeric IL-17 leads to heterodimerization of the receptor (Ely et al, 2009; Liu et al, 2013; Goepfert et al, 2017) and recruitment of a cytoplasmic protein ACT1 (Chang et al, 2006; Qian et al, 2007). ACT1 was described to enhance the expression of genes encoding proinflammatory cytokines by stabilizing their mRNAs or by activating downstream signaling pathways leading to the activation of their transcription (Li et al, 2019). TRAF6 creates non-degradative K63-polyubiquitin linkages which serve as docking sites for a variety of signaling molecules and promote activation of downstream signaling pathways, especially mitogen-activated protein kinase (MAPK) or nuclear factor-jB (NF-jB) and subsequent production of a 2020 The Authors.

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