Structural basis of regulation of pro-inflammatory IL-17RA by TAOK1 and Act1

01 January 2019 → Ongoing
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Immunology
    • Immunology
    • Microbiology
    • Immunology
Inflammation and autoimmunity Interleukin-17 receptor A regulation structural and biophysical dissection
Project description

Dysregulation of pro-inflammatory interleukin-17 (IL-17) signaling drives a multitude of widespread inflammatory and autoimmune disorders, such as rheumatoid arthritis, psoriasis, Crohn's disease and Sjögren's syndrome. Therefore, downstream regulation of molecular signals initiated by IL-17 via its binding to its cognate receptors need be tightly regulated. The IL-17 receptor A (IL-17RA) is a hallmark receptor for IL-17 signal transduction, which is amongst others positively regulated by NF-κB activator (Act1) and negatively by thousand and one kinase 1 (TAOK1). However, the understanding of the intracellular regulation of IL-17RA is very incomplete, in part due to the lack of structural insights into its complexes with intracellular partner proteins. The latter is a major bottleneck in our fundamental understanding of IL-17-mediated inflammatory and autoimmune diseases and in harnessing fully the therapeutic potential of IL-17 signaling. The aim of this research project is to obtain structural snapshots of the complexes between IL-17RA and Act1 and TAOK1. Such knowledge will allow for a better understanding of the mechanism behind the competition for activation or inhibition of IL-17RA-mediated signaling by Act1 or TAOK1, respectively. Furthermore, it will contribute to ongoing research towards novel therapeutics for IL-17RA-mediated inflammatory and autoimmune diseases.