Project

Investigating the molecular mechanisms and therapeutic use of A20 and MYSM1 in inflammatory signaling and pathology

Code
3E012020
Duration
01 October 2020 → 17 May 2022
Funding
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Cell death
    • Inflammation
    • Innate immunity
    • Cell signalling
Keywords
inflammation cell death ubiquitin
 
Project description

Inflammatory signaling cascades are heavily controlled by ubiquitination, and several proteins including A20 and MYSM1 interfere with these processes. A20 was initially believed to inhibit NF-κB signaling by its deubiquitinase (DUB) and E3 ligase activities. However, using new mutant knockin mouse lines, we recently demonstrated the critical importance of A20’s ubiquitin binding activities for its in vivo function. This project will build on my previous research investigating the molecular mechanisms by which A20 controls inflammatory signaling, especially in the context of TNF and TLR signaling. Since we have recently demonstrated that the ubiquitin binding ZnF7 domain of A20 is essential to suppress inflammatory signaling, we will develop A20-ZnF7 nanoparticles for in vivo delivery to try to prevent inflammatory signaling and pathology. Finally, the deubiquitinase MYSM1 was recently shown to be a critical regulator of TLR and NOD-like receptor signaling, but its role in TNFR signaling is still unexplored. In this project, we will use in vivo and in vitro approaches to identify the role of MYSM1 in TNF-induced inflammatory signaling and cell death.