The ubiquitin editing protein A20, a novel 90kDa zinc-finger protein has an universal anti-inflammatory activity by inhibiting NF-kappaB activation. In endothelial cells, the induction of A20 by inflammatory stimuli renders cells resistant to apoptosis. However, A20 can have pro-apoptotic activities in other cell types. We will focus on the respective role of A20 in both endothelial cells and neutrophils, two cardinal cell players in inflammation associated with autoimmune vasculitis in which A20 could be a suitable therapeutic target and has never been investigated. We hypothesized that this differential effect of A20 in modulating apoptosis and inflammation is dependent on different molecular partner A20. Hence, we proposeto i) identify the A20 interactome by proteomic and modelisation approaches in both endothelial cells and neutrophils, ii) investigate the function of A20 in neutrophils, iii) study A20 modulation of neutrophil-mediated endothelial cell toxicity, iii) investigate A20 expression in patients with vasculitis. Through its interdisciplinary and integrative approaches combining molecular biology, cell biology, functional biology, molecular modeling and clinical investigations, this project directed by Dr Daniel, an expert of A20, constitutes a timely and novative approach to unravel the role of A20 and A20-binding proteins in modulating apoptosis and inflammation and identify novel therapeutic tools.
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