A20APOPTOSIS

Molecular and structural analysis of A20 in the modulation of apoptosis: anti-inflammatory potential in vasculitis

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

An EU-funded project is investigating the molecular basis of vasculitis, the inflammation of blood vessels.

Descrizione progetto (Article)

Vasculitis can cause undesirable changes like thickening, scarring, narrowing and weakening in the vessel walls. Inflammation is the result of the body's autoimmune system attacking the blood vessels and the aetiology is unclear.

Autoimmune vasculitis has been associated with the activation of neutrophils; regulating neutrophil apoptosis (cell death) could reduce inflammation to ameliorate vasculitis symptoms. The A20 (zinc-finger) protein produces anti-inflammatory activity by inhibiting activation of nuclear factor kappa-light-chain-enhancer of B (NF-kB) cells. NF-kB cells are activated in response to tumour necrosis factor (TNF)-alpha and lipopolysaccharide (LPS)-mediated NF-kB pathways (associated with endothelial and neutrophil cell survival).

The EU-funded A20APOPTOSIS project will assess the structure and function of the A20 protein in regulating neutrophil and endothelial cell apoptosis. Elucidating the role of A20 and A20-binding proteins will enable the development of novel therapeutic targets for vasculitis. Molecular biology, cell biology, functional biology, molecular modelling and clinical investigations will be used for this purpose.

Research results revealed the presence of the A20 protein in inflammatory neutrophils. Work is ongoing to identify if A20 has a pro- or anti-apoptotic role in neutrophils.

Project outcomes could uncover an as yet unexplored role of A20 expression in modulating neutrophil apoptosis and thereby a novel means to treat vasculitis.