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A20 Prevents Inflammasome-Dependent Arthritis by Inhibiting Macrophage Necroptosis Through Its ZnF7 Ubiquitin-Binding Domain

A20 Prevents Inflammasome-Dependent Arthritis by Inhibiting Macrophage Necroptosis Through Its ZnF7 Ubiquitin-Binding Domain

Apostolos Polykratis, Arne Martens, Remzi Onur Eren, Yoshitaka Shirasaki, Mai Yamagishi, Yoshifumi Yamaguchi, Sotaro Uemura, Masayuki Miura, Bernhard Holzmann, George Kollias, Marietta Armaka, Geert van Loo, etc.

Nat Cell Biol. 2019 Jun;21(6):731-742.

PMID: 31086261

Abstract:

Deficiency in the deubiquitinating enzyme A20 causes severe inflammation in mice, and impaired A20 function is associated with human inflammatory diseases. A20 has been implicated in negatively regulating NF-κB signalling, cell death and inflammasome activation; however, the mechanisms by which A20 inhibits inflammation in vivo remain poorly understood. Genetic studies in mice revealed that its deubiquitinase activity is not essential for A20 anti-inflammatory function. Here we show that A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis and that this function depends on its zinc finger 7 (ZnF7). We provide genetic evidence that RIPK1 kinase-dependent, RIPK3-MLKL-mediated necroptosis drives inflammasome activation in A20-deficient macrophages and causes inflammatory arthritis in mice. Single-cell imaging revealed that RIPK3-dependent death caused inflammasome-dependent IL-1β release from lipopolysaccharide-stimulated A20-deficient macrophages. Importantly, mutation of the A20 ZnF7 ubiquitin binding domain caused arthritis in mice, arguing that ZnF7-dependent inhibition of necroptosis is critical for A20 anti-inflammatory function in vivo.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413759	A20 human			Price

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