A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain

被引：142

作者：

Polykratis, Apostolos ^{[1
,2
]}

Martens, Arne ^{[3
,4
]}

Eren, Remzi Onur ^{[1
,2
]}

Shirasaki, Yoshitaka ^{[5
,6
]}

Yamagishi, Mai ^{[6
]}

Yamaguchi, Yoshifumi ^{[7
,8
]}

Uemura, Sotaro ^{[6
]}

Miura, Masayuki ^{[7
]}

Holzmann, Bernhard ^{[9
]}

Kollias, George ^{[10
,11
]}

Armaka, Marietta ^{[10
]}

van Loo, Geert ^{[3
,4
]}

Pasparakis, Manolis ^{[1
,2
]}

机构：

[1] Univ Cologne, Inst Genet, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany

[2] Univ Cologne, Ctr Mol Med, Cologne, Germany

[3] VIB, Ctr Inflammat Res, Ghent, Belgium

[4] Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium

[5] Japan Sci & Technol Agcy, Precursory Res Embryon Sci & Technol, Tokyo, Japan

[6] Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Tokyo, Japan

[7] Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Genet, Tokyo, Japan

[8] Hokkaido Univ, Inst Low Temp Sci, Sapporo, Hokkaido, Japan

[9] Tech Univ Munich, Sch Med, Dept Surg, Munich, Germany

[10] Biomed Sci Res Ctr Alexander Fleming, Vari, Greece

[11] Univ Athens, Med Sch, Dept Physiol, Athens, Greece

来源：

NATURE CELL BIOLOGY | 2019年 / 21卷 / 06期

基金：

欧洲研究理事会;

关键词：

NF-KAPPA-B; NLRP3; INFLAMMASOME; CELL-DEATH; RESTRICTS UBIQUITINATION; LINEAR POLYUBIQUITIN; TNFAIP3; A20; TNF; ACTIVATION; GENE; DEFICIENCY;

D O I：

10.1038/s41556-019-0324-3

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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-.B 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-1 beta 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.

引用

页码：731 / 742

页数：12

共 64 条

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