Polykratis, Apostolos ORCID: 0000-0001-6720-3302, Martens, A, Eren, RO, Shirasaki, Y, Yamagishi, M, Yamaguchi, Y, Uemura, S, Miura, M, Holzmann, B, Kollias, G, Armaka, M, van Loo, G and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2019). A20 Prevents Inflammasome-Dependent Arthritis by Inhibiting Macrophage Necroptosis Through Its ZnF7 Ubiquitin-Binding Domain. Nature Cell Biology, 6 (21). pp. 731-742.

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Identification Number:10.1038/s41556-019-0324-3

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.

Item Type: Article
Creators:
Creators
Email
ORCID
ORCID Put Code
Polykratis, Apostolos
UNSPECIFIED
https://orcid.org/0000-0001-6720-3302
UNSPECIFIED
Martens, A
UNSPECIFIED
UNSPECIFIED
UNSPECIFIED
Eren, RO
UNSPECIFIED
UNSPECIFIED
UNSPECIFIED
Shirasaki, Y
UNSPECIFIED
UNSPECIFIED
UNSPECIFIED
Yamagishi, M
UNSPECIFIED
UNSPECIFIED
UNSPECIFIED
Yamaguchi, Y
UNSPECIFIED
UNSPECIFIED
UNSPECIFIED
Uemura, S
UNSPECIFIED
UNSPECIFIED
UNSPECIFIED
Miura, M
UNSPECIFIED
UNSPECIFIED
UNSPECIFIED
Holzmann, B
UNSPECIFIED
UNSPECIFIED
UNSPECIFIED
Kollias, G
UNSPECIFIED
UNSPECIFIED
UNSPECIFIED
Armaka, M
UNSPECIFIED
UNSPECIFIED
UNSPECIFIED
van Loo, G
UNSPECIFIED
UNSPECIFIED
UNSPECIFIED
Pasparakis, Manolis
pasparakis@uni-koeln.de
https://orcid.org/0000-0002-9870-0966
UNSPECIFIED
URN: urn:nbn:de:hbz:38-112727
Identification Number: 10.1038/s41556-019-0324-3
Journal or Publication Title: Nature Cell Biology
Volume: 6
Number: 21
Page Range: pp. 731-742
Date: 13 May 2019
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: Life sciences
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/11272

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