Polykratis, A, 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, M
(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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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: | Journal Article | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Creators: |
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| URN: | urn:nbn:de:hbz:38-112727 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DOI: | 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 |
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| Subjects: | Life sciences | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Refereed: | Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| URI: | http://kups.ub.uni-koeln.de/id/eprint/11272 |
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