A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain.
In: Nature cell biology, Jg. 21 (2019-06-01), Heft 6, S. 731-742
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Zugriff:
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.
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A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain.
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Autor/in / Beteiligte Person: | 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 ; Pasparakis, M |
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Zeitschrift: | Nature cell biology, Jg. 21 (2019-06-01), Heft 6, S. 731-742 |
Veröffentlichung: | London : Macmillan Magazines Ltd., [1999-, 2019 |
Medientyp: | academicJournal |
ISSN: | 1476-4679 (electronic) |
DOI: | 10.1038/s41556-019-0324-3 |
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