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

Nat Cell Biol. 2019 Jun;21(6):731-742. doi: 10.1038/s41556-019-0324-3. Epub 2019 May 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis / chemically induced
  • Arthritis / genetics*
  • Arthritis / pathology
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / metabolism
  • Inflammation / chemically induced
  • Inflammation / genetics*
  • Inflammation / pathology
  • Interleukin-1beta / genetics
  • Kruppel-Like Transcription Factors / genetics*
  • Lipopolysaccharides / toxicity
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mutation
  • NF-kappa B / genetics
  • Necrosis / genetics
  • Necrosis / pathology
  • Protein Binding
  • Protein Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3 / genetics*
  • Ubiquitin / genetics

Substances

  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Kruppel-Like Transcription Factors
  • Lipopolysaccharides
  • NF-kappa B
  • Ubiquitin
  • ZNF7 protein, human
  • MLKL protein, mouse
  • Protein Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Ripk3 protein, mouse
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Tnfaip3 protein, mouse