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β1 integrin signaling governs necroptosis via the chromatin-remodeling factor CHD4

Zhiqi Sun1, Filippo M Cernilogar2, Helena Horvatic3

  • 1Gene Center and Department of Biochemistry, Ludwig Maximilian University of Munich, Munich, Germany; Research Group Molecular Mechanisms of Inflammation, Max-Planck Institute of Biochemistry, Martinsried, Germany.

Cell Reports
|October 26, 2023
PubMed

Insights

Fibroblast activation and inflammation in fibrosis are linked by β1 integrin signaling. This pathway regulates Receptor-interacting protein kinase 3 (RIPK3) expression through a novel mechanism involving chromodomain helicase DNA-binding protein 4 (CHD4).

Area of Science:

  • Cell biology
  • Molecular biology
  • Immunology

Background:

  • Fibrosis involves myofibroblast activation and excessive extracellular matrix (ECM) deposition, often linked to chronic inflammation.
  • Receptor-interacting protein kinase 3 (RIPK3) is a key kinase in necroptosis signaling, upregulated in fibrosis, and contributes to TNF-mediated inflammation.

Purpose of the Study:

  • Investigate the role of RIPK3 in liver fibrosis.
  • Elucidate the mechanism by which β1 integrin signaling influences RIPK3 expression in myofibroblasts.
  • Characterize the function of chromodomain helicase DNA-binding protein 4 (CHD4) in regulating RIPK3.

Main Methods:

  • Bile-duct-ligation-induced liver fibrosis model in mice.
  • Genetic ablation of β1 integrin in fibroblasts.
  • Analysis of RIPK3 expression in myofibroblasts.
  • Chromatin immunoprecipitation and gene expression analysis to study CHD4 function.

Main Results:

  • Myofibroblasts were identified as the primary RIPK3-expressing cells in liver fibrosis.
  • Genetic ablation of β1 integrin reduced ECM deposition and blunted RIPK3 expression.
  • RIPK3 downregulation was mediated by the chromatin-remodeling factor CHD4.
  • CHD4 repressed Ripk3 expression independently of NuRD or ChAHP complexes, indicating a novel mode of action.

Conclusions:

  • β1 integrin signaling is crucial for linking fibrotic processes to RIPK3-driven inflammation.
  • CHD4 plays a novel, locus-specific role in repressing Ripk3 gene expression, independent of known complexes.
  • This study uncovers a new mechanism connecting ECM receptor signaling to inflammatory kinase regulation in fibrosis.
Keywords:
CHD4CP: ImmunologyRIPK3fibrosisinflammationintegrinsnecroptosis

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