Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling

Nat Commun. 2015 Sep 18:6:8371. doi: 10.1038/ncomms9371.


The receptor-interacting protein kinase 3 (RIPK3) plays crucial roles in programmed necrosis and innate inflammatory responses. However, a little is known about the involvement of RIPK3 in NKT cell-mediated immune responses. Here, we demonstrate that RIPK3 plays an essential role in NKT cell function via activation of the mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5). RIPK3-mediated activation of PGAM5 promotes the expression of cytokines by facilitating nuclear translocation of NFAT and dephosphorylation of dynamin-related protein 1 (Drp1), a GTPase is essential for mitochondrial homoeostasis. Ripk3(-/-) mice show reduced NKT cell responses to metastatic tumour cells, and both deletion of RIPK3 and pharmacological inhibition of Drp1 protects mice from NKT cell-mediated induction of acute liver damage. Collectively, the results identify a crucial role for RIPK3-PGAM5-Drp1/NFAT signalling in NKT cell activation, and further suggest that RIPK3-PGAM5 signalling may mediate crosstalk between mitochondrial function and immune signalling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Blotting, Western
  • Cytokines / immunology
  • Dynamins / immunology*
  • Dynamins / metabolism
  • HEK293 Cells
  • Hepatocytes
  • Humans
  • Immunity, Cellular / immunology*
  • Inflammation
  • Interferon-gamma / immunology
  • Interleukin-4 / immunology
  • Jurkat Cells
  • Liver / immunology*
  • Melanoma, Experimental
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • NFATC Transcription Factors / metabolism
  • Natural Killer T-Cells / immunology*
  • Neoplasm Transplantation
  • Phosphoprotein Phosphatases
  • Phosphoric Monoester Hydrolases / immunology*
  • Phosphoric Monoester Hydrolases / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / immunology*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / immunology


  • Cytokines
  • NFATC Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • Interferon-gamma
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • PGAM5 protein, mouse
  • Phosphoprotein Phosphatases
  • Phosphoric Monoester Hydrolases
  • Dnm1l protein, mouse
  • Dynamins