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

Academic Article
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Overview

authors

  • Kang, Young Jun
  • Bang, B. R.
  • Han, K. H.
  • Hong, L.
  • Shim, E. J.
  • Ma, J. H.
  • Lerner, Richard
  • Otsuka, M.

publication date

  • September 2015

journal

  • Nature Communications  Journal

abstract

  • 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.

subject areas

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

PubMed Central ID

  • PMC4576739

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms9371

PubMed ID

  • 26381214
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Additional Document Info

start page

  • 8371

volume

  • 6

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