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

• Published in: Nature communications 2015-09, Vol.6 (1), p.8371-8371, Article 8371
• Main Authors: Kang, Young Jun, Bang, Bo-Ram, Han, Kyung Ho, Hong, Lixin, Shim, Eun-Jin, Ma, Jianhui, Lerner, Richard A., Otsuka, Motoyuki
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/51; 13/95; 38; 38/109; 631/250/1619/554/383; 631/250/249/2510; 631/67/1813/1634; 631/80/86; 64; 64/60; 96; 96/31; Active Transport, Cell Nucleus; Animals; Blotting, Western; Cell activation; Clonal deletion; Crosstalk; Cytokines; Cytokines - immunology; Damage detection; Dephosphorylation; Dynamin; Dynamins - immunology; Dynamins - metabolism; Guanosine triphosphatases; HEK293 Cells; Hepatocytes; Humanities and Social Sciences; Humans; Immune response (cell-mediated); Immunity, Cellular - immunology; Inflammation; Interferon-gamma - immunology; Interleukin-4 - immunology; Jurkat Cells; Kinases; Liver; Liver - immunology; Melanoma, Experimental; Metastases; Mice; Mice, Knockout; Mitochondria; Mitochondria - metabolism; multidisciplinary; Natural Killer T-Cells - immunology; Necrosis; Neoplasm Transplantation; NF-AT protein; NFATC Transcription Factors - metabolism; Nuclear transport; Pharmacology; Phosphoglycerate mutase; Phosphoprotein Phosphatases; Phosphoric Monoester Hydrolases - immunology; Phosphoric Monoester Hydrolases - metabolism; Protein kinase; Proteins; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - immunology; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Science; Science (multidisciplinary); Signal Transduction; Signaling; Translocation; Tumor Necrosis Factor-alpha - immunology; Tumors
• ISSN: 2041-1723; 2041-1723
• 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. RIPK3-mediated signalling regulates the induction of necroptosis and inflammation. Here the authors show that RIPK3-PGAM5-Drp1 pathway is crucial for NKT cell activation independently of cell death in mouse models of melanoma and acute inflammatory liver injury.