title: Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling.
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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Bo-Ram
authors.initials: BR
authors.lastname: Bang
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Han
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Hong
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Shim
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lerner
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Motoyuki
authors.identifier: http://orcid.org/0000-0003-2869-2881
authors.initials: M
authors.lastname: Otsuka
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000276:immunology; D034281:Dynamins / Q000276:immunology* / Q000378:metabolism; D057809:HEK293 Cells; D022781:Hepatocytes; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D007249:Inflammation; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D019169:Jurkat Cells; D008099:Liver / Q000276:immunology*; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology*; D009368:Neoplasm Transplantation; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000276:immunology* / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D016207:Cytokines; D050778:NFATC Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C570696:PGAM5 protein, mouse; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; C486391:Dnm1l protein, mouse; D034281:Dynamins