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

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

Author information

1
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
2
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
3
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.

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.

PMID:
26381214
PMCID:
PMC4576739
DOI:
10.1038/ncomms9371
[Indexed for MEDLINE]
Free PMC Article

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