Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling.
Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling.
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DOI：
10.1038/ncomms9371
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发表时间：
2015-09-18
影响因子：
16.6
通讯作者：
Otsuka M
中科院分区：
文献类型：
--
作者：
Kang YJ;Bang BR;Han KH;Hong L;Shim EJ;Ma J;Lerner RA;Otsuka M
受体相互作用蛋白激酶3（RIPK 3）在程序性坏死和先天性炎症反应中起着至关重要的作用。然而，人们对RIPK 3参与NKT细胞介导的免疫反应知之甚少。在这里，我们证明了RIPK 3通过激活线粒体磷酸甘油酸酶PGAM 5在NKT细胞功能中起着至关重要的作用。RIPK 3介导的PGAM 5激活通过促进NFAT的核转位和动力蛋白相关蛋白1（Drp 1）的去磷酸化来促进细胞因子的表达，动力蛋白相关蛋白1（Drp 1）是线粒体稳态所必需的GT3。Ripk 3 −/−小鼠显示NKT细胞对转移性肿瘤细胞的反应降低，RIPK 3的缺失和Drp 1的药理学抑制均保护小鼠免受NKT细胞介导的急性肝损伤诱导。总的来说，结果确定了RIPK 3-PGAM 5-Drp 1/NFAT信号传导在NKT细胞活化中的关键作用，并进一步表明RIPK 3-PGAM 5信号传导可能介导线粒体功能和免疫信号传导之间的串扰。 RIPK 3介导的信号传导调节坏死性凋亡和炎症的诱导。在这里，作者表明RIPK 3-PGAM 5-Drp 1通路对于NKT细胞活化至关重要，而不依赖于黑色素瘤和急性炎症性肝损伤小鼠模型中的细胞死亡。
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.