Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system

作者：Shim Hyeseok; Wu Chuan; Ramsamooj Shivan; Bosch Kaitlyn N; Chen Zuojia; Emerling Brooke M; Yun Jihye; Liu Hui; Choo Wing Rayman; Yang Zhiwei; Wulf Gerburg M; Kuchroo Vijay Kumar; Cantley Lewis C^*

来源：Proceedings of the National Academy of Sciences, 2016, 113(27): 7596-7601.

DOI：10.1073/pnas.1600934113

• PIP4K2C
• mTORC1
• autoimmunity
• PI5P4K
• inflammation

Type 2 phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) converts phosphatidylinositol-5-phosphate to phosphatidylinositol-4,5-bisphosphate. Mammals have three enzymes PI5P4K alpha, PI5P4K beta, and PI5P4K gamma, and these enzymes have been implicated in metabolic control, growth control, and a variety of stress responses. Here, we show that mice with germline deletion of type 2 phosphatidylinositol-5-phosphate 4-kinase gamma (Pip4k2c), the gene encoding PI5P4K., appear normal in regard to growth and viability but have increased inflammation and T-cell activation as they age. Immune cell infiltrates increased in Pip4k2c(-/-) mouse tissues. Also, there was an increase in proinflammatory cytokines, including IFN gamma, interleukin 12, and interleukin 2 in plasma of Pip4k2c(-/-) mice. Pip4k2c(-/-) mice had an increase in T-helper-cell populations and a decrease in regulatory T-cell populations with increased proliferation of T cells. Interestingly, mammalian target of rapamycin complex 1 (mTORC1) signaling was hyperactivated in several tissues from Pip4k2c(-/-) mice and treating Pip4k2c(-/-) mice with rapamycin reduced the inflammatory phenotype, resulting in a decrease in mTORC1 signaling in tissues and a decrease in proinflammatory cytokines in plasma. These results indicate that PI5P4K gamma plays a role in the regulation of the immune system via mTORC1 signaling.

• 出版日期2016-7-5