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

TitleDeletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system.
Publication TypeJournal Article
Year of Publication2016
AuthorsShim H, Wu C, Ramsamooj S, Bosch KN, Chen Z, Emerling BM, Yun J, Liu H, Choo-Wing R, Yang Z, Wulf GM, Kuchroo VKumar, Cantley LC
JournalProc Natl Acad Sci U S A
Date Published2016 Jul 05

Type 2 phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) converts phosphatidylinositol-5-phosphate to phosphatidylinositol-4,5-bisphosphate. Mammals have three enzymes PI5P4Kα, PI5P4Kβ, and PI5P4Kγ, 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 PI5P4Kγ, 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 IFNγ, 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 PI5P4Kγ plays a role in the regulation of the immune system via mTORC1 signaling.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID27313209
PubMed Central IDPMC4941458
Grant ListP01 CA120964 / CA / NCI NIH HHS / United States
R00 AI110649 / AI / NIAID NIH HHS / United States
R01 GM041890 / GM / NIGMS NIH HHS / United States

Weill Cornell Medicine
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