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Proc Natl Acad Sci U S A. 2016 Jul 5;113(27):7596-601. doi: 10.1073/pnas.1600934113. Epub 2016 Jun 16.

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

Author information

1
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065; Biological and Biomedical Sciences Graduate Program, Harvard Medical School, Boston, MA 02115;
2
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115;
3
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065;
4
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02115.
5
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065; lcantley@med.cornell.edu.

Abstract

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.

KEYWORDS:

PI5P4K; PIP4K2C; autoimmunity; inflammation; mTORC1

PMID:
27313209
PMCID:
PMC4941458
DOI:
10.1073/pnas.1600934113
[Indexed for MEDLINE]
Free PMC Article

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