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

Hyeseok Shim, Chuan Wu, Shivan Ramsamooj, Kaitlyn N. Bosch, Zuojia Chen, Brooke M. Emerling, Jihye Yun, Hui Liu, Rayman Choo-Wing, Zhiwei Yang, Gerburg M. Wulf, Vijay Kumar Kuchroo, Lewis C. Cantley

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7596-7601
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number27
DOIs
StatePublished - Jul 5 2016
Externally publishedYes

Keywords

  • Autoimmunity
  • Inflammation
  • MTORC1
  • PI5P4K
  • PIP4K2C

ASJC Scopus subject areas

  • General

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