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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Inflammation / genetics*
  • Lymphocyte Activation / genetics*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / metabolism*
  • Phenotype
  • Phosphotransferases (Alcohol Group Acceptor) / physiology*
  • Polymorphism, Single Nucleotide
  • Sirolimus
  • T-Lymphocytes / physiology
  • TOR Serine-Threonine Kinases / metabolism*


  • Multiprotein Complexes
  • Phosphotransferases (Alcohol Group Acceptor)
  • Pip4k2c protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Sirolimus