Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system.
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.
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;
Hyeseok
H
Shim
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115;
Chuan
C
Wu
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065;
Shivan
S
Ramsamooj
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065;
Kaitlyn N
KN
Bosch
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115;
Zuojia
Z
Chen
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065;
Brooke M
BM
Emerling
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065;
Jihye
J
Yun
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02115.
Hui
H
Liu
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065;
Rayman
R
Choo-Wing
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065;
Zhiwei
Z
Yang
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02115.
Gerburg M
GM
Wulf
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115;
Vijay Kumar
VK
Kuchroo
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.
Lewis C
LC
Cantley
D000818:Animals; D005260:Female; D007249:Inflammation / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D020123:Sirolimus; D013601:T-Lymphocytes / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D046912:Multiprotein Complexes; D017853:Phosphotransferases (Alcohol Group Acceptor); C546220:Pip4k2c protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
PI5P4K; PIP4K2C; autoimmunity; inflammation; mTORC1