PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORγ

Yutaka Kurebayashi; Shigenori Nagai; Ai Ikejiri; Masashi Ohtani; Kenji Ichiyama; Yukiko Baba; Taketo Yamada; Shohei Egami; Takayuki Hoshii; Atsushi Hirao; Satoshi Matsuda; Shigeo Koyasu

doi:10.1016/j.celrep.2012.02.007

PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORγ

Cell Rep. 2012 Apr 19;1(4):360-73. doi: 10.1016/j.celrep.2012.02.007. Epub 2012 Mar 29.

Authors

Yutaka Kurebayashi¹, Shigenori Nagai, Ai Ikejiri, Masashi Ohtani, Kenji Ichiyama, Yukiko Baba, Taketo Yamada, Shohei Egami, Takayuki Hoshii, Atsushi Hirao, Satoshi Matsuda, Shigeo Koyasu

Affiliation

¹ Department of Microbiology and Immunology, Keio University School of Medicine, Shinanomachi, Tokyo 160-8582, Japan.

PMID: 22832227
DOI: 10.1016/j.celrep.2012.02.007

Abstract

The PI3K-Akt-mTORC1 axis contributes to the activation, survival, and proliferation of CD4(+) T cells upon stimulation through TCR and CD28. Here, we demonstrate that the suppression of this axis by deletion of p85α or PI3K/mTORC1 inhibitors as well as T cell-specific deletion of raptor, an essential component of mTORC1, impairs Th17 differentiation in vitro and in vivo in a S6K1/2-dependent fashion. Inhibition of PI3K-Akt-mTORC1-S6K1 axis impairs the downregulation of Gfi1, a negative regulator of Th17 differentiation. Furthermore, we demonstrate that S6K2, a nuclear counterpart of S6K1, is induced by the PI3K-Akt-mTORC1 axis, binds RORγ, and carries RORγ to the nucleus. These results point toward a pivotal role of PI3K-Akt-mTORC1-S6K1/2 axis in Th17 differentiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / drug effects
Cell Differentiation / physiology
Cell Nucleus / metabolism
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Gene Expression Regulation
Mechanistic Target of Rapamycin Complex 1
Mice
Multiprotein Complexes
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
Phosphatidylinositol 3-Kinases / metabolism
Phosphatidylinositol 3-Kinases / physiology*
Protein Transport
Proteins / metabolism
Proteins / physiology*
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-akt / physiology*
Ribosomal Protein S6 Kinases, 90-kDa / metabolism
Ribosomal Protein S6 Kinases, 90-kDa / physiology*
Sirolimus / pharmacology
TOR Serine-Threonine Kinases
Th17 Cells / cytology*
Th17 Cells / drug effects
Th17 Cells / metabolism
Transcription Factors / genetics*
Transcription Factors / metabolism

Substances

DNA-Binding Proteins
Gfi1 protein, mouse
Multiprotein Complexes
Nuclear Receptor Subfamily 1, Group F, Member 3
Proteins
Rorc protein, mouse
Transcription Factors
Mechanistic Target of Rapamycin Complex 1
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases, 90-kDa
Rps6ka1 protein, mouse
TOR Serine-Threonine Kinases
Sirolimus