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.

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
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • Sirolimus