title: PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORγ.
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.
authors: Department of Microbiology and Immunology, Keio University School of Medicine, Shinanomachi, Tokyo 160-8582, Japan.
authors: Yutaka
authors: Y
authors: Kurebayashi
authors: Shigenori
authors: S
authors: Nagai
authors: Ai
authors: A
authors: Ikejiri
authors: Masashi
authors: M
authors: Ohtani
authors: Kenji
authors: K
authors: Ichiyama
authors: Yukiko
authors: Y
authors: Baba
authors: Taketo
authors: T
authors: Yamada
authors: Shohei
authors: S
authors: Egami
authors: Takayuki
authors: T
authors: Hoshii
authors: Atsushi
authors: A
authors: Hirao
authors: Satoshi
authors: S
authors: Matsuda
authors: Shigeo
authors: S
authors: Koyasu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D058504:Th17 Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C079873:Gfi1 protein, mouse; C539901:Rorc protein, mouse; C512964:Rps6ka1 protein, mouse