The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex

Nat Immunol. 2014 May;15(5):457-64. doi: 10.1038/ni.2867. Epub 2014 Apr 6.

Abstract

SGK1 is an AGC kinase that regulates the expression of membrane sodium channels in renal tubular cells in a manner dependent on the metabolic checkpoint kinase complex mTORC2. We hypothesized that SGK1 might represent an additional mTORC2-dependent regulator of the differentiation and function of T cells. Here we found that after activation by mTORC2, SGK1 promoted T helper type 2 (TH2) differentiation by negatively regulating degradation of the transcription factor JunB mediated by the E3 ligase Nedd4-2. Simultaneously, SGK1 repressed the production of interferon-γ (IFN-γ) by controlling expression of the long isoform of the transcription factor TCF-1. Consistent with those findings, mice with selective deletion of SGK1 in T cells were resistant to experimentally induced asthma, generated substantial IFN-γ in response to viral infection and more readily rejected tumors.

Publication types

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

MeSH terms

  • Adaptive Immunity / genetics
  • Animals
  • Asthma / immunology*
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Gene Expression Regulation / genetics
  • Hepatocyte Nuclear Factor 1-alpha
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Mechanistic Target of Rapamycin Complex 2
  • Melanoma, Experimental / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / immunology*
  • Nedd4 Ubiquitin Protein Ligases
  • Poxviridae Infections / immunology*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • T Cell Transcription Factor 1 / genetics
  • T Cell Transcription Factor 1 / metabolism
  • TOR Serine-Threonine Kinases / immunology*
  • Th1 Cells / immunology*
  • Th2 Cells / immunology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Burden / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Vaccinia virus / immunology*

Substances

  • Endosomal Sorting Complexes Required for Transport
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Immediate-Early Proteins
  • JunB protein, mouse
  • Multiprotein Complexes
  • T Cell Transcription Factor 1
  • Transcription Factors
  • Interferon-gamma
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4l protein, mouse
  • Ubiquitin-Protein Ligases
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase