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.

Emily B Heikamp ¹, Chirag H Patel ¹, Sam Collins ², Adam Waickman ¹, Min-Hee Oh ², Im-Hong Sun ¹, Peter Illei ³, Archna Sharma ⁴, Aniko Naray-Fejes-Toth ⁵, Geza Fejes-Toth ⁵, Jyoti Misra-Sen ⁴, Maureen R Horton ², Jonathan D Powell ¹

Affiliations

1 Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4 Immune Cells and Inflammation Section, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
5 Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire, USA.

PMID: 24705297 DOI: 10.1038/ni.2867

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.

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