The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex.
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.
Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Emily B
EB
Heikamp
Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Chirag H
CH
Patel
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Sam
S
Collins
Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Adam
A
Waickman
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Min-Hee
MH
Oh
Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Im-Hong
IH
Sun
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Peter
P
Illei
Immune Cells and Inflammation Section, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
Archna
A
Sharma
Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
Aniko
A
Naray-Fejes-Toth
Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
Geza
G
Fejes-Toth
Immune Cells and Inflammation Section, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
Jyoti
J
Misra-Sen
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Maureen R
MR
Horton
Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jonathan D
JD
Powell
D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D001249:Asthma / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000276:immunology*; D000075702:Nedd4 Ubiquitin Protein Ligases; D011213:Poxviridae Infections / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014616:Vaccinia virus / Q000276:immunology*; D000099184:Serum-Glucocorticoid Regulated Kinases
D056827:Endosomal Sorting Complexes Required for Transport; D051538:Hepatocyte Nuclear Factor 1-alpha; D017874:Immediate-Early Proteins; D007371:Interferon-gamma; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases; D051822:T Cell Transcription Factor 1; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C496488:Hnf1a protein, mouse; C584097:JunB protein, mouse; C000618461:Nedd4l protein, mouse