PMID:22761423

Citation	Oh, HM, Yu, CR, Dambuza, I, Marrero, B and Egwuagu, CE (2012) STAT3 protein interacts with Class O Forkhead transcription factors in the cytoplasm and regulates nuclear/cytoplasmic localization of FoxO1 and FoxO3a proteins in CD4(+) T cells. J. Biol. Chem. 287:30436-43
Abstract	An important feature of the adaptive immune response is its remarkable capacity to regulate the duration of inflammatory responses, and effector T cells have been shown to limit excessive immune responses by producing anti-inflammatory cytokines such as IL-10 and IL-27. However, how anti-inflammatory cytokines mediate their suppressive activities is not well understood. In this study, we show that STAT3 contributes to mechanisms that control the duration of T cell proliferation by regulating the subcellular location of FoxO1 and FoxO3a, two Class O Forkhead transcription factors that mediate lymphocyte quiescence and inhibit T cell activation. We show that active FoxO1 and FoxO3a reside exclusively in the nucleus of naïve T cells whereas inactive pFoxO1 and pFoxO3a were most abundant in activated T cells and sequestered in their cytoplasm in association with unphosphorylated STAT3 (U-STAT3) and 14-3-3. We further show that FoxO1/FoxO3a rapidly relocalized into the nucleus in response to pSTAT3 activation by IL-6 or IL-10, and the accumulation of FoxO1/FoxO3a in their nuclei coincided with increased expression of p27(Kip1) and p21(WAF1). STAT3 inhibitors completely abrogated cytokine-induced translocation of FoxO1/FoxO3a into the nucleus. In naïve or resting STAT3-deficient T cells, expression of pFoxO1/pFoxO3a was predominantly in the cytoplasm and correlated with defects in p27(Kip1) and p21(WAF1) expression, suggesting requirement of STAT3 for importation or retention of FoxO in the nucleus and attenuation of lymphocyte proliferation. Taken together, these results suggest that U-STAT3 collaborates with 14-3-3 to sequester pFoxO1/pFoxO3a in cytoplasm and thus prolong T cell activation, whereas pSTAT3 activation by anti-inflammatory cytokines would curtail the duration of TCR activation and re-establish lymphocyte quiescence by inducing nuclear localization of FoxO1/FoxO3a and FoxO-mediated expression of growth-inhibitory proteins.
Links	PubMed PMC3436293 Online version:10.1074/jbc.M112.359661
Keywords	14-3-3 Proteins/genetics; 14-3-3 Proteins/immunology; 14-3-3 Proteins/metabolism; Active Transport, Cell Nucleus/immunology; Animals; CD4-Positive T-Lymphocytes/cytology; CD4-Positive T-Lymphocytes/immunology; CD4-Positive T-Lymphocytes/metabolism; Cell Nucleus/genetics; Cell Nucleus/immunology; Cell Nucleus/metabolism; Cyclin-Dependent Kinase Inhibitor p21/genetics; Cyclin-Dependent Kinase Inhibitor p21/immunology; Cyclin-Dependent Kinase Inhibitor p21/metabolism; Cyclin-Dependent Kinase Inhibitor p27/genetics; Cyclin-Dependent Kinase Inhibitor p27/immunology; Cyclin-Dependent Kinase Inhibitor p27/metabolism; Cytokines/genetics; Cytokines/immunology; Cytokines/metabolism; Cytoplasm/genetics; Cytoplasm/immunology; Cytoplasm/metabolism; Forkhead Box Protein O1; Forkhead Box Protein O3; Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/immunology; Forkhead Transcription Factors/metabolism; Gene Expression Regulation/immunology; Humans; Jurkat Cells; Lymphocyte Activation/physiology; Mice; Mice, Knockout; Receptors, Antigen, T-Cell/genetics; Receptors, Antigen, T-Cell/immunology; Receptors, Antigen, T-Cell/metabolism; STAT3 Transcription Factor/genetics; STAT3 Transcription Factor/immunology; STAT3 Transcription Factor/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:STAT3	Colocalizes with	GO:0005737: cytoplasm	ECO:0000316:	UniProtKB:Q9R1E0 UniProtKB:Q9WVH4	C		Organism: Mus musculus Protein: Stat3 // Stat3 with FOXO1 and FOXO3a // Foxo1 and Foxo3 Figure 1: "STAT3 co-localized and interacted with pFoxO1 and pFoxO3a in the cytoplasm of activated T cells."	complete CACAO 12864
MOUSE:STAT3		GO:0005737: cytoplasm	ECO:0000314:		C		Organism: Mus musculus Protein STAT3// Stat3 Figure 1 shows the protein localizes in the cytoplasm.	complete CACAO 12865

References

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