Interaction between GATA-3 and the Transcriptional Coregulator Pias1 Is Important for the Regulation of Th2 Immune Responses

Zhao, Xinyan; Zheng, Bo; Huang, Yanfang; Yang, Dan; Katzman, Shoshana D.; Chang, Chawnshang; Fowell, Deborah J.; Zeng, Weiping

doi:10.4049/jimmunol.179.12.8297

Cited by 16 publications

(17 citation statements)

References 51 publications

(47 reference statements)

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“…C-maf regulates IL-4 production but is not required for production of other Th2 cytokines (43). Similarly, Pias1 increases IL-13 production without affecting IL-4 or IL-5 expression (44). We have shown that PU.1 decreases expression of many Th2 cytokines, but increases expression of CCL22, a chemokine associated with Th2 inflammation (8).…”

Section: Discussionmentioning

confidence: 99%

IFN Regulatory Factor 4 Regulates the Expression of a Subset of Th2 Cytokines

Ahyi

Chang²,

Dent

et al. 2009

The Journal of Immunology

121

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Th2 cells can be subdivided into subpopulations depending on the level of a cytokine and the subsets of cytokines they produce. We have recently identified the ETS family transcription factor PU.1 as regulating heterogeneity in Th2 populations. To define additional factors that might contribute to Th2 heterogeneity, we examined the PU.1 interacting protein IFN-regulatory factor (IRF)4. When Th2 cells are separated based on levels of IL-10 secretion, IRF4 expression segregates into the subset of Th2 cells expressing high levels of IL-10. Infection of total Th2 cells, and IL-10 nonsecreting cells, with retrovirus-expressing IRF4, resulted in increased IL-4 and IL-10 expression, no change in IL-5 or IL-13 production and decreased Il9 transcription. Transfection of an IRF4-specific small interfering RNA into Th2 cells decreases IL-10 production. IRF4 directly binds the Il10 gene as evidenced by chromatin immunoprecipitation assay, and regulates Il10 control elements in a reporter assay. IRF4 interacts with PU.1, and in PU.1-deficient T cells there was an increase in IRF4 binding to the Il10 gene, and in the ability of IRF4 to induce IL-10 production compared with wild-type cells and Il10 promoter activity in a reporter assay. Further heterogeneity of IRF4 expression was observed in Th2 cells analyzed for expression of multiple Th2 cytokines. Thus, IRF4 promotes the expression of a subset of Th2 cytokines and contributes to Th2 heterogeneity.

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Section: Discussionmentioning

confidence: 99%

IFN Regulatory Factor 4 Regulates the Expression of a Subset of Th2 Cytokines

Ahyi

Chang²,

Dent

et al. 2009

The Journal of Immunology

121

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“…GATA-3 associates with Ubc9 and the SUMO-E3 ligase PIAS1 in yeast two-hybrid assays, suggesting that sumoylation is possible; but studies focusing on PIAS1 suggest this may have the opposite effect as that seen with c-Maf (59). Overexpression of PIAS1 in DO11.10Ca −/− splenocytes enhances GATA-3 binding to the IL-13 promoter and increases IL-13 production.…”

Section: Discussionmentioning

confidence: 99%

SUMO Conjugation Contributes to Immune Deviation in Nonobese Diabetic Mice by Suppressing c-Maf Transactivation of IL-4

Leavenworth¹,

Mo³

et al. 2009

The Journal of Immunology

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It is not clear why the development of protective Th2 cells is poor in type 1 diabetes (T1D). c-Maf transactivates the IL-4 gene promoting Th2 cell development; therefore, abnormalities in c-Maf may contribute to reduced IL-4 production by CD4 cells from nonobese diabetic (NOD) mice. In this study we demonstrate that despite normal expression, c-Maf binds poorly to the IL-4 promoter (IL-4p) in NOD CD4 cells. Immunoblotting demonstrates that c-Maf can be modified at lysine 33 by SUMO-1 (small ubiquitin-like modifier 1). Sumoylation is facilitated by direct interaction with the E2-conjugating enzyme Ubc9 and increases following T cell stimulation. In transfected cells, sumoylation decreases c-Maf transactivation of IL-4p-driven luciferase reporter activity, reduces c-Maf binding to the IL-4p in chromatin immunoprecipitation assays, and enhances c-Maf localization into promyelocytic leukemia nuclear bodies. Sumoylation of c-Maf is increased in NOD CD4 cells as compared with CD4 cells from diabetes-resistant B10.D2 mice, suggesting that increased c-Maf sumoylation contributes to immune deviation in T1D by reducing c-Maf access to and transactivation of the IL-4 gene.

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“…Therefore, distinct structural features of GATA3 are important for IL-13 production. A study showing that protein inhibitor of activated STAT1 (PIAS1) binds to GATA3 in T H 2 cells and controls IL-13 production but not IL-5 or IL-4 production indicates that distinct co-activators may be recruited for individual cytokines110.…”

Section: Structural Insights Into Gata3 Functionmentioning

confidence: 99%

GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation

2009

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Many advances in our understanding of the molecules that regulate the development, differentiation and function of T cells have been made over the past few years. One important regulator of T-cell differentiation is the transcription factor GATA3 (GATA-binding protein 3). Although the main function of GATA3 is to act as a master transcription factor for the differentiation of T helper 2 (T H 2) cells, new research has helped to uncover crucial functions of GATA3 in T cells that go beyond T H 2-cell differentiation, and that are important at earlier stages of haematopoietic-and lymphoid-cell development. This Review focuses on the functions of GATA3 from early thymocyte development to effector T-cell differentiation. In addition, we discuss the interactions between GATA3 and other transcription factors and signalling pathways, and highlight the functional significance of GATA3 protein structure.The GATA family of transcription factors are conserved proteins that contain one or two C2-C2-type zinc-finger motifs that recognize the consensus DNA sequence WGATAR (where W denotes A or T and R denotes A or G)1 , 2. The six members of the mammalian GATA family (GATA1 to GATA6) contain two zinc-finger motifs, which probably arose by gene duplication (FIG. 1). The different GATA proteins have distinct and restricted patterns of tissue expression and can be divided into the haematopoietic factors (GATA1, GATA2 and GATA3) and the endodermal factors (GATA4, GATA5 and GATA6). The GATA proteins have a common structure, which comprises distinct N-terminal regions that have transactivating activity, highly conserved zinc-finger motifs in the C-terminal region, conserved basic regions located immediately after the second zinc finger and distinct Cterminal regions of varying lengths (FIG. 1). GATA3 is the main GATA-family member that is expressed by immune cells, and can be easily detected in developing and mature T cells, natural killer (NK) cells and CD1-restricted NKT cells3 -5. Indeed, several recent studies have revealed an emerging role for GATA3 in invariant NKT cells (BOX 1). By contrast, mature mast cells express GATA1 and GATA2 but not GATA36 , 7. Beyond the immune system, GATA3 is expressed in many embryonic and adult tissues, including the adrenal glands, kidneys, central nervous system, inner ear, hair follicles, skin and breast tissue, and important functions in several these tissues have been demonstrated in knockout and conditional knockout mouse models8 -14 (for additional references, see REF. 15).In immune cells, GATA3 is best known to function as a master regulator of T helper 2 (T H 2)-cell differentiation. However, in recent years, GATA3 has been found to have additional crucial functions in early T-cell commitment, β-selection and CD4 + T-cell NIH Public Access

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Interaction between GATA-3 and the Transcriptional Coregulator Pias1 Is Important for the Regulation of Th2 Immune Responses

Cited by 16 publications

References 51 publications

IFN Regulatory Factor 4 Regulates the Expression of a Subset of Th2 Cytokines

IFN Regulatory Factor 4 Regulates the Expression of a Subset of Th2 Cytokines

SUMO Conjugation Contributes to Immune Deviation in Nonobese Diabetic Mice by Suppressing c-Maf Transactivation of IL-4

GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation

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