Distinct structural requirements of GATA-3 for the regulation of thymocyte and Th2 cell differentiation.
GATA-3, the only T cell-specific member of the GATA family of transcription factors, is essential for the intrathymic development of CD4+ T cells and for the differentiation of Th2 cells. However, whether distinct biochemical features, unique to GATA-3 compared with other GATA family members, are required to drive T cell transcriptional programs or whether the T cell-specific functions of GATA-3 can simply be ascribed to its expression pattern is unclear. Nor do we understand the protein structural requirements for each individual function of GATA-3. In this study, we report that a heterologous GATA factor, GATA-4, was competent in supporting the development of CD4+ T cells but could not fully compensate for GATA-3 in regulating the expression of Th cytokines. Specifically, GATA-3 was more potent than GATA-4 in driving the production of IL-13 due to a mechanism independent of DNA binding or chromatin remodeling of the IL-13 locus. The difference was mapped to a partially conserved region C-terminal to the second zinc finger. Converting a single proline residue located in this region of GATA-4 to its counterpart, a methionine of GATA-3, was sufficient to enhance the IL-13-promoting function of GATA-4 but had no effect on other cytokines. Taken together, our data demonstrate that the unique function of GATA-3 is conferred by both its cell type-specific expression and distinct protein structure.
Pai
Sung-Yun
SY
Division of Pediatric Hematology-Oncology, Children's Hospital, Department of Pediatric Oncology, Harvard Medical School, Boston, MA 02115, USA.
Kang
Bok Yun
BY
Sabadini
Amelia M
AM
Parisini
Emilio
E
Truitt
Morgan L
ML
Ho
I-Cheng
IC
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D002454:Cell Differentiation / Q000235:genetics; D017124:Conserved Sequence; D050990:GATA3 Transcription Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics*; D008715:Methionine / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D011392:Proline / Q000737:chemistry / Q000235:genetics; D011401:Promoter Regions, Genetic; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
D015704:CD4 Antigens; D050990:GATA3 Transcription Factor; D050991:GATA4 Transcription Factor; D018793:Interleukin-13; D007377:Interleukin-3; D011392:Proline; D008715:Methionine