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PMID:11483607

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Citation

Schubert, LA, Jeffery, E, Zhang, Y, Ramsdell, F and Ziegler, SF (2001) Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J. Biol. Chem. 276:37672-9

Abstract

We have recently identified and cloned Foxp3, the gene defective in mice with the scurfy mutation. The immune dysregulation documented in these mice and in humans with mutations in the orthologous gene indicates that the foxp3 gene product, scurfin, is involved in the regulation of T cell activation and differentiation. The autoimmune state observed in these patients with the immune dysregulation polyendocrinopathy, enteropathy, X-linked syndrome, or X-linked autoimmunity-allergic dysregulation syndrome also points to a critical role for scurfin in the regulation of T cell homeostasis. FOXP3 encodes a novel member of the forkhead family of transcription factors. Here we demonstrate that this structural domain is required for nuclear localization and DNA binding. Scurfin, transiently expressed in heterologous cells, represses transcription of a reporter containing a multimeric forkhead binding site. Upon overexpression in CD4 T cells, scurfin attenuates activation-induced cytokine production and proliferation. We have identified FKH binding sequences adjacent to critical NFAT regulatory sites in the promoters of several cytokine genes whose expression is sensitive to changes in SFN abundance. Our findings indicate that the ability of scurfin to bind DNA, and presumably repress transcription, plays a paramount role in determining the amplitude of the response of CD4 T cells to activation.

Links

PubMed Online version:10.1074/jbc.M104521200

Keywords

Animals; CD4-Positive T-Lymphocytes/drug effects; CD4-Positive T-Lymphocytes/physiology; COS Cells; Cells, Cultured; Cytokines/biosynthesis; Cytokines/metabolism; DNA/drug effects; DNA/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/pharmacology; DNA-Binding Proteins/physiology; Forkhead Transcription Factors; Gene Silencing/drug effects; Gene Silencing/physiology; Humans; Lymphocyte Activation/drug effects; Lymphocyte Activation/physiology; Mutation; NFATC Transcription Factors; Nuclear Proteins; Transcription Factors/physiology; Transcription, Genetic/drug effects; Transcription, Genetic/physiology; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:FOXP3

involved_in

GO:0001818: negative regulation of cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FOXP3

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FOXP3

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FOXP3

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:FOXP3

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:FOXP3

involved_in

GO:0043029: T cell homeostasis

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FOXP3

involved_in

GO:0042036: negative regulation of cytokine biosynthetic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FOXP3

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FOXP3

involved_in

GO:0046007: negative regulation of activated T cell proliferation

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FOXP3

involved_in

GO:0050710: negative regulation of cytokine secretion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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