9d22

Structural highlights

Disease

FOXP3_MOUSE Defects in Foxp3 are the cause of the scurfy phenotype (sf). It results in a lethal disorder of immunoregulation, characterized by infections, diarrhea, anemia, thrombocytopenia, hypogonadism, gastrointestinal bleeding, lymphadenopathy and leukocytosis.

Function

FOXP3_MOUSE Transcriptional regulator which is crucial for the development and inhibitory function of regulatory T-cells (Treg). Plays an essential role in maintaining homeostasis of the immune system by allowing the acquisition of full suppressive function and stability of the Treg lineage, and by directly modulating the expansion and function of conventional T-cells. Can act either as a transcriptional repressor or a transcriptional activator depending on its interactions with other transcription factors, histone acetylases and deacetylases. The suppressive activity of Treg involves the coordinate activation of many genes, including CTLA4 and TNFRSF18 by FOXP3 along with repression of genes encoding cytokines such as interleukin-2 (IL2) and interferon-gamma (IFNG). Inhibits cytokine production and T-cell effector function by repressing the activity of two key transcription factors, RELA and NFATC2 (PubMed:15790681). Mediates transcriptional repression of IL2 via its association with histone acetylase KAT5 and histone deacetylase HDAC7 (By similarity). Can activate the expression of TNFRSF18, IL2RA and CTLA4 and repress the expression of IL2 and IFNG via its association with transcription factor RUNX1 (PubMed:17377532). Inhibits the differentiation of IL17 producing helper T-cells (Th17) by antagonizing RORC function, leading to down-regulation of IL17 expression, favoring Treg development (PubMed:18368049). Inhibits the transcriptional activator activity of RORA (By similarity). Can repress the expression of IL2 and IFNG via its association with transcription factor IKZF4 (PubMed:19696312).[UniProtKB:Q9BZS1]^{[1] [2] [3] [4]}

References

1. ↑ Bettelli E, Dastrange M, Oukka M. Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5138-43. Epub 2005 Mar 24. PMID:15790681 doi:http://dx.doi.org/10.1073/pnas.0501675102
2. ↑ Ono M, Yaguchi H, Ohkura N, Kitabayashi I, Nagamura Y, Nomura T, Miyachi Y, Tsukada T, Sakaguchi S. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature. 2007 Apr 5;446(7136):685-9. Epub 2007 Mar 21. PMID:17377532 doi:http://dx.doi.org/10.1038/nature05673
3. ↑ Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008 May 8;453(7192):236-40. doi: 10.1038/nature06878. Epub 2008 Mar 26. PMID:18368049 doi:http://dx.doi.org/10.1038/nature06878
4. ↑ Pan F, Yu H, Dang EV, Barbi J, Pan X, Grosso JF, Jinasena D, Sharma SM, McCadden EM, Getnet D, Drake CG, Liu JO, Ostrowski MC, Pardoll DM. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science. 2009 Aug 28;325(5944):1142-6. doi: 10.1126/science.1176077. Epub 2009, Aug 20. PMID:19696312 doi:http://dx.doi.org/10.1126/science.1176077