多發(fā)性硬化癥、糖尿病和關(guān)節(jié)炎等疾病都是自體免疫疾病,，這是由于一種稱為調(diào)節(jié)性T細(xì)胞的白血球發(fā)生問題所致。
在之前的研究中，科學(xué)家們發(fā)現(xiàn)調(diào)節(jié)性T細(xì)胞受到一種名為Foxp3的主調(diào)控基因的控制,。主調(diào)控基因與單個(gè)基因結(jié)合，進(jìn)而控制它們的活動進(jìn)而影響細(xì)胞的行為,。實(shí)際上,，如果 Foxp3停止工作，人體就無法生產(chǎn)調(diào)節(jié)性T細(xì)胞,。在這種情況下,，普通T細(xì)胞就會破壞人體器官，引起各種自免疫性疾病,。而直到現(xiàn)在,，科學(xué)家們對Foxp3 到底如何控制調(diào)節(jié)性T細(xì)胞所知甚少，因?yàn)樗麄儗δ切┲苯邮艿紽oxp3影響的基因幾乎一無所知,。
根據(jù)一篇發(fā)表于Proceedings of the National Academy of Sciences的新研究中,，賓州大學(xué)醫(yī)學(xué)院的研究人員發(fā)現(xiàn)如何修改作用于FOXP3 蛋白質(zhì)的酵素，并使調(diào)節(jié)性T細(xì)胞能更順利地發(fā)揮其功能,。
這些研究結(jié)果對于自體免疫疾病的治療意義重大,。FOXP3蛋白質(zhì)可以作用于一套復(fù)雜的酵素：組蛋白去乙?；?HDACs)。這些酵素使FOXP3 蛋白質(zhì)與另外一套稱為組蛋白乙酰轉(zhuǎn)移酶(HATs)的酵素產(chǎn)生關(guān)連性,。
研究人員發(fā)現(xiàn),，當(dāng)HATs啟動或當(dāng)HDACs關(guān)閉時(shí)，免疫調(diào)節(jié)細(xì)胞的運(yùn)作更順利且更長久,。如果FOXP3 蛋白質(zhì)的功能被關(guān)閉,，會導(dǎo)致自體免疫疾病。因此研究人員認(rèn)為可以針對這二種酵素研發(fā)藥物,，以控制免疫調(diào)節(jié)細(xì)胞的運(yùn)作,，進(jìn)而治療自體免疫疾病。
(資料來源 : biocompare)
FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression
Bin Li, Arabinda Samanta, Xiaomin Song, Kathryn T. Iacono, Kathryn Bembas, Ran Tao, Samik Basu, James L. Riley, Wayne W. Hancock, Yuan Shen, Sandra J. Saouaf, and Mark I. Greene*
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-6082
Communicated by Peter C. Nowell, University of Pennsylvania School of Medicine, Philadelphia, PA, January 20, 2007 (received for review November 21, 2006)
Abstract
The forkhead family protein FOXP3 acts as a repressor of transcription and is both an essential and sufficient regulator of the development and function of regulatory T cells. The molecular mechanism by which FOXP3-mediated transcriptional repression occurs remains unclear. Here, we report that transcriptional repression by FOXP3 involves a histone acetyltransferase–deacetylase complex that includes histone acetyltransferase TIP60 (Tat-interactive protein, 60 kDa) and class II histone deacetylases HDAC7 and HDAC9. The N-terminal 106–190 aa of FOXP3 are required for TIP60–FOXP3, HDAC7–FOXP3 association, as well as for the transcriptional repression of FOXP3 via its forkhead domain. FOXP3 can be acetylated in primary human regulatory T cells, and TIP60 promotes FOXP3 acetylation in vivo. Overexpression of TIP60 but not its histone acetyltransferase-deficient mutant promotes, whereas knockdown of endogenous TIP60 relieved, FOXP3-mediated transcriptional repression. A minimum FOXP3 ensemble containing native TIP60 and HDAC7 is necessary for IL-2 production regulation in T cells. Moreover, FOXP3 association with HDAC9 is antagonized by T cell stimulation and can be restored by the protein deacetylation inhibitor trichostatin A, indicating a complex dynamic aspect of T suppressor cell regulation. These findings identify a previously uncharacterized complex-based mechanism by which FOXP3 actively mediates transcriptional repression.
A central theme that has emerged over the last 25 years is that a process of self-regulation of the immune response occurs to limit self-reactivity. Biochemical details of how the immune system distinguishes and regulates self and non-self remain to be fully documented (1). A recently characterized CD4+CD25+ regulatory T cell subset expresses the Foxp3 transcription factor. As a transcriptional repressor of cytokine gene expression (2), Foxp3 was subsequently identified as an essential and sufficient regulator of natural regulatory T cell development and function (3–5).
Mammalian transcriptional repressors can execute their function by either passive or active mechanisms (6, 7). FOXP3 may, for example, function as a passive transcriptional repressor in the case of its association with NFAT and NF-B (8, 9). In this study, we explore the role of FOXP3 as an active transcriptional repressor by revealing the dynamic FOXP3 ensemble formation with a specific histone acetyltransferase (HAT) and certain class II histone deacetylases (HDACs) in expanded human CD4+CD25+ regulatory T cells (10, 11).
Histone acetylation and histone deacetylation affect chromatin remodeling during T cell development and differentiation (12, 13). HAT and HDAC abnormalities have been associated with leukemia (14, 15), diabetes (16) and other diseases of the immune system (17–19). The linkage of HAT and HDAC as components of a single complex permits dynamic responsiveness to extracellular stimulation (18, 20). The HAT TIP60 (Tat-interactive protein, 60 kDa), originally isolated as an HIV-1 TAT-interactive protein (21), functions as either a transcriptional coactivator or transcriptional corepressor (22, 23). Activated TIP60 can exert its acetyltransferase activity on a variety of proteins, including histone H2A, H3, and H4 (21), protein kinase ATM (24), and transcription factors such as c-myc (25) and p53 (26, 27). TIP60 also functions as a transcriptional corepressor of STAT3 in part through the recruitment of HDAC7 (28, 29).
Class II HDAC subfamily members include HDAC4, HDAC5, HDAC7, HDAC9, and HDAC10, all of which contain an N-terminal 17-aa MEF2D-binding motif, but only HDAC7 and HDAC9 are highly expressed in CD4+ T cells (30, 31). HDAC7 is highly expressed in CD4+CD8+ double positive T cells and regulates negative selection in the thymus by means of inhibition of Nur77 transcription through the specific recruitment of MEF2D to its binding site on the Nur77 promoter (30). HDAC9 expression is notably higher in mouse Foxp3gfp+CD4+ T cells than Foxp3gfp–CD4+ T cells (31).
Here, we provide evidence that FOXP3 actively represses transcription through its association with HAT TIP60 and HDAC7 and HDAC9 in vivo. We identified the N-terminal 106- to 190-aa proline-rich region of FOXP3, which has little similarity with other FOXP subfamily members, as a critical region for FOXP3 forkhead domain-mediated transcriptional repression, dependent on its dynamic association with TIP60 and HDAC7. Moreover, we demonstrate that FOXP3 is acetylated in primary human regulatory T cells and show that this process is promoted by TIP60. Whereas overexpression of TIP60, but not its HAT-deficient mutant, promotes FOXP3-mediated transcriptional repression, endogenous knockdown of TIP60 relieves this repression.
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