Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms.
Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms.
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组蛋白脱乙酰基酶6和9和Sirtuin-1控制FOXP3+调节性T细胞功能通过共享和同工型特异性机制。
DOI：
10.1126/scisignal.2002873
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发表时间：
2012-06-19
影响因子：
7.3
通讯作者：
Hancock WW
中科院分区：
文献类型：
--
作者：
Beier UH;Wang L;Han R;Akimova T;Liu Y;Hancock WW
靶向治疗组蛋白/蛋白去乙酰化酶6 （HDAC6）、HDAC9或sirtuin-1 （Sirt1）增强了含有转录因子Foxp3的调节性T细胞（Tregs）的抑制功能。然而，尚不清楚是否涉及不同的机制，或者联合抑制这些靶点是否更有益。我们比较了野生型C57BL/6小鼠Tregs的抑制功能与具有全全性（HDAC6−/−，HDAC9−/−和HDAC6−/−HDAC9−/−）或条件性（fl-Sirt1/CD4-Cre或fl-Sirt1/Foxp3-Cre） HDAC缺失以及同种异型选择性HDAC抑制剂治疗的小鼠Tregs的抑制功能。我们发现热休克反应对HDAC6抑制介导的Treg抑制功能的改善有重要作用，而对Sirt1抑制不起作用。此外，尽管HDAC6、HDAC9和Sirt1都使Foxp3去乙酰化，但每种蛋白对控制Foxp3基因表达的转录因子有不同的影响。例如，HDAC9的缺失与信号换能器和转录激活子5 （STAT5）的乙酰化及其转录活性的稳定有关。因此，靶向不同HDAC可通过多种加性机制增加Treg功能，这表明HDAC抑制剂联合治疗自身免疫和器官移植具有治疗潜力。
Therapeutic targeting of histone/protein deacetylase 6 (HDAC6), HDAC9, or the sirtuin-1 (Sirt1) augments the suppressive functions of regulatory T cells (Tregs) that contain the transcription factor Foxp3. However, it is unclear whether distinct mechanisms are involved or whether combined inhibition of these targets would be more beneficial. We compared the suppressive functions of Tregs from wild-type C57BL/6 mice with those from mice with either global (HDAC6−/−, HDAC9−/−, and HDAC6−/−HDAC9−/−), or conditional (fl-Sirt1/CD4-Cre or fl-Sirt1/Foxp3-Cre) HDAC deletion, as well as treatment with isoform-selective HDAC inhibitors. We found that the heat shock response was important for the improvement of Treg suppressive function mediated by HDAC6 inhibition, but not Sirt1 inhibition. Furthermore, although HDAC6, HDAC9, and Sirt1 all deacetylated Foxp3, each protein had diverse effects on transcription factors controlling Foxp3 gene expression. For example, loss of HDAC9 was associated with stabilization of the acetylation of signal transducer and activator of transcription 5 (STAT5) and of its transcriptional activity. Hence, targeting different HDACs increased Treg function by multiple and additive mechanisms, which indicates the therapeutic potential for combinations of HDAC inhibitors in the management of autoimmunity and organ transplantation.
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DOI：
10.1073/pnas.0700298104
发表时间：
2007-03-13
影响因子：
11.1
作者：
Li, Bin;Samanta, Arabinda;Greene, Mark I.
通讯作者：
Greene, Mark I.
影响因子：
5.7
作者：
Lee, Ju-Hee;Park, Jung-Hyun;Bang, Yung-Jue
通讯作者：
Bang, Yung-Jue
影响因子：
5.3
作者：
de Zoeten, Edwin F.;Wang, Liqing;Hancock, Wayne W.
通讯作者：
Hancock, Wayne W.
影响因子：
29.4
作者：
de Zoeten EF;Wang L;Sai H;Dillmann WH;Hancock WW
通讯作者：
Hancock WW
影响因子：
5.3
作者：
Hunt, CR;Dix, DJ;Pandita, TK
通讯作者：
Pandita, TK