Tiam1/Rac1 complex controls Il17a transcription and autoimmunity.
Tiam1/Rac1 complex controls Il17a transcription and autoimmunity.
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DOI：
10.1038/ncomms13048
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发表时间：
2016-10-11
影响因子：
16.6
通讯作者：
Elyaman, Wassim
中科院分区：
文献类型：
--
作者：
Kurdi, Ahmed T.;Bassil, Ribal;Olah, Marta;Wu, Chuan;Xiao, Sheng;Taga, Mariko;Frangieh, Michael;Buttrick, Thomas;Orent, William;Bradshaw, Elizabeth M.;Khoury, Samia J.;Elyaman, Wassim
RORγt是Th 17细胞的主要转录因子，被认为是治疗自身免疫性疾病的一个很有前途的药物靶点。在这里，我们显示鸟嘌呤核苷酸交换因子，Tiam 1，和它的同源Rho家族G蛋白，Rac 1，调节白细胞介素（IL）17 A转录和自身免疫。Tiam 1基因缺陷部分削弱IL-17 A表达并抑制实验性自身免疫性脑脊髓炎（EAE）的发展，而T细胞中Rac 1的缺失对Th 17细胞和EAE表现出更强的作用。我们证明Tiam 1和Rac 1在Th 17细胞的核区室中与RORγt形成复合物，并且一起结合并激活IL 17启动子。这些发现的临床相关性通过Rac 1的药理学靶向作用来强调，Rac 1抑制鼠和人Th 17细胞以及EAE。因此，我们的研究结果强调了Tiam 1/Rac 1在Th 17细胞中的调节途径，并表明它可能是多发性硬化症的治疗靶点。 Tiam 1是Rho家族GTdR Rac 1的鸟嘌呤核苷酸交换因子。在这里，作者表明，细胞核Tiam 1和Rac 1与IL-17启动子上的RORγt结合，激活其转录，并且抑制Tiam 1/Rac 1在小鼠自身免疫模型中是有益的。
RORγt is a master transcription factor of Th17 cells and considered as a promising drug target for the treatment of autoimmune diseases. Here, we show the guanine nucleotide exchange factor, Tiam1, and its cognate Rho-family G protein, Rac1, regulate interleukin (IL)17A transcription and autoimmunity. Whereas Tiam1 genetic deficiency weakens IL-17A expression partially and inhibits the development of experimental autoimmune encephalomyelitis (EAE), deletion of Rac1 in T cells exhibits more robust effects on Th17 cells and EAE. We demonstrate Tiam1 and Rac1 form a complex with RORγt in the nuclear compartment of Th17 cells, and together bind and activate the Il17 promoter. The clinical relevance of these findings is emphasized by pharmacological targeting of Rac1 that suppresses both murine and human Th17 cells as well as EAE. Thus, our findings highlight a regulatory pathway of Tiam1/Rac1 in Th17 cells and suggest that it may be a therapeutic target in multiple sclerosis. Tiam1 is a guanine nucleotide exchange factor for the Rho-family GTPase Rac1. Here, the authors show that nuclear Tiam1 and Rac1 bind to RORγt on the IL-17 promoter, activating its transcription, and that inhibiting Tiam1/Rac1 is beneficial in a mouse model of autoimmunity.
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影响因子：
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作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
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Feig, LA
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