DCAF1 controls T-cell function via p53-dependent and -independent mechanisms.
DCAF1 controls T-cell function via p53-dependent and -independent mechanisms.
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DOI：
10.1038/ncomms10307
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发表时间：
2016-01-05
影响因子：
16.6
通讯作者：
Wan YY
中科院分区：
文献类型：
--
作者：
Guo Z;Kong Q;Liu C;Zhang S;Zou L;Yan F;Whitmire JK;Xiong Y;Chen X;Wan YY
激活后，初始T细胞的大小不断增大并进入细胞周期以激发免疫反应。T细胞生长和细胞周期进入的基本过程是如何调节的，人们对此知之甚少。在这里，我们报告，DCAF 1（Ddb 1-cullin 4-associated-factor 1）是必不可少的这些过程。T细胞中DCAF 1的缺失损害了它们的外周稳态。DCAF 1在T细胞受体活化时上调，对活化诱导的T细胞生长、细胞周期进入和增殖至关重要。此外，DCAF 1是体内抗病毒和自身免疫反应期间T细胞扩增和功能所必需的。DCAF 1缺失导致p53蛋白的急剧稳定，这可以归因于MDM 2介导的p53多聚泛素化需要DCAF 1。重要的是，p53缺失挽救了细胞周期进入缺陷，但不能挽救DCAF 1缺陷细胞的生长缺陷。因此，DCAF 1通过p53依赖性和非依赖性机制对T细胞功能至关重要。 DCAF 1（VprBP）是一种HIV靶蛋白，是参与植物和动物发育过程的遍在蛋白连接酶复合物的组成部分。在这里，DCAF 1被证明是活化诱导的T细胞生长和增殖至关重要，部分是因为p53的泛素化和降解所必需的。
On activation, naive T cells grow in size and enter cell cycle to mount immune response. How the fundamental processes of T-cell growth and cell cycle entry are regulated is poorly understood. Here we report that DCAF1 (Ddb1–cullin4-associated-factor 1) is essential for these processes. The deletion of DCAF1 in T cells impairs their peripheral homeostasis. DCAF1 is upregulated on T-cell receptor activation and critical for activation-induced T-cell growth, cell cycle entry and proliferation. In addition, DCAF1 is required for T-cell expansion and function during anti-viral and autoimmune responses in vivo. DCAF1 deletion leads to a drastic stabilization of p53 protein, which can be attributed to a requirement of DCAF1 for MDM2-mediated p53 poly-ubiquitination. Importantly, p53 deletion rescues the cell cycle entry defect but not the growth defect of DCAF1-deficient cells. Therefore, DCAF1 is vital for T-cell function through p53-dependent and -independent mechanisms. DCAF1 (VprBP), an HIV target protein, is a component of an ubiquitin ligase complex involved in developmental processes in plants and animals. Here, DCAF1 is shown to be vital for activation-induced T cell growth and proliferation, partly by being required for p53's ubiquitination and degradation.