Post-translational control of T cell development by the ESCRT protein CHMP5
Post-translational control of T cell development by the ESCRT protein CHMP5
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DOI：
10.1038/ni.3764
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发表时间：
2017-07-01
影响因子：
30.5
通讯作者：
Glimcher, Laurie H.
中科院分区：
文献类型：
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作者：
Adoro, Stanley;Park, Kwang Hwan;Glimcher, Laurie H.
保护性脊椎动物免疫系统的获得取决于胸腺通过尚未完全解决的机制有效产生多样化但自我耐受的T细胞库。在这里，我们确定了运输所需的内体分选复合物（ESCRT）蛋白CHMP5，已知是形成多泡体所必需的，作为T细胞发育所必需的T细胞抗原受体（TCR）信号传导阈值的关键传感器。CHMP5通过稳定促生存蛋白Bcl-2促进选择后胸腺细胞存活，从而实现正向选择。因此，胸腺细胞前体细胞中CHMP5的缺失会破坏T细胞的发育，这种表型可以通过基因缺失促凋亡蛋白Bim或转基因表达Bcl-2来“拯救”。从机制上说，正选择通过诱导CHMP5与去泛素酶USP8的相互作用来稳定CHMP5。因此，我们的研究结果确定了CHMP5是T细胞发育所需的翻译后机制的重要组成部分。
The acquisition of a protective vertebrate immune system hinges on the efficient generation of a diverse but self-tolerant repertoire of T cells by the thymus through mechanisms that remain incompletely resolved. Here we identified the endosomal-sorting-complex-required-for-transport (ESCRT) protein CHMP5, known to be required for the formation of multivesicular bodies, as a key sensor of thresholds for signaling via the T cell antigen receptor (TCR) that was essential for T cell development. CHMP5 enabled positive selection by promoting post-selection thymocyte survival in part through stabilization of the pro-survival protein Bcl-2. Accordingly, loss of CHMP5 in thymocyte precursor cells abolished T cell development, a phenotype that was 'rescued' by genetic deletion of the pro-apoptotic protein Bim or transgenic expression of Bcl-2. Mechanistically, positive selection resulted in the stabilization of CHMP5 by inducing its interaction with the deubiquitinase USP8. Our results thus identify CHMP5 as an essential component of the post-translational machinery required for T cell development.