Regulation of T-cell survival and mitochondrial homeostasis by TSC1.
Regulation of T-cell survival and mitochondrial homeostasis by TSC1.
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DOI：
10.1002/eji.201141411
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发表时间：
2011-11
影响因子：
5.4
通讯作者：
Zhong, Xiao-Ping
中科院分区：
文献类型：
--
作者：
O'Brien, Thomas F.;Gorentla, Balachandra K.;Xie, Danli;Srivatsan, Sruti;McLeod, Ian X.;He, You-Wen;Zhong, Xiao-Ping
哺乳动物雷帕霉素靶蛋白（mTOR）是细胞生长和代谢的关键调节因子。它与多种蛋白质结合，形成两种不同的信号复合物，mTORC1和mTORC2。越来越多的证据揭示了完整的mTOR信号在T细胞活化和对微生物感染的反应中的关键作用。然而，mTOR调控在T细胞中的重要性尚未被探索。在细胞系模型中，TSC1/TSC2复合物已被证明可以抑制mTORC1信号传导。我们在这里表明，小鼠T细胞谱系中TSC1的缺失导致外周T细胞池的急剧减少，与细胞死亡增加相关。虽然mTORC1被组成性激活，但Akt磷酸化和活性反映的mTORC2信号在tsc1缺陷T细胞中减少。此外，tsc1缺陷T细胞含有较高的活性氧，并表现出线粒体含量和膜电位降低，这与内在死亡途径的激活有关。总之，我们的研究结果表明，TSC1对mTORC1和mTORC2活性有差异调节，促进T细胞存活，对T细胞正常线粒体稳态至关重要。
The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and metabolism. It associates with multiple proteins and forms two distinct signaling complexes, mTORC1 and mTORC2. Accumulating evidence has revealed critical roles for intact mTOR signaling during T cell activation and responses to microbial infection. However, the importance of mTOR regulation in T cells has yet to be explored. The TSC1/TSC2 complex has been shown to inhibit mTORC1 signaling in cell line models. We show here that deletion of TSC1 in the murine T cell lineage resulted in a dramatic reduction of the peripheral T cell pool, correlating with increased cell death. While mTORC1 is constitutively activated, mTORC2 signaling, reflected by Akt phosphorylation and activity, is decreased in TSC1-deficient T cells. Furthermore, TSC1-deficient T cells contain elevated reactive oxygen species and exhibit decreased mitochondrial content and membrane potential, which is correlated with the activation of the intrinsic death pathway. Together, our results demonstrate that TSC1 differentially regulates mTORC1 and mTORC2 activity, promotes T cell survival, and is critical for normal mitochondrial homeostasis in T cells.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
13.5
作者：
Gonzalez-Rodriguez, Agueda;Alba, Javier;Zimmerman, Valeri;Kozma, Sara C.;Valverde, Angela M.
通讯作者：
Valverde, Angela M.
DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
DOI：
10.1084/jem.20081297
发表时间：
2008-09-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen C;Liu Y;Liu R;Ikenoue T;Guan KL;Liu Y;Zheng P
通讯作者：
Zheng P
影响因子：
4.4
作者：
Salmond, Robert J.;Emery, Juliet;Zamoyska, Rose
通讯作者：
Zamoyska, Rose