mTORC1型
生物
细胞生物学
细胞凋亡
自噬
TSC1
化学
核糖体生物发生
PI3K/AKT/mTOR通路
信号转导
核糖核酸
生物化学
核糖体
基因
作者
Zhanfeng Liang,Qian Zhang,Zhaoqi Zhang,Lina Sun,Xue Dong,Tianxiu Li,Liang Tan,Xubiao Xie,Liguang Sun,Yong Zhao
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2021-10-15
卷期号:207 (8): 2039-2050
被引量:11
标识
DOI:10.4049/jimmunol.2100463
摘要
Thymic epithelial cells (TECs) are critical for the development and generation of functionally competent T cells. Until now, the mechanism that regulates the survival of TECs is poorly understood. In the current study, we found that Tsc1 controls the homeostasis of medullary TECs (mTECs) by inhibiting lysosomal-mediated apoptosis pathway in mice. TEC-specific deletion of Tsc1 predominately decreased the cell number of mTECs and, to a lesser content, affected the development cortical TECs. The defect of mTECs caused by Tsc1 deficiency in mice impaired thymocyte development and peripheral T cell homeostasis. Mechanistically, Tsc1 deficiency did not affect the cell proliferation of mTECs but increased the apoptosis of mTECs significantly. RNA-sequencing analysis showed that pathways involved in lysosomal biogenesis, cell metabolism, and apoptosis were remarkably elevated in Tsc1-deficient mTECs compared with their wild-type counterparts. Tsc1-deficient mTECs exhibited overproduction of reactive oxygen species and malfunction of lysosome, with lysosome membrane permeabilization and the release of cathepsin B and cathepsin L to the cytosol, which then lead to Bid cleaved into active truncated Bid and subsequently intrinsic apoptosis. Finally, we showed that the impaired development of mTECs could be partially reversed by decreasing mTORC1 activity via haploinsufficiency of Raptor Thus, Tsc1 is essential for the homeostasis of mTECs by inhibiting lysosomal-mediated apoptosis through mTORC1-dependent pathways.
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