Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Immunology, Hubei University of Medicine, Shiyan, 442000, China.
Cell Mol Immunol. 2021 Jan;18(1):138-149. doi: 10.1038/s41423-019-0293-2. Epub 2019 Sep 20.
Mechanistic target of rapamycin complex 1 (mTORC1) regulates CD8 T-cell differentiation and function. Despite the links between PI3K-AKT and mTORC1 activation in CD8 T cells, the molecular mechanism underlying mTORC1 activation remains unclear. Here, we show that both the kinase activity and the death domain of DAPK1 are required for maximal mTOR activation and CD8 T-cell function. We found that TCR-induced activation of calcineurin activates DAPK1, which subsequently interacts with TSC2 via its death domain and phosphorylates TSC2 to mediate mTORC1 activation. Furthermore, both the kinase domain and death domain of DAPK1 are required for CD8 T-cell antiviral responses in an LCMV infection model. Together, our data reveal a novel mechanism of mTORC1 activation that mediates optimal CD8 T-cell function and antiviral activity.
雷帕霉素复合物 1（mTORC1）的作用机制 调节 CD8 T 细胞的分化和功能。尽管 CD8 T 细胞中 PI3K-AKT 和 mTORC1 的激活之间存在联系，但 mTORC1 激活的分子机制仍不清楚。在这里，我们表明 DAPK1 的激酶活性和死亡结构域对于最大程度的 mTOR 激活和 CD8 T 细胞功能都是必需的。我们发现 TCR 诱导的钙调神经磷酸酶的激活激活了 DAPK1，DAPK1 通过其死亡结构域与 TSC2 相互作用，并磷酸化 TSC2 以介导 mTORC1 的激活。此外，在 LCMV 感染模型中，DAPK1 的激酶结构域和死亡结构域对于 CD8 T 细胞抗病毒反应都是必需的。总之，我们的数据揭示了一种新的 mTORC1 激活机制，介导了最佳的 CD8 T 细胞功能和抗病毒活性。
