DAPK1 (death associated protein kinase 1) mediates mTORC1 activation and antiviral activities in CD8+ T cells

• Published in: Cellular & molecular immunology 2021-01, Vol.18 (1), p.138-149
• Main Authors: Wei, Zhengping, Li, Pingfei, He, Ran, Liu, Huicheng, Liu, Na, Xia, Yu, Bi, Guoyu, Du, Qiuyang, Xia, Minghui, Pei, Lei, Wang, Jing, Wang, Guihua, Tang, Zhao-Hui, Cheng, Xiang, Li, Huabin, Li, Zhuoya, Ye, Lilin, Laurence, Arian, Lu, Youming, Yang, Xiang-Ping
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/250/1619/554/1834; 631/250/256/2516; AKT protein; Animals; Antibodies; Antiviral activity; Antiviral Agents - pharmacology; Arenaviridae Infections - immunology; Arenaviridae Infections - prevention & control; Arenaviridae Infections - virology; Biomedical and Life Sciences; Biomedicine; Calcineurin; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell Differentiation; Death-associated protein kinase; Death-Associated Protein Kinases - physiology; Immunology; Kinases; Lymphocyte Activation; Lymphocytes T; Lymphocytic choriomeningitis virus - drug effects; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Medical Microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Protein kinase; Rapamycin; Signal Transduction; T cell receptors; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Vaccine
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/s41423-019-0293-2

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.