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

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Abstract

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.

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Acknowledgements

This work was supported by grants from the National Scientific Foundation of China to X.-P.Y. (81671539, 31470851, and 31870892) and Z.H.T. (81873870), and the Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, HUST (2019kfyXKJC066) to X.-P.Y.

Author information

Z.W., P.L., and X.-P.Y. conceived and designed the study and wrote the manuscript with critical input from G.W., Y.L., Z.L., and A.L.; Z.W., P.L., R.H., H.C.L., N.L., Y.X., G.B., Q.D., M.X., J.W., L.P., and Z.-H.T. performed the experiments and analyzed the data; Z.L. and A.L. helped analyze the data and assisted with the experimental design; X.C., H.B.L., and Y.L. provided essential reagents and assisted with experimental design and data analysis. X.-P.Y. wrote the paper and supervised the project.

Correspondence to Xiang-Ping Yang.

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Keywords

  • mTORC1; CD8+ T cells
  • antiviral function