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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325–338 (2012).
Powell, J. D., Pollizzi, K. N., Heikamp, E. B. & Horton, M. R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).
Saxton, R. A. & Sabatini, D. M. mTOR Signaling in growth, metabolism, and disease. Cell 169, 361–371 (2017).
Delgoffe, G. M., Kole, T. P., Zheng, Y., Zarek, P. E., Matthews, K. L. & Xiao, B. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).
Delgoffe, G. M., Pollizzi, K. N., Waickman, A. T., Heikamp, E., Meyers, D. J. & Horton, M. R. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303 (2011).
Xu, L., Huang, Q., Wang, H., Hao, Y., Bai, Q. & Hu, J. et al. The kinase mTORC1 promotes the generation and suppressive function of follicular regulatory T cells. Immunity 47, 538–551 (2017).
Zeng, H., Yang, K., Cloer, C., Neale, G., Vogel, P. & Chi, H. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499, 485–490 (2013).
Zeng, H., Cohen, S., Guy, C., Shrestha, S., Neale, G. & Brown, S. A. et al. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity 45, 540–554 (2016).
Ray, J. P., Staron, M. M., Shyer, J. A., Ho, P. C., Marshall, H. D. & Gray, S. M. et al. The interleukin-2-mTORc1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 43, 690–702 (2015).
Rao, R. R., Li, Q., Odunsi, K. & Shrikant, P. A. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and eomesodermin. Immunity 32, 67–78 (2010).
Pollizzi, K. N., Sun, I. H., Patel, C. H., Lo, Y. C., Oh, M. H. & Waickman, A. T. et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation. Nat. Immunol. 17, 704–711 (2016).
Araki, K., Turner, A. P., Shaffer, V. O., Gangappa, S., Keller, S. A. & Bachmann, M. F. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).
Li, Q., Rao, R. R., Araki, K., Pollizzi, K., Odunsi, K. & Powell, J. D. et al. A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity. Immunity 34, 541–553 (2011).
Sowell, R. T., Rogozinska, M., Nelson, C. E., Vezys, V. & Marzo, A. L. Cutting edge: generation of effector cells that localize to mucosal tissues and form resident memory CD8 T cells is controlled by mTOR. J. Immunol. 193, 2067–2071 (2014).
Pollizzi, K. N., Patel, C. H., Sun, I. H., Oh, M. H., Waickman, A. T. & Wen, J. et al. mTORC1 and mTORC2 selectively regulate CD8(+) T cell differentiation. J. Clin. Investig. 125, 2090–2108 (2015).
Zhang, J., Kim, J., Alexander, A., Cai, S., Tripathi, D. N. & Dere, R. et al. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nat. Cell Biol. 15, 1186–1196 (2013).
Yang, K., Shrestha, S., Zeng, H., Karmaus, P. W., Neale, G. & Vogel, P. et al. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 39, 1043–1056 (2013).
Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012).
Boyman, O. & Sprent, J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat. Rev. Immunol. 12, 180–190 (2012).
Liao, W., Lin, J. X. & Leonard, W. J. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38, 13–25 (2013).
Jones, R. G. & Pearce, E. J. MenTORing immunity: mTOR signaling in the development and function of tissue-resident immune cells. Immunity 46, 730–742 (2017).
Pollizzi, K. N. & Powell, J. D. Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol. 36, 13–20 (2015).
Macintyre, A. N., Finlay, D., Preston, G., Sinclair, L. V., Waugh, C. M. & Tamas, P. et al. Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism. Immunity 34, 224–236 (2011).
Finlay, D. K., Rosenzweig, E., Sinclair, L. V., Feijoo-Carnero, C., Hukelmann, J. L. & Rolf, J. et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209, 2441–2453 (2012).
Hamilton, K. S., Phong, B., Corey, C., Cheng, J., Gorentla, B. & Zhong, X. et al. T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10. Sci. Signal 7, ra55 (2014).
Deiss, L. P., Feinstein, E., Berissi, H., Cohen, O. & Kimchi, A. Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev. 9, 15–30 (1995).
Singh, P., Ravanan, P. & Talwar, P. Death associated protein kinase 1 (DAPK1): a regulator of apoptosis and autophagy. Front. Mol. Neurosci. 9, 46 (2016).
Shohat, G., Spivak-Kroizman, T., Cohen, O., Bialik, S., Shani, G. & Berrisi, H. et al. The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism. J. Biol. Chem. 276, 47460–47467 (2001).
Shohat, G., Shani, G., Eisenstein, M. & Kimchi, A. The DAP-kinase family of proteins: study of a novel group of calcium-regulated death-promoting kinases. Biochim. Biophys. Acta 1600, 45–50 (2002).
Stevens, C., Lin, Y., Harrison, B., Burch, L., Ridgway, R. A. & Sansom, O. et al. Peptide combinatorial libraries identify TSC2 as a death-associated protein kinase (DAPK) death domain-binding protein and reveal a stimulatory role for DAPK in mTORC1 signaling. J. Biol. Chem. 284, 334–344 (2009).
Shiloh, R., Bialik, S. & Kimchi, A. The DAPK family: a structure-function analysis. Apoptosis 19, 286–297 (2014).
Zhao, J., Zhao, D., Poage, G. M., Mazumdar, A., Zhang, Y. & Hill, J. L. et al. Death-associated protein kinase 1 promotes growth of p53-mutant cancers. J. Clin. Investig. 125, 2707–2720 (2015).
Chuang, Y. T., Fang, L. W., Lin-Feng, M. H., Chen, R. H. & Lai, M. Z. The tumor suppressor death-associated protein kinase targets to TCR-stimulated NF-kappa B activation. J. Immunol. 180, 3238–3249 (2008).
Chou, T. F., Chuang, Y. T., Hsieh, W. C., Chang, P. Y., Liu, H. Y. & Mo, S. T. et al. Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1alpha for Th17 suppression. Nat. Commun. 7, 11904 (2016).
McGargill, M. A., Wen, B. G., Walsh, C. M. & Hedrick, S. M. A deficiency in Drak2 results in a T cell hypersensitivity and an unexpected resistance to autoimmunity. Immunity 21, 781–791 (2004).
Pei, L., Wang, S., Jin, H., Bi, L., Wei, N. & Yan, H. et al. A novel mechanism of spine damages in stroke via DAPK1 and Tau. Cereb. Cortex 25, 4559–4571 (2015).
Shu, S., Zhu, H., Tang, N., Chen, W., Li, X. & Li, H. et al. Selective degeneration of entorhinal-CA1 synapses in Alzheimer’s disease via activation of DAPK1. J. Neurosci. 36, 10843–10852 (2016).
Hukelmann, J. L., Anderson, K. E., Sinclair, L. V., Grzes, K. M., Murillo, A. B. & Hawkins, P. T. et al. The cytotoxic T cell proteome and its shaping by the kinase mTOR. Nat. Immunol. 17, 104–112 (2016).
Ross, S. H., Rollings, C., Anderson, K. E., Hawkins, P. T., Stephens, L. R. & Cantrell, D. A. Phosphoproteomic analyses of interleukin 2 signaling reveal integrated JAK kinase-dependent and -independent networks in CD8(+) T cells. Immunity 45, 685–700 (2016).
Potter, C. J., Pedraza, L. G. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 4, 658–665 (2002).
Salmond, R. J., Emery, J., Okkenhaug, K. & Zamoyska, R. MAPK, phosphatidylinositol 3-kinase, and mammalian target of rapamycin pathways converge at the level of ribosomal protein S6 phosphorylation to control metabolic signaling in CD8 T cells. J. Immunol. 183, 7388–7397 (2009).
Salmond, R. J., Brownlie, R. J., Meyuhas, O. & Zamoyska, R. Mechanistic target of rapamycin complex 1/S6 kinase 1 signals influence T cell activation independently of ribosomal protein S6 phosphorylation. J. Immunol. 195, 4615–4622 (2015).
Liu, W. L., Yang, H. C., Hsu, C. S., Wang, C. C., Wang, T. S. & Kao, J. H. et al. Pegylated IFN-alpha suppresses hepatitis C virus by promoting the DAPK-mTOR pathway. Proc. Natl Acad. Sci. USA 113, 14799–14804 (2016).
Zeng, H. & Chi, H. mTOR signaling in the differentiation and function of regulatory and effector T cells. Curr. Opin. Immunol. 46, 103–111 (2017).
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
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Wei, Z., Li, P., He, R. et al. DAPK1 (death associated protein kinase 1) mediates mTORC1 activation and antiviral activities in CD8+ T cells. Cell Mol Immunol 18, 138–149 (2021). https://doi.org/10.1038/s41423-019-0293-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41423-019-0293-2
Keywords
This article is cited by
-
Plasma Levels of mir-34a-5p Correlate with Systemic Inflammation and Low Naïve CD4 T Cells in Common Variable Immunodeficiency
Journal of Clinical Immunology (2024)
-
Genetic haplotypes associated with immune response to Leishmania infantum infection in dogs
Veterinary Research Communications (2023)
-
Immunological and genomic characterization of Ibizan Hound dogs in an endemic Leishmania infantum region
Parasites & Vectors (2022)