The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway

Research output: Contribution to journal › Journal article › Research › peer-review

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The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway. / Takahashi, Mariko; Lio, Chan-Wang J; Campeau, Anaamika; Steger, Martin; Ay, Ferhat; Mann, Matthias; Gonzalez, David J; Jain, Mohit; Sharma, Sonia.

In: Nature Immunology, Vol. 22, No. 4, 04.2021, p. 485-496.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Takahashi, M, Lio, C-WJ, Campeau, A, Steger, M, Ay, F, Mann, M, Gonzalez, DJ, Jain, M & Sharma, S 2021, 'The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway', Nature Immunology, vol. 22, no. 4, pp. 485-496. https://doi.org/10.1038/s41590-021-00896-3

APA

Takahashi, M., Lio, C-W. J., Campeau, A., Steger, M., Ay, F., Mann, M., Gonzalez, D. J., Jain, M., & Sharma, S. (2021). The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway. Nature Immunology, 22(4), 485-496. https://doi.org/10.1038/s41590-021-00896-3

Vancouver

Takahashi M, Lio C-WJ, Campeau A, Steger M, Ay F, Mann M et al. The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway. Nature Immunology. 2021 Apr;22(4):485-496. https://doi.org/10.1038/s41590-021-00896-3

Author

Takahashi, Mariko ; Lio, Chan-Wang J ; Campeau, Anaamika ; Steger, Martin ; Ay, Ferhat ; Mann, Matthias ; Gonzalez, David J ; Jain, Mohit ; Sharma, Sonia. / The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway. In: Nature Immunology. 2021 ; Vol. 22, No. 4. pp. 485-496.

Bibtex

@article{0c7a059e87ff42ffa74b83f33d6c8449,
title = "The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway",
abstract = "Evasion of host immunity is a hallmark of cancer; however, mechanisms linking oncogenic mutations and immune escape are incompletely understood. Through loss-of-function screening of 1,001 tumor suppressor genes, we identified death-associated protein kinase 3 (DAPK3) as a previously unrecognized driver of anti-tumor immunity through the stimulator of interferon genes (STING) pathway of cytosolic DNA sensing. Loss of DAPK3 expression or kinase activity impaired STING activation and interferon (IFN)-β-stimulated gene induction. DAPK3 deficiency in IFN-β-producing tumors drove rapid growth and reduced infiltration of CD103+CD8α+ dendritic cells and cytotoxic lymphocytes, attenuating the response to cancer chemo-immunotherapy. Mechanistically, DAPK3 coordinated post-translational modification of STING. In unstimulated cells, DAPK3 inhibited STING K48-linked poly-ubiquitination and proteasome-mediated degradation. After cGAMP stimulation, DAPK3 was required for STING K63-linked poly-ubiquitination and STING-TANK-binding kinase 1 interaction. Comprehensive phospho-proteomics uncovered a DAPK3-specific phospho-site on the E3 ligase LMO7, critical for LMO7-STING interaction and STING K63-linked poly-ubiquitination. Thus, DAPK3 is an essential kinase for STING activation that drives tumor-intrinsic innate immunity and tumor immune surveillance.",
author = "Mariko Takahashi and Lio, {Chan-Wang J} and Anaamika Campeau and Martin Steger and Ferhat Ay and Matthias Mann and Gonzalez, {David J} and Mohit Jain and Sonia Sharma",
year = "2021",
month = apr,
doi = "10.1038/s41590-021-00896-3",
language = "English",
volume = "22",
pages = "485--496",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "nature publishing group",
number = "4",

}

RIS

TY - JOUR

T1 - The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway

AU - Takahashi, Mariko

AU - Lio, Chan-Wang J

AU - Campeau, Anaamika

AU - Steger, Martin

AU - Ay, Ferhat

AU - Mann, Matthias

AU - Gonzalez, David J

AU - Jain, Mohit

AU - Sharma, Sonia

PY - 2021/4

Y1 - 2021/4

N2 - Evasion of host immunity is a hallmark of cancer; however, mechanisms linking oncogenic mutations and immune escape are incompletely understood. Through loss-of-function screening of 1,001 tumor suppressor genes, we identified death-associated protein kinase 3 (DAPK3) as a previously unrecognized driver of anti-tumor immunity through the stimulator of interferon genes (STING) pathway of cytosolic DNA sensing. Loss of DAPK3 expression or kinase activity impaired STING activation and interferon (IFN)-β-stimulated gene induction. DAPK3 deficiency in IFN-β-producing tumors drove rapid growth and reduced infiltration of CD103+CD8α+ dendritic cells and cytotoxic lymphocytes, attenuating the response to cancer chemo-immunotherapy. Mechanistically, DAPK3 coordinated post-translational modification of STING. In unstimulated cells, DAPK3 inhibited STING K48-linked poly-ubiquitination and proteasome-mediated degradation. After cGAMP stimulation, DAPK3 was required for STING K63-linked poly-ubiquitination and STING-TANK-binding kinase 1 interaction. Comprehensive phospho-proteomics uncovered a DAPK3-specific phospho-site on the E3 ligase LMO7, critical for LMO7-STING interaction and STING K63-linked poly-ubiquitination. Thus, DAPK3 is an essential kinase for STING activation that drives tumor-intrinsic innate immunity and tumor immune surveillance.

AB - Evasion of host immunity is a hallmark of cancer; however, mechanisms linking oncogenic mutations and immune escape are incompletely understood. Through loss-of-function screening of 1,001 tumor suppressor genes, we identified death-associated protein kinase 3 (DAPK3) as a previously unrecognized driver of anti-tumor immunity through the stimulator of interferon genes (STING) pathway of cytosolic DNA sensing. Loss of DAPK3 expression or kinase activity impaired STING activation and interferon (IFN)-β-stimulated gene induction. DAPK3 deficiency in IFN-β-producing tumors drove rapid growth and reduced infiltration of CD103+CD8α+ dendritic cells and cytotoxic lymphocytes, attenuating the response to cancer chemo-immunotherapy. Mechanistically, DAPK3 coordinated post-translational modification of STING. In unstimulated cells, DAPK3 inhibited STING K48-linked poly-ubiquitination and proteasome-mediated degradation. After cGAMP stimulation, DAPK3 was required for STING K63-linked poly-ubiquitination and STING-TANK-binding kinase 1 interaction. Comprehensive phospho-proteomics uncovered a DAPK3-specific phospho-site on the E3 ligase LMO7, critical for LMO7-STING interaction and STING K63-linked poly-ubiquitination. Thus, DAPK3 is an essential kinase for STING activation that drives tumor-intrinsic innate immunity and tumor immune surveillance.

U2 - 10.1038/s41590-021-00896-3

DO - 10.1038/s41590-021-00896-3

M3 - Journal article

C2 - 33767426

VL - 22

SP - 485

EP - 496

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 4

ER -

ID: 259827245