期刊
NATURE IMMUNOLOGY
卷 22, 期 4, 页码 485-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41590-021-00896-3
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资金
- Shared Instrumentation Grant (SIG) program [S10 RR027366]
- National Institutes of Health (NIH) [R01CA199376, U01DE028227, U54CA260591]
- NIH [S10OD020025, R01ES027595]
- Cancer Research Institute (CRI) Irvington Postdoc Fellowship
- UCSD Microbial Sciences Initiative Graduate Research Fellowship
- UCSD Graduate Training Program in Cellular and Molecular Pharmacology, through an institutional training grant from the National Institute of General Medical Sciences [T32 GM007752]
In this study, Sharma and colleagues identified DAPK3 as a positive regulator of the STING-interferon-beta activation pathway, essential for driving tumor-intrinsic innate immunity and tumor immune surveillance. Loss of DAPK3 expression or kinase activity impaired STING activation, reduced infiltration of immune cells, and attenuated the response to cancer chemo-immunotherapy. DAPK3 coordinates post-translational modification of STING and is critical for maintaining STING activation and immune response against tumors.
Sharma and colleagues identify the kinase DAPK3 as a positive regulator of the STING-interferon-beta activation pathway. DAPK3 acts to modify E3 ubiquitin ligases that regulate STING K63-linked poly-ubiquitination. 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)-beta-stimulated gene induction. DAPK3 deficiency in IFN-beta-producing tumors drove rapid growth and reduced infiltration of CD103(+)CD8 alpha(+) 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.
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