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

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)-?-stimulated gene induction. DAPK3 deficiency in IFN-?-producing tumors drove rapid growth and reduced infiltration of CD103+CD8?+ 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.
Mesh Terms:
Animals, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Tumor, Death-Associated Protein Kinases, Female, Gene Expression Regulation, Neoplastic, Human Umbilical Vein Endothelial Cells, Humans, Immune Checkpoint Inhibitors, Immunity, Innate, Interferon-beta, LIM Domain Proteins, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Neoplasms, Phosphorylation, Signal Transduction, Transcription Factors, Tumor Escape, Ubiquitination
Nat Immunol
Date: Dec. 01, 2020
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