| First Author | Takahashi M | Year | 2021 |
| Journal | Nat Immunol | Volume | 22 |
| Issue | 4 | Pages | 485-496 |
| PubMed ID | 33767426 | Mgi Jnum | J:305970 |
| Mgi Id | MGI:6706729 | Doi | 10.1038/s41590-021-00896-3 |
| Citation | Takahashi M, et al. (2021) The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-beta pathway. Nat Immunol 22(4):485-496 |
| abstractText | 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(+)CD8alpha(+) 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. |
