|開催日時：||2017年10月13日 １３：００ ～ １４：００|
|所属：||Postdoctoral fellow , Division of Cell Biology-Sharma, La Jolla Institute for Allergy and Immunology
|演題：||Genome-scale screening identifies new kinases in the IFN-I pathway: Death-Associated Protein Kinases regulate STING
Recent studies show that innate immune sensing of dsDNA through the STING-IRF3 pathway is essential for eliciting immunity to a variety of microbial infections and immunogenic tumors. However, many aspects of STING regulation remain poorly defined. Using high-throughput RNAi screening, we identified kinases of the death-associated protein kinase (DAPK) family as new positive regulators of STING activation. DAPK3 was originally identified as a regulator of cellular apoptosis and autophagy. DAPK3 is a tumor suppressor and loss-of-function isolated from primary human tumors promote increased cell survival and proliferation in transformed cells. We find that depletion of DAPK3 in several different cell types, including primary endothelial cells, fibroblasts and monocytes, results in reduction of IRF3 nuclear translocation and production of type I Interferon and many other pro-inflammatory cytokines and anti-viral genes in response to dsDNA stimulation or DNA virus infection. To identify targets of DAPK3 in dsDNA-stimulated cells, we performed global phosphoproteomic profiling using SILAC mass spectrometry, and found that DAPK3 regulates DNA-induced phosphorylation of multiple proteins involved in the innate immune response, NFB and IRF signaling, apoptosis, and ubiquitination. Our preliminary results suggest that DAPK3 controls ubiquitination of STING in a kinase-dependent manner, and we are examining interactions among DAPK3, STING, and several ubiquitin-related enzymes in the context of tumor growth and immunogenicity.
|世話人：||〇北村 俊雄 （細胞療法分野）
三宅 健介 （感染遺伝学分野）