Fig. 7
Working model. EBV-EBNA1 interacts with IGF2BP3 in the nucleus and recognizes ADAR1 mRNA through m6A modifications. EBNA1 subsequently recruits the translation initiation factor EIF4G1, increasing the ribosomal translation efficiency of ADAR1 mRNA. As a result, increased levels of ADAR1 protein lead to increased editing of A-to-I in dsRNA, reducing non-self dsRNA. This reduction weakens the ability of downstream RNA sensors to recognize dsRNA, causing interferon pathway inactivity and decreased interferon release, ultimately decreasing the sensitivity of tumor cells to immunotherapy. When we added the EBNA1-PROTAC degrader, EBNA1 was degraded, which reduced the binding of IGF2BP3 to ADAR1 mRNA. This further decreases the recruitment of EIF4G and the translation efficiency of ADAR1, leading to a decrease in ADAR1 protein levels. This results in reduced A-to-I editing of dsRNA, increasing non-self dsRNA, thereby activating the interferon pathway and IFN release, ultimately increasing the sensitivity of tumor cells to immunotherapy. The schematic illustration was generated using Adobe Illustrator
