Researchers from the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences found that, 2′3′-cyclic GMP-AMP (2′3′-cGAMP), the only mammalian cyclic dinucleotide, could directly bind with translation elongation factor EF1A1 and lead to protein synthesis slowing down.
2′3′-cGAMP is generated under DNA exposed to cytosol. This phenomenon is often observed in virus infected cells and tumor cells. 2′3′-cGAMP transmits danger signal to stimulator of interferon genes and activates innate immune response to fight virus and tumors. However, other functions of 2′3′-cGAMP are less known.
In order to study the biological functions of 2′3′-cGAMP, it is important to know what proteins 2′3′-cGAMP can bind in mammalian cells. But, there are no tools suitable for the identification of unknown binding proteins of 2′3′-cGAMP.
In this study, the researchers designed and synthesized the 2′3′-cGAMP-based photoaffinity probes that can capture and isolate 2′3′-cGAMP-binding proteins for visualization, identification and validation.
Among several potential binding proteins identified from HeLa cells using these affinity probes, EF1A1 in EF1 complex, which has a pivotal role in protein synthesis, was demonstrated to associate with 2′3′-cGAMP in vitro and in cells to impede protein synthesis.
According to the researchers, intrinsic 2′3′-cGAMP generated in mammalian cells may also restrict virus replication and suppress tumor cell proliferation via EF1A1 as well.
This work was supported by grants from the National Natural Science Foundation of China, the National Program on Key Basic Research Project of China, and the Natural Science Foundation of Shanghai.
