Abstract

The ability of cells to sense and respond to environmental cues is critical for survival. Cells integrate environmental cues to regulate the synthesis and degradation of second messengers, which mediate many essential processes in archaea, eubacteria, and eukaryotes. Cyclic dinucleotides, such as c-di-GMP, c-di-AMP and cGAMP, are newly discovered second messengers in all the three domains of life. In Gram-negative, Gram-positive bacteria and mycobacteria, cyclic dinucleotides orchestrate a dizzying array of processes that include biofilm formation, virulence factors production, cell wall remodeling and antibiotic resistance. Cyclic dinucleotides also affect mammalian cells, particularly immune cells, and play important roles related to inflammation, T-cell maturation and antigen presentation. Due to the essential roles played by these fascinating second molecules, there are now intense research efforts to identify macromolecular targets in the cell that sense these molecules. Recently, the activation of immune response to cyclic dinucleotides (CDNs) via STING has come to the forefront. Many drug companies have initiated programs aimed at identifying activators or inhibitors of STING as cancer immunotherapy and anti-inflammatory agents respectively. Accumulating evidences indicate that CDNs remodel many key cellular processes via non-STING-TBK1-IRF3 pathways but the exact mechanisms or key players that respond to CDNs remain to be elucidated. Using chemical biology approaches (chemical probes and proteomics), the Sintim group has identified various pathways (non-STING-TBK1-IRF3), which are regulated by cyclic dinucleotides.