Cyclic Nucleotide Second Messenger Signaling in Antiviral Immunity and Development

• Applicant: Professorin Dr. Carina de Oliveira Mann
• Subject Area: Cell Biology ; Structural Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458004906

Cyclic nucleotide second messengers are crucial in the control of signaling pathways in all organisms and are involved in a variety of processes from biofilm formation, motility, differentiation and anti-phage responses in bacteria to antiviral immune responses in eukaryotes. In humans, the only described cyclic-di-nucleotide is cyclic 2´–5´ GMP 3´–5´ AMP (2´3´-cGAMP). cGAMP synthesis by the DNA pathogen recognition receptor cGAS leads to the production of type I interferons and pro-inflammatory cytokines via the downstream adaptor protein STING. As a drug, 2’3’ cGAMP and analogs were shown to inhibit tumor growth and to improve survival, even against tumors that were resistant to checkpoint blockade. The potent therapeutic potential together with the diversity of biological functions associated with known cyclic nucleotides highlight the importance of discovering novel cyclic nucleotides in humans. Cyclic nucleotides are synthesized by enzymes from the superfamily of nucleotidyltransferases (NTases), which are known to be involved in tightly regulated biological processes during infection and development. However, our knowledge on many subfamilies of NTases is currently hampered by the lack of activity in the absence of the cognate ligand. Our strategy to identify novel cyclic nucleotides is to reveal the molecular function of these NTases a) during an immune response using viral infection and b) during development using cell differentiation as a stimulus to induce NTase activity. Our results will open novel research avenues to study cyclic nucleotide second messenger signaling and impact immune-related and other areas in human biology.

• DFG Programme: Independent Junior Research Groups
• Major Instrumentation: FPLC