D3SC: Signaling Axes Modulated by Cyclic Dinucleotides

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With this award, the Chemistry of Life Processes program is supporting the research of Professors Herman O. Sintim and Uma Aryal, from Purdue University, West Lafayette, to determine the details of how various molecular components of viruses and bacteria activate immune cells to cause inflammation. Immune cells play important roles in eliminating tumors and also protecting organisms against invading pathogenic bacteria and viruses. A new pathway or signaling was recently discovered in immune cells, which sense molecules called cyclic dinucleotides to control inflammation response. This project uses chemical probes and proteomics to discover proteins that bind cyclic dinucleotides in order to regulate signaling in immune cells. In addition, this research increases workforce capacity in STEM by training graduate students and advanced undergraduates to acquire a diverse set of specialized skills in chemical synthesis, mass spectrometry, immunology and molecular biology methods. Cyclic dinucleotides, such as cyclic di-guanosine monophosphate, cyclic di-adenosine monophosphate and cyclic guanosine monophosphate–adenosine monophosphate, are known to signal via a stimulator of interferon genes (STING)-controlled innate immune pathway and play major roles in a wide variety of human diseases including various cancers, viral and bacterial infections as well as autoimmune diseases. Thus far, the cyclic dinucleotide-STING-TBK1 axis is well characterized, but other pathways and/or protein targets that cyclic dinucleotides also affect are poorly characterized. Understanding how cyclic dinucleotides regulate host cells physiology could provide valuable insights into key determinants that shape the host-pathogen interaction. The principal investigators use various STING-axis knockout cell lines and proteomics to uncover cyclic dinucleotide mediated pathways that channel through STING and non-STING pathways. They also globally profile post-translational modifications of proteins in the presence of cyclic dinucleotide signals. Using novel chemical probes, the investigators uncover mammalian proteins that bind to cyclic dinucleotides or associate with STING. This study provides insights into how cyclic dinucleotides affect signaling pathways in mammalian cells beyond the well-characterized STING-TBK1 axis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.