# Exploring cyclic di-nucleotide signaling across the tree of life

> **NIH NIH R35** · MICHIGAN STATE UNIVERSITY · 2021 · $526,213

## Abstract

Summary: Exploring cyclic di-nucleotide signaling across the tree of life
All organisms utilize molecular regulatory mechanisms connecting external sensory systems to phenotypic
output. Cyclic di-nucleotide (cdN) second messenger molecules are one such fundamental system conserved
from bacteria to humans. In bacteria, cdNs regulate numerous phenotypes including but not limited to biofilm
formation, motility, virulence, stress responses, DNA repair, cell morphology, and phage defense. Eukaryotes
also utilize cdNs for complex multicellular development pathways and activation of the innate immune system
to mobilize anti-viral and anti-cancer immune responses. Although cdNs play such important functions across
the phylogenetic tree, they have only been intensively studied for about 15 years in bacteria and only a few
years in eukaryotic systems. There remain many outstanding questions such as the diversity of cdN signaling
systems, the environmental signals that induce their production, the molecular mechanisms that sense and
respond to them, the phenotypes cdNs regulate, and the adaptive benefit of such signaling systems. My
laboratory has studied cdN signaling since its inception in 2008, and we have made fundamental contributions
to this field. Our research has elucidated both transcriptional and post-transcriptional mechanisms by which the
cdN cyclic di-GMP regulates gene expression in the bacterial pathogen Vibrio cholerae. We have also greatly
expanded our understanding of the phenotypes controlled by cyclic di-GMP including DNA repair, stress
responses, and cell curvature. We discovered and characterized the first bacterial protein receptor of cyclic
GMP-AMP, a phospholipase encoded by V. cholerae we named CapV. Our search for novel cdNs led us to
discover that the yeast Saccharomyces cerevisiae synthesizes cyclic di-UMP, the first pyrimidine cdN detected
in vivo, in response to heat shock. We propose to answer fundamental questions about cdNs by defining cyclic
di-GMP gene regulation and phenotypic control in V. cholerae and deciphering how such regulatory networks
impact bacterial fitness. Our studies will also further characterize the novel cyclic GMP-AMP pathway we have
discovered in V. cholerae and extend our studies of cyclic GMP-AMP-like signaling pathways into other
bacteria. Finally, we will identify the cyclic di-UMP synthase in S. cerevisiae, determine the impact of this cdN
on yeast physiology, and search for cyclic di-UMP signaling in other eukaryotic cells. Our explorations
spanning bacteria to eukaryotes will make significant contributions to answering fundamental questions about
cdN signaling.

## Key facts

- **NIH application ID:** 10086172
- **Project number:** 1R35GM139537-01
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** CHRISTOPHER M WATERS
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $526,213
- **Award type:** 1
- **Project period:** 2021-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086172

## Citation

> US National Institutes of Health, RePORTER application 10086172, Exploring cyclic di-nucleotide signaling across the tree of life (1R35GM139537-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10086172. Licensed CC0.

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