# Defining the role of cyclic trinucleotide signaling in bacteriophage immunity through the activation and regulation of HORMA-associated cGAS/DncV-related nucleotidyltransferases

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $37,835

## Abstract

PROJECT SUMMARY
Defining the role of cyclic trinucleotide signaling in bacteriophage immunity through the activation and
regulation of HORMA-associated cGAS/DncV-related nucleotidyltransferases
In their natural environment, bacterial cells are in a constant conflict with the surrounding cells and
bacteriophages. Therefore, they have developed a variety of signaling pathways which are responsible for
detecting and adapting to changes both their internal and external environment. These signals can be
propagated through the synthesis of small molecules, also called second messengers, which amplify the signal
and can bind to downstream effectors. It has recently been discovered that one class of enzymes, cGAS/DncV-
related nucleotidyltransferases, are responsible for synthesizing a wide variety of cyclic di- and tri-nucleotides,
which have been shown to act as second messengers. In bacteria, dinucleotides regulate a plethora of behaviors
ranging from biofilm formation, to intracellular ion concentration, to defense against bacteriophage infection. With
the rise in bacterial resistance to small molecule drugs and increased interest in alternative approaches, including
phage therapy, it is imperative that we understand the responses to bacteriophage infection. Furthermore, there
is growing evidence that cyclic dinucleotides are sensed by hosts upon infection, leading to high interest in
bacterial cyclic oligonucleotide signaling. In this study, we propose to study the molecular mechanisms and
biological roles of a novel bacteriophage defense pathway recently discovered in a diverse set of environmental
and pathogenic bacterial strains. This pathway, whose components are contained in an operon, has an enzyme,
CdnC, which synthesizes cyclic tri-AMP (cAAA) and co-exists with the first-identified bacterial proteins containing
the HORMA domain, a peptide-binding domain found in many critical signaling pathways in eukaryotes. The
operons also encode an ortholog of the AAA+ ATPase Pch2, an important regulator of eukaryotic HORMA
domain proteins. Our extensive preliminary data shows that CdnC is inactive on its own, but synthesizes cAAA
when bound to the HORMA in a closed conformation as well as DNA. cAAA in turn binds and activates a DNA
endonuclease, NucC, also found in the operon. I have found that this pathway confers immunity to bacteriophage
, and that immunity requires the CdnC, HORMA, and NucC proteins. In this project, I will identify the
bacteriophage protein(s) recognized by HORMA to initiate signaling, and define the spectrum of bacteriophage
immunity imparted by the operon. I will further define the activities of NucC and determine whether it specifically
targets phage DNA, or rather degrades the bacterium’s own genome. Finally, I will determine how the CdnC
operon is regulated transcriptionally, through the activity of a DNA binding protein/metallopeptidase pair with
homology to transcriptional control proteins in Deinococcus. Overall, this work...

## Key facts

- **NIH application ID:** 9993098
- **Project number:** 1F31GM137600-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Rebecca Kavaler Lau
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,835
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993098

## Citation

> US National Institutes of Health, RePORTER application 9993098, Defining the role of cyclic trinucleotide signaling in bacteriophage immunity through the activation and regulation of HORMA-associated cGAS/DncV-related nucleotidyltransferases (1F31GM137600-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9993098. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*