# Discovery of cGAS-like signaling enzymes in innate immunity and disease

> **NIH NIH DP2** · DANA-FARBER CANCER INST · 2021 · $1,430,400

## Abstract

Project Summary
Human cells use signals called "RNA second messengers" to stimulate the immune response and prevent
disease. These signals are produced in response to pathogen infection and cellular stress, and are important for
controlling cellular communication. Recent evidence demonstrates that RNA second messenger signaling
controlled by the enzyme cyclic GMP–AMP synthase (cGAS) is a critical component of the immune response to
many types of cancer, and drug analogues developed from these natural signals are rapidly emerging as
promising new treatments. The potent antitumor potential of these drugs illustrates the importance of discovery
and mechanistic understanding of naturally occurring RNA second messenger signals.
Surprisingly, our work has revealed that cGAS is part of a broad family of signaling enzymes we named
cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzymes, and many RNA second messenger pathways
remain to be discovered in human biology. Potential human CD-NTases include uncharacterized immune cGAS-
like receptors previously implicated as genes frequently mutated in cancer. Our results demonstrate that RNA
second messenger signaling pathways are a new rich area of research and likely impact many areas of basic
human biology and disease. We have developed an innovative approach to uncover the function of these
enzymes and discover the biology and natural products responsible for signaling.
Our proposed research will provide a new detailed understanding of the enzymes that control RNA second
messenger signaling and enable discovery of entirely new classes of RNA signals. Specifically, the proposed
experiments will use kingdom-wide analysis of CD-NTase enzymes to determine the mechanism of specific RNA
product synthesis, X-ray crystallography to define the structural and molecular basis of metazoan CD-NTase
function, and an innovative set of cell biology experiments using newly identified CD-NTase RNA signals for
direct cell stimulation and chemical-proteomics. Our experiments will define the function of newly discovered
cGAS-like enzymes in human biology and explain the molecular rules that allow RNA second messengers to
control downstream cellular responses.

## Key facts

- **NIH application ID:** 10245968
- **Project number:** 1DP2GM146250-01
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Philip J Kranzusch
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,430,400
- **Award type:** 1
- **Project period:** 2021-09-24 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245968

## Citation

> US National Institutes of Health, RePORTER application 10245968, Discovery of cGAS-like signaling enzymes in innate immunity and disease (1DP2GM146250-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10245968. Licensed CC0.

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