# The Expanded Repertoire of cGAMP Signal Transduction During Innate Immune Responses

> **NIH NIH F30** · UNIVERSITY OF WASHINGTON · 2021 · $15,827

## Abstract

PROJECT SUMMARY/ABSTRACT
Infections with oncogenic, DNA viruses account for twelve percent of human cancers and are a major cause of
mortality and morbidity throughout the world. The development of new therapeutics to treat viral infections
would significantly benefit from a detailed understanding of the host response to this infectious insult. The
ability of the immune system to counteract viral infection is often mediated through a sophisticated repertoire of
proteins that bind to viral nucleic acids. In response to DNA derived from viruses, the host protein cyclic GMP-
AMP (cGAMP) Synthase (cGAS) produces the signaling nucleotide cGAMP, which initiates host inflammation
to clear infection by binding to the protein Stimulatory of Interferon Genes (STING). However, second
messenger signal transduction systems often rely on a variety of protein receptors to drive cellular responses.
Whether cGAMP can function beyond STING activation to restrict viral infection and oncogenesis remains
largely unknown. Recent studies have shown that cGAS and STING can have non-overlapping effects on
infection outcome, suggesting that cGAS plays multiple roles in response to viral infection beyond signaling
through STING. To systematically address this hypothesis, we have generated beads coated in cGAMP that
are able to isolate cGAMP-binding proteins from cell extracts. Using this method, we have identified two new
proteins other than STING that can bind to cGAMP. These novel cGAMP binding proteins have known roles in
regulating cellular processes involved in the host response to infection including how the cell produces energy
as well as biosynthetic building blocks, fundamental aspects of cellular physiology that viruses rely upon in
order to facilitate replication. Here, I propose to utilize structure-function analysis coupled with biochemical and
infection models to interrogate the biological relevance of these previously unrecognized cGAMP-binding
proteins and detail their effects on viral restriction. The findings from these studies will significantly inform the
mechanisms by which the host immune system can restrict viral infection and oncogenesis and may provide
new therapeutic strategies to combat infectious and malignant diseases.

## Key facts

- **NIH application ID:** 10183204
- **Project number:** 5F30CA239659-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Shivam Zaver
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $15,827
- **Award type:** 5
- **Project period:** 2019-06-16 → 2021-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183204

## Citation

> US National Institutes of Health, RePORTER application 10183204, The Expanded Repertoire of cGAMP Signal Transduction During Innate Immune Responses (5F30CA239659-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10183204. Licensed CC0.

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