# Deciphering the Role of dNTP Metabolism in Innate Immunity

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $410,000

## Abstract

Project Summary
A balanced supply of deoxynucleoside triphosphates (dNTPs), the building blocks for DNA, is vital for the
synthesis or repair of both nuclear and mitochondrial genomes, whereas its imbalance results in genome
instability that precipitates cellular damage and breach of homeostasis. Research on dNTP metabolism has
been traditionally conducted in highly proliferative (e.g. tumor cells), metabolically active (e.g. muscle cells) or
virus-infected cells due to the key roles of dNTPs in fulfilling demands for cell growth, energy production and
viral replication. However, little is known regarding the role of dNTP metabolism in innate immunity, especially
in the context of nonpathogen-induced immune activation. A hallmark of innate immune activation is the
assembly of the Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome—a dominant innate
immune sensor for tissue damage. The NLRP3 inflammasome is composed of the sensor NLRP3, the adaptor
ASC (apoptosis associated spike-like protein) and the effector pro-caspase-1. Assembly of the NLRP3
inflammasome proceeds with two distinct steps: ‘priming’ and ‘activation’. Priming entails rapid NF-kB
activation for initiating de novo synthesis of pro-IL-1β as well as increasing the amount of NLRP3. In contrast,
activation involves the assembly of the NLRP3 inflammasome machinery, resulting in autocleavage and
activation of caspase-1 which then converts immature pro-IL-1β into bioactive IL-1β—a powerful
proinflammatory cytokine that ignites inflammation. Although properly controlled NLRP3 inflammasome activity
allows for restoration of homeostasis after traumatic tissue injury by stimulating damage clearance and tissue
repair, its aberrant and prolonged activation also promotes the rapid progression of many devastating
disorders, including gouty arthritis, Alzheimer’s disease, atherosclerosis, macular degeneration and cancer. It
is therefore crucial to understand how NLRP3 inflammasome activity is regulated in innate immune cells.
Recently, we discovered that genetic deletion of CMPK2 or SAMHD1, two key enzymes within the dNTP
metabolic pathways responsible for synthesizing or degrading dNTPs respectively, orchestrates NLRP3
inflammasome activation. Therefore, the ultimate goal of this MIRA R35 project is to establish dNTP
metabolism as a new layer for innate immune regulation and further delineate its underlying mechanism of
action. To achieve this goal, three major scientific questions will be pursued: (1) how does inflammasome
priming regulate the function of dNTP metabolic enzymes? (2) how does dNTP metabolism control NLRP3
inflammasome activation? Lastly, since NLRP3 inflammasome overactivation is a shared pathogenic hallmark
of many diseases, we further asked: (3) do common disease risk factors, such as aging and obesity,
dysregulate macrophage dNTP metabolism, thereby permitting NLRP3 inflammasome overactivation?
Completion of this project will not only fill an important knowledge ...

## Key facts

- **NIH application ID:** 10480862
- **Project number:** 5R35GM142654-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Zhenyu Zhong
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2021-09-03 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480862

## Citation

> US National Institutes of Health, RePORTER application 10480862, Deciphering the Role of dNTP Metabolism in Innate Immunity (5R35GM142654-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10480862. Licensed CC0.

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