# Elucidating the roles of CMPK2 in mitochondrial homeostasis and antiviral immunity

> **NIH NIH F31** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2021 · $37,043

## Abstract

PROJECT SUMMARY
 Cytidine/uridine monophosphate kinase 2 (CMPK2) is an interferon-regulated enzyme that was originally
reported to catalyze the ATP-dependent phosphorylation of dCMP and dUMP to diphosphate forms in vitro. Due
to a putative mitochondrial targeting sequence, CMPK2 was postulated to function in the mitochondrial
deoxyribonucleotide salvage pathway necessary for the synthesis and maintenance of mitochondrial DNA
(mtDNA). However, more recent data have revealed that CMPK2 prefers ribonucleotide diphosphate substrates
in vitro and functions to restrict HIV and other RNA viruses in cell based assays. Beyond these seemingly
contrasting findings, no other studies have addressed the cellular localization and tissue expression patterns of
CMPK2 or utilized genetic knockouts to determine true biological activity. Therefore, the overall objective of this
proposal is to close these knowledge gaps and mechanistically advance understanding of CMPK2 in
mitochondrial function, tissue homeostasis, and antiviral innate immunity using a diverse toolkit of cell and animal
models. The central hypothesis is that by maintaining mitochondrial homeostasis, CMPK2 boosts cell-intrinsic
innate immunity and limits runaway inflammation triggered by mitochondrial stressors and viral infection. In
support of this hypothesis, ongoing studies have revealed that CMPK2 localizes strongly to mitochondria and
that ectopic overexpression of CMPK2 is sufficient to protect cells from RNA virus infection. Moreover, after
systemic challenge with innate immune agonists, CMPK2 is markedly upregulated in the lungs and liver, and
CMPK2 knockout mice exhibit elevated expression of proinflammatory cytokines and type I interferon (IFN-I)
responses after Toll-like receptor (TLR) stimulation. To gain additional insight into how CMPK2 functions in
mitochondria and antiviral immunity, two related, but independent aims are proposed. Aim 1 will elucidate the
molecular mechanisms by which CMPK2 maintains mitochondrial homeostasis at rest and during stress. Here,
CMPK2 knockout cells, novel lines reconstituted with mutant CMPK2 vectors lacking nucleotide kinase activity
or mitochondrial targeting, and whole body CMPK2 knockout mice will be utilized. Aim 2 will determine that the
mitochondrial activity of CMPK2 restricts coronavirus replication and maintains mitochondrial function during
infection. Here, an intranasal mouse hepatitis virus challenge protocol that models acute respiratory distress
syndrome and closely mirrors coronavirus pneumonia in humans will be employed. This research will
fundamentally advance our understanding of how CMPK2 functions in mitochondrial homeostasis and antiviral
innate immunity at both the cellular and organismal levels. Moreover, it may have a positive impact on public
health by revealing novel CMPK2-centered strategies to maintain mitochondrial homeostasis, boost antiviral
immunity, and limit damaging inflammation during coronavirus infection.

## Key facts

- **NIH application ID:** 10313146
- **Project number:** 1F31HL160141-01
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Sylvia Torres-Odio
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,043
- **Award type:** 1
- **Project period:** 2021-09-30 → 2024-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313146

## Citation

> US National Institutes of Health, RePORTER application 10313146, Elucidating the roles of CMPK2 in mitochondrial homeostasis and antiviral immunity (1F31HL160141-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10313146. Licensed CC0.

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