# Transcriptional regulation of NK cell metabolism and effector function by MEF2C

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $44,651

## Abstract

PROJECT SUMMARY
NK cells are required for antiviral immunity against viral infection in mice and humans. Patients with NK cell
deficiencies display increased susceptibility to infection from human cytomegalovirus (HCMV), varicella zoster
virus, and other herpesviruses. During the response to viral infection, activated NK cells expand, produce
inflammatory cytokines such as interferon-γ (IFN-γ), and directly kill virally infected host cells. Potent induction of
these effector functions is tightly linked to metabolic reprogramming, as NK cells undergo drastic metabolic
changes to optimize energy production. Recent studies have identified the mammalian target of rapamycin
complex 1 (mTORc1) and the sterol regulatory element-binding protein (SREBP) family of transcription factors
as being key regulators of activated NK cell metabolism. Despite the importance of these metabolic adaptations,
however, the precise molecular regulators linking extracellular activating signals to these intracellular metabolic
mediators remain poorly understood. Our results indicate that the transcription factor myocyte enhancing factor
2C (MEF2C) is a central regulator of mature human NK cell proliferation, IFN-γ production, and cytotoxicity.
CRISPR-Cas9 ribonucleoprotein (RNP)-mediated knockout of MEF2C resulted in impaired human NK cell
effector function in vitro. Likewise, MEF2C loss resulted in impaired expansion of mouse NK cells during mouse
cytomegalovirus (MCMV) infection in vivo. Metabolic analyses revealed that MEF2C promotes glycolysis,
oxidative phosphorylation, and lipid uptake and accumulation in cytokine-activated human NK cells. MEF2C
expression was induced by IL-2 and IL-15 stimulation in a phosphoinositol-3-kinase (PI3K)-dependent manner,
while Cleavage Under Targets & Tagmentation (CUT&Tag) analysis indicated that MEF2C binds at the SREBF1
locus encoding SREBP1 to increase transcript expression. These results suggest that MEF2C is required for
cytokine-activated NK cell proliferation, effector function, and metabolism through regulation of SREBP1. Thus,
we propose studies to test the hypothesis that MEF2C activates SREBP1 to increase lipid synthesis and import
after IL-2/15 activation to fuel NK cell effector function and proliferation to mediate protective antiviral responses
during CMV infection. Aim 1 will i) test whether MEF2C is required for mouse NK cell antiviral activity during in
vivo MCMV infection and ii) determine if MEF2C augments human NK cell clearance of HCMV-infected targets.
Aim 2 will i) determine the MEF2C-dependent metabolic pathways in human NK cells and ii) test whether neutral
lipid supplementation can restore effector function and metabolism in MEF2C-deficient human NK cells. Our
proposal will delineate a novel transcriptional regulator of human NK cell metabolism that enhances our
understanding of basic NK cell biology as well as clinically relevant mechanisms of antiviral immunity.

## Key facts

- **NIH application ID:** 10825293
- **Project number:** 1F30AI181449-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Joey H. T. Li
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,651
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825293

## Citation

> US National Institutes of Health, RePORTER application 10825293, Transcriptional regulation of NK cell metabolism and effector function by MEF2C (1F30AI181449-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10825293. Licensed CC0.

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