Document text
Principal Investigator: Joey H. T. Li
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $44,651
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Acetates><Activated Natural Killer Cell><Address><Anti-viral Agents><Anti-viral Response><Anti-viral Therapy><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Binding><CMV><CMV infection><COVID-19><CRISPR><CRISPR approach><CRISPR based approach><CRISPR editing screen><CRISPR method><CRISPR methodology><CRISPR screen><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based screen><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 screen><CRISPR/Cas9 technology><CV-19><Carbon><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cells><Cellular Metabolic Process><Cellular Proliferation><Cellular biology><Chickenpox Virus><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Co-Stimulator><Complex><Coronavirus Infectious Disease 2019><Costimulator><Cytokine Activation><Cytolysis><Cytomegalic Inclusion Disease><Cytomegalovirus><Cytomegalovirus Infections><Cytotoxic cell><D-Glucose><Data><Dextrose><Effector Cell><Epidermal Thymocyte Activating Factor><Equilibrium><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Fibroblasts><Foreskin><Gas Chromatography><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><Glucose><Glycolysis><HCMV><HCV infection><HHV-3><HHV3><HIV-1><HIV-I><HIV1><Hepatitis C><Hepatitis C virus infection><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Herpes infection><Herpes zoster Virus><Herpesviridae><Herpesviridae Infections><Herpesviridae disease><Herpesvirus 1 (beta), Murid><Herpesvirus Infections><Herpesvirus Type 3><Herpesvirus varicellae><Herpesviruses><Homeostasis><Host Defense><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-15><IL-2><IL15><IL15 Protein><IL2 Protein><Immune Interferon><Impairment><In Vitro><Inclusion Disease><Incubated><Infection><Infection Control><Inflammatory><Interferon Gamma><Interferon Type II><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-15><Interleukin-15 Precursor><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intermediary Metabolism><Intracellular Communication and Signaling><K lymphocyte><Kinases><Knock-out><Knockout><Link><Lipids><Lymphocyte Mitogenic Factor><Lysis><Lytotoxicity><MGC9721><Male Prepuce><Mechanistic Target of Rapamycin><Mediating><Mediator><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitogenic Factor><Modern Man><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Mouse Cytomegalovirus><Murid herpesvirus 1><Murine><Murine Cytomegalovirus><Mus><Muscle Cells><Muscle Fibers><Myocytes><Myotubes><NK Cell Activation><NK Cells><Natural Killer Cell Activation><Natural Killer Cells><Ocular Herpes zoster Virus><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Patients><Phosphotransferase Gene><Phosphotransferases><Physiological Homeostasis><Predisposition><Preputium Penis><Production><Proliferating><Protein Family><RAFT1><RNA Expression><Regulation><Rhabdomyocyte><Ribonucleoproteins><Role><SRE-1 binding protein><SREBP-1><Salivary Gland Virus Disease><Salivary Gland Viruses><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Fiber><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Supplementation><Susceptibility><T cell growth factor><T-Cell Growth Factor><T-Cell Stimulating Factor><Testing><Thymocyte Stimulating Factor><Transcript><Transcription><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Transphosphorylases><Up-Regulation><Upregulation><VZ Virus><Varicella-Zoster Virus><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Physiology><Virus Diseases><anti-viral compound><anti-viral drugs><anti-viral immunity><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral immunity><balance><balance function><biological signal transduction><cell biology><cell metabolism><cellular metabaolism><chronic infection><clinical relevance><clinically relevant><clustered regularly interspaced short palindromic repeats screen><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cytokine><cytomegalovirus group><cytotoxicity><enhancing factor><extracellular><hep C><hepatitis non A non B><herpes virus><hypoimmunity><immune deficiency><immunodeficiency><improved><in vivo><infection by hepatitis c virus><lFN-Gamma><mTOR><mammalian target of rapamycin><mortality><non A, non B hepatitis><non-A, non-B hepatitis><novel><penis foreskin><persistent infection><pre-clinical study><preclinical study><response><social role><sterol regulatory element-binding protein 1><tandem mass spectrometry><transcription factor><uptake><vapor phase chromatography><viral infection><viral infectious disease treatment><virus infection><virus-induced disease>