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MEF2C regulates NK cell effector functions through control of lipid metabolism.
Li, Joey H; Zhou, Adalia; Lee, Cassidy D; Shah, Siya N; Ji, Jeong Hyun; Senthilkumar, Vignesh; Padilla, Eddie T; Ball, Andréa B; Feng, Qinyan; Bustillos, Christian G; Riggan, Luke; Greige, Alain; Divakaruni, Ajit S; Annese, Fran; Cooley Coleman, Jessica A; Skinner, Steven A; Cowan, Christopher W; O'Sullivan, Timothy E.
  • Li JH; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Zhou A; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Lee CD; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Shah SN; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Ji JH; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Senthilkumar V; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Padilla ET; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Ball AB; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Feng Q; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Bustillos CG; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Riggan L; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Greige A; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Divakaruni AS; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Annese F; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Cooley Coleman JA; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Skinner SA; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Cowan CW; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • O'Sullivan TE; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Nat Immunol ; 25(5): 778-789, 2024 May.
Article en En | MEDLINE | ID: mdl-38589619
ABSTRACT
Natural killer (NK) cells are a critical first line of defense against viral infection. Rare mutations in a small subset of transcription factors can result in decreased NK cell numbers and function in humans, with an associated increased susceptibility to viral infection. However, our understanding of the specific transcription factors governing mature human NK cell function is limited. Here we use a non-viral CRISPR-Cas9 knockout screen targeting genes encoding 31 transcription factors differentially expressed during human NK cell development. We identify myocyte enhancer factor 2C (MEF2C) as a master regulator of human NK cell functionality ex vivo. MEF2C-haploinsufficient patients and mice displayed defects in NK cell development and effector function, with an increased susceptibility to viral infection. Mechanistically, MEF2C was required for an interleukin (IL)-2- and IL-15-mediated increase in lipid content through regulation of sterol regulatory element-binding protein (SREBP) pathways. Supplementation with oleic acid restored MEF2C-deficient and MEF2C-haploinsufficient patient NK cell cytotoxic function. Therefore, MEF2C is a critical orchestrator of NK cell antiviral immunity by regulating SREBP-mediated lipid metabolism.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Células Asesinas Naturales / Metabolismo de los Lípidos / Factores de Transcripción MEF2 Límite: Animals / Humans Idioma: En Año: 2024 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Células Asesinas Naturales / Metabolismo de los Lípidos / Factores de Transcripción MEF2 Límite: Animals / Humans Idioma: En Año: 2024 Tipo del documento: Article