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Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation

Author

Listed:
  • Meiyue Wang

    (Ludwig-Maximilians-Universität München)

  • Heinrich Flaswinkel

    (Ludwig-Maximilians-Universität München)

  • Abhinav Joshi

    (Technische Universität München
    Technische Universität München)

  • Matteo Napoli

    (Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München)

  • Sergi Masgrau-Alsina

    (Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München)

  • Julia M. Kamper

    (Ludwig-Maximilians-Universität München)

  • Antonia Henne

    (Biotechnology and Bioinformatics, Technische Universität Braunschweig)

  • Alexander Heinz

    (Biotechnology and Bioinformatics, Technische Universität Braunschweig)

  • Marleen Berouti

    (Ludwig-Maximilians-Universität München)

  • Niklas A. Schmacke

    (Ludwig-Maximilians-Universität München)

  • Karsten Hiller

    (Biotechnology and Bioinformatics, Technische Universität Braunschweig)

  • Elisabeth Kremmer

    (Ludwig-Maximilians-Universität München)

  • Benedikt Wefers

    (Helmholtz Zentrum München
    Technische Universität München
    German Center for Neurodegenerative Diseases (DZNE) site Munich
    Munich Cluster for Systems Neurology (SyNergy))

  • Wolfgang Wurst

    (Helmholtz Zentrum München
    Technische Universität München
    German Center for Neurodegenerative Diseases (DZNE) site Munich
    Munich Cluster for Systems Neurology (SyNergy))

  • Markus Sperandio

    (Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München)

  • Jürgen Ruland

    (Technische Universität München
    Technische Universität München)

  • Thomas Fröhlich

    (Ludwig-Maximilians-Universität München)

  • Veit Hornung

    (Ludwig-Maximilians-Universität München)

Abstract

Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis.

Suggested Citation

  • Meiyue Wang & Heinrich Flaswinkel & Abhinav Joshi & Matteo Napoli & Sergi Masgrau-Alsina & Julia M. Kamper & Antonia Henne & Alexander Heinz & Marleen Berouti & Niklas A. Schmacke & Karsten Hiller & E, 2024. "Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50104-7
    DOI: 10.1038/s41467-024-50104-7
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    References listed on IDEAS

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    1. Daniel B. Graham & Christine E. Becker & Aivi Doan & Gautam Goel & Eduardo J. Villablanca & Dan Knights & Amanda Mok & Aylwin C.Y. Ng & John G. Doench & David E. Root & Clary B. Clish & Ramnik J. Xavi, 2015. "Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    2. Jesse J. Balic & Hassan Albargy & Kevin Luu & Francis J. Kirby & W. Samantha N. Jayasekara & Finbar Mansell & Daniel J. Garama & Dominic Nardo & Nikola Baschuk & Cynthia Louis & Fiachra Humphries & Ka, 2020. "STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    3. Liangchun Yang & Min Xie & Minghua Yang & Yan Yu & Shan Zhu & Wen Hou & Rui Kang & Michael T. Lotze & Timothy R. Billiar & Haichao Wang & Lizhi Cao & Daolin Tang, 2014. "PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis," Nature Communications, Nature, vol. 5(1), pages 1-9, December.
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