Class IIa Histone Deacetylases Drive Toll-like Receptor-Inducible Glycolysis and Macrophage Inflammatory Responses via Pyruvate Kinase M2
| Autor: | Mark P. Hodson, Brett M. Collins, Weijun Xu, Alexander J. Stevenson, Alun Jones, Gregory M. Kelly, Antje Blumenthal, Wayne A. Johnston, Robert Reid, Shayli Varasteh Moradi, James E. B. Curson, Kathryn A. Tunny, Divya Ramnath, Melanie R. Shakespear, Kirill Alexandrov, Matthew J. Sweet, Jessica B. von Pein, Lin Luo, Ambika M. V. Murthy, Kaustav Das Gupta, David P. Fairlie, Daniel M. Hohenhaus, Abishek Iyer, Jennifer L. Stow, Vikas A. Tillu, Jennifer H. Gunter, Takumi Kobayashi |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Pyruvate Kinase Inflammation PKM2 General Biochemistry Genetics and Molecular Biology Histone Deacetylases Proinflammatory cytokine 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Humans Glycolysis lcsh:QH301-705.5 Toll-like receptor Chemistry Macrophages Toll-Like Receptors HDAC7 Acetylation Hypoxia-Inducible Factor 1 alpha Subunit Cell biology Mice Inbred C57BL 030104 developmental biology HEK293 Cells RAW 264.7 Cells lcsh:Biology (General) Anaerobic glycolysis medicine.symptom 030217 neurology & neurosurgery Pyruvate kinase Protein Binding |
| Zdroj: | Cell Reports, Vol 30, Iss 8, Pp 2712-2728.e8 (2020) |
| ISSN: | 2211-1247 |
| Popis: | Summary: Histone deacetylases (HDACs) drive innate immune cell-mediated inflammation. Here we identify class IIa HDACs as key molecular links between Toll-like receptor (TLR)-inducible aerobic glycolysis and macrophage inflammatory responses. A proteomic screen identified the glycolytic enzyme pyruvate kinase M isoform 2 (Pkm2) as a partner of proinflammatory Hdac7 in murine macrophages. Myeloid-specific Hdac7 overexpression in transgenic mice amplifies lipopolysaccharide (LPS)-inducible lactate and promotes a glycolysis-associated inflammatory signature. Conversely, pharmacological or genetic targeting of Hdac7 and other class IIa HDACs attenuates LPS-inducible glycolysis and accompanying inflammatory responses in macrophages. We show that an Hdac7-Pkm2 complex acts as an immunometabolism signaling hub, whereby Pkm2 deacetylation at lysine 433 licenses its proinflammatory functions. Disrupting this complex suppresses inflammatory responses in vitro and in vivo. Class IIa HDACs are thus pivotal intermediates connecting TLR-inducible glycolysis to inflammation via Pkm2. : Das Gupta et al. show that HDAC7 and other class IIa HDAC enzymes control macrophage metabolism. They initiate TLR-inducible glycolysis in these cells and interact with the glycolytic enzyme PKM2 to drive inflammatory responses in vitro and in vivo. Class IIa HDAC inhibitors may have potential for attenuating immunometabolism-linked inflammation. Keywords: glycolysis, histone deacetylases, immunometabolism, inflammation, lysine acetylation, macrophage, post-translational modification, pyruvate kinase, toll-like receptor |
| Databáze: | OpenAIRE |
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