Class IIa Histone Deacetylases Drive Toll-like Receptor-Inducible Glycolysis and Macrophage Inflammatory Responses via Pyruvate Kinase M2

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 kinas...

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Published in:	Cell reports (Cambridge) 2020-02, Vol.30 (8), p.2712-2728.e8
Main Authors:	Das Gupta, Kaustav, Shakespear, Melanie R., Curson, James E.B., Murthy, Ambika M.V., Iyer, Abishek, Hodson, Mark P., Ramnath, Divya, Tillu, Vikas A., von Pein, Jessica B., Reid, Robert C., Tunny, Kathryn, Hohenhaus, Daniel M., Moradi, Shayli Varasteh, Kelly, Gregory M., Kobayashi, Takumi, Gunter, Jennifer H., Stevenson, Alexander J., Xu, Weijun, Luo, Lin, Jones, Alun, Johnston, Wayne A., Blumenthal, Antje, Alexandrov, Kirill, Collins, Brett M., Stow, Jennifer L., Fairlie, David P., Sweet, Matthew J.
Format:	Article
Language:	eng
Subjects:	Acetylation - drug effects Animals glycolysis Glycolysis - drug effects HEK293 Cells histone deacetylases Histone Deacetylases - metabolism Humans Hypoxia-Inducible Factor 1, alpha Subunit - metabolism immunometabolism inflammation Inflammation - pathology Lipopolysaccharides - pharmacology lysine acetylation macrophage Macrophages - drug effects Macrophages - enzymology Macrophages - pathology Mice Mice, Inbred C57BL post-translational modification Protein Binding - drug effects pyruvate kinase Pyruvate Kinase - metabolism RAW 264.7 Cells toll-like receptor Toll-Like Receptors - metabolism
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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. [Display omitted] •The class IIa HDAC, HDAC7, drives TLR4-inducible glycolysis in macrophages•An interaction between HDAC7 and PKM2 drives macrophage immunometabolic responses•Deacetylation of PKM2 at K433 licenses it to drive proinflammatory IL-1β expression•Multiple class IIa HDACs can engage the PKM2 immunometabolic signaling hub 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.
ISSN:	2211-1247 2211-1247