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

• DOI: 10.1016/j.celrep.2020.02.007
• Publication Date: 2020-02-25T15:58:39Z
• Authors: Kaustav Das Gupta; Melanie R. Shakes...; James E.B. Curson; Ambika M.V. Murthy; Abishek Iyer; Mark P. Hodson; Divya Ramnath; Vikas A. Tillu; Jessica B. von Pein; Robert C. Reid; Kathryn Tunny; Daniel M. Hohenhaus; Shayli Varasteh M...; Gregory M. Kelly; Takumi Kobayashi; Jennifer H. Gunter; Alexander J. Stev...; Weijun Xu; Lin Luo; Alun Jones; Wayne A. Johnston; Antje Blumenthal; Kirill Alexandrov; Brett M. Collins; Jennifer L. Stow; David P. Fairlie; Matthew J. Sweet
• Keywords: Lipopolysaccharides; 1300 Biochemistry; QH301-705.5; immunometabolism; Pyruvate Kinase; 610; Genetics and Molecular Biology; macrophage; pyruvate kinase; Histone Deacetylases; Mice; 03 medical and health sciences; 616; Animals; Humans; Biology (General); lysine acetylation; Inflammation; 0303 health sciences; Macrophages; Toll-Like Receptors; Acetylation; glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Mice, Inbred C57BL; HEK293 Cells; RAW 264.7 Cells; post-translational modification; inflammation; toll-like receptor; Glycolysis; histone deacetylases; Protein Binding

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.