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

Das Gupta, Kaustav and Shakespear, Melanie R. and Curson, James E.B. and Murthy, Ambika M.V. and Iyer, Abishek and Hodson, Mark P. and Ramnath, Divya and Tillu, Vikas A. and von Pein, Jessica B. and Reid, Robert C. and Tunny, Kathryn and Hohenhaus, Daniel M. and Moradi, Shayli Varasteh and Kelly, Gregory M. and Kobayashi, Takumi and Gunter, Jennifer H. and Stevenson, Alexander J. and Xu, Weijun and Luo, Lin and Jones, Alun and Johnston, Wayne A. and Blumenthal, Antje and Alexandrov, Kirill and Collins, Brett M. and Stow, Jennifer L. and Fairlie, David P. and Sweet, Matthew J. (2020) Class IIa Histone Deacetylases Drive Toll-like Receptor-Inducible Glycolysis and Macrophage Inflammatory Responses via Pyruvate Kinase M2. Cell Reports, 30 (8). pp. 2712-2728.e8. ISSN 22111247

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Link to published document: http://doi.org/10.1016/j.celrep.2020.02.007

Abstract

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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 02 Mar 2020 03:11
Last Modified: 12 Oct 2021 02:32
URI: http://eprints.victorchang.edu.au/id/eprint/935

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