期刊
CELL REPORTS
卷 30, 期 8, 页码 2712-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.02.007
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资金
- National Health and Medical Research Council (NHMRC) of Australia [APP1047921, APP1184885]
- Australian Research Council Discovery Project [DP170102321]
- University of Queensland
- NHMRC [APP1107914, APP1136021, APP1027369, APP1117017, APP1037320]
- Australian Research Council (ARC) [LP150100689]
- CSIRO Future Science platform in synthetic biology
- ARC Discovery Early Career Researcher Award (DECRA) [DE180100524]
- Institute for Molecular Bioscience Dynamic Imaging Facility for Cancer Biology at The University of Queensland
- Australian Cancer Research Foundation
- IMB Mass Spectrometry Facility
- ARC Centre of Excellence in Advanced Molecular Imaging [CE140100011]
- Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS)
- Transgenic Animal Facility of Queensland (a division of The University of Queensland Biological Resources Department)
- Australian Research Council [LP150100689, DE180100524] Funding Source: Australian Research Council
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, where by 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.
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