IIa 类组蛋白去乙酰化酶通过丙酮酸激酶 M2 驱动 Toll 样受体诱导的糖酵解和巨噬细胞炎症反应。
Class IIa Histone Deacetylases Drive Toll-like Receptor-Inducible Glycolysis and Macrophage Inflammatory Responses via Pyruvate Kinase M2.
机构信息
Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia; IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland 4072, Australia.
Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia; IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland 4072, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, IMB, The University of Queensland, Brisbane, Queensland 4072, Australia.
出版信息
Cell Rep. 2020 Feb 25;30(8):2712-2728.e8. doi: 10.1016/j.celrep.2020.02.007.
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.
组蛋白去乙酰化酶（HDACs）驱动固有免疫细胞介导的炎症反应。在这里，我们发现 IIa 类 HDACs 是 Toll 样受体（TLR）诱导的需氧糖酵解与巨噬细胞炎症反应之间的关键分子联系。蛋白质组学筛选鉴定出糖酵解酶丙酮酸激酶 M 同工酶 2（Pkm2）是促炎性 Hdac7 在小鼠巨噬细胞中的伙伴。在转基因小鼠中，髓样细胞特异性过表达 Hdac7 可放大脂多糖（LPS）诱导的乳酸，并促进与糖酵解相关的炎症特征。相反，HDAC7 和其他 IIa 类 HDACs 的药理学或遗传学靶向作用可减弱 LPS 诱导的糖酵解和伴随的巨噬细胞炎症反应。我们表明，Hdac7-Pkm2 复合物作为免疫代谢信号枢纽发挥作用，其中 Pkm2 在赖氨酸 433 处的去乙酰化使其具有促炎功能。破坏这种复合物可抑制体外和体内的炎症反应。因此，IIa 类 HDACs 是通过 Pkm2 将 TLR 诱导的糖酵解与炎症联系起来的关键中介。
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