Histone Deacetylase 3 Couples Mitochondria to Drive IL-1β-Dependent Inflammation by Configuring Fatty Acid Oxidation
Histone Deacetylase 3 Couples Mitochondria to Drive IL-1β-Dependent Inflammation by Configuring Fatty Acid Oxidation
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组蛋白脱乙酰酶 3 耦合线粒体通过配置脂肪酸氧化驱动 IL-1β 依赖性炎症
DOI：
10.1016/j.molcel.2020.08.015
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发表时间：
2020-10-01
期刊：
影响因子：
16
通讯作者：
Wang, Di
中科院分区：
文献类型：
--
作者：
Chi, Zhexu;Chen, Sheng;Wang, Di
免疫细胞功能取决于线粒体决定的特定代谢程序，包括营养氧化，大分子合成和翻译后修饰。线粒体适应性改变与急性和慢性炎症有关，但其代谢线索和确切机制仍不清楚。在这里，我们揭示了组蛋白去乙酰化酶3（HDAC 3）是至关重要的塑造线粒体适应IL-1 β的生产在巨噬细胞通过非组蛋白去乙酰化。在体内，HDAC 3通过增强NLRP 3依赖性caspase-1活化促进脂多糖诱导的急性炎症和高脂饮食诱导的慢性炎症。HDAC 3在刺激的巨噬细胞中配置脂质谱，并在外源性脂肪酸的支持下限制脂肪酸氧化（FAO），以使线粒体获得其适应和去极化。HDAC 3不影响核基因表达，而是转移到线粒体去乙酰化和修饰FAO酶，线粒体三功能酶亚基α。HDAC 3可以作为一个控制节点，在获得线粒体适应性和维持它们对IL-1 β依赖性炎症的适应性之间进行平衡。
Immune cell function depends on specific metabolic programs dictated by mitochondria, including nutrient oxidation, macromolecule synthesis, and post-translational modifications. Mitochondrial adaptations have been linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Here we reveal that histone deacetylase 3 (HDAC3) is essential for shaping mitochondrial adaptations for IL-1 beta production in macrophages through non-histone deacetylation. In vivo, HDAC3 promoted lipopolysaccharide-induced acute inflammation and high-fat diet-induced chronic inflammation by enhancing NLRP3-dependent caspase-1 activation. HDAC3 configured the lipid profile in stimulated macrophages and restricted fatty acid oxidation (FAO) supported by exogenous fatty acids for mitochondria to acquire their adaptations and depolarization. Rather than affecting nuclear gene expression, HDAC3 translocated to mitochondria to deacetylate and inactivate an FAO enzyme, mitochondrial trifunctional enzyme subunit alpha. HDAC3 may serve as a controlling node that balances between acquiring mitochondrial adaptations and sustaining their fitness for IL-1 beta-dependent inflammation.