Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation
Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation
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DOI：
10.1016/j.cmet.2019.05.003
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发表时间：
2019-08-06
期刊：
影响因子：
29
通讯作者：
Pearce, Erika L.
中科院分区：
文献类型：
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作者：
Puleston, Daniel J.;Buck, Michael D.;Pearce, Erika L.
细胞如何调整新陈代谢以满足需求是整个生物学领域的一个活跃的研究领域。在广泛的功能中，多胺亚精胺需要对翻译因子真核起始因子 5A (eIF5A) 进行 hypusinate。我们在此表明，hypuslated eIF5A (eIF5A(H)) 促进参与 TCA 循环和氧化磷酸化 (OXPHOS) 的线粒体蛋白子集的有效表达。其中一些蛋白质具有线粒体！靶向序列（MTS）在一定程度上增加了对 eIF5AH 的依赖性。在巨噬细胞中，OXPHOS 和糖酵解之间的代谢转换支持激活信号刺激的不同功能命运。在这些细胞中，eIF5A 的兴奋性似乎在激活后受到动态调节。使用体内和体外模型，我们表明对该途径的急性抑制会削弱 OXPHOS 依赖性替代激活，同时使有氧糖酵解依赖性经典激活完好无损。这些结果可能对通过靶向多胺-eIF5A-亚丁氨酸轴来治疗性控制巨噬细胞活化具有影响。
How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5A(H)) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondria! targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regu- lated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis.