Aberrant NAD+ metabolism underlies Zika virus-induced microcephaly
Aberrant NAD+ metabolism underlies Zika virus-induced microcephaly
复制标题
异常的 NAD( ) 代谢是寨卡病毒诱发小头畸形的基础
DOI：
10.1038/s42255-021-00437-0
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发表时间：
2021-08-12
影响因子：
20.8
通讯作者：
Hu, Zeping
中科院分区：
文献类型：
--
作者：
Pang, Huanhuan;Jiang, Yisheng;Hu, Zeping
妊娠期间感染寨卡病毒（ZIKV）可导致新生儿小头畸形，但其潜在机制在很大程度上尚未探索。在这里，我们通过进行包括转录组学、蛋白质组学、磷酸蛋白质组学和代谢组学方法的多组学研究，揭示了ZIKV感染小鼠大脑中广泛和大规模的代谢重编程事件。我们的蛋白质组学和代谢组学分析揭示了烟酰胺腺嘌呤二核苷酸（NAD（+））相关代谢途径的显著改变，包括氧化磷酸化，TCA循环和色氨酸代谢。磷酸蛋白质组学分析表明，MAPK和环GMP蛋白激酶G信号传导可能与ZIKV诱导的小头畸形有关。值得注意的是，我们通过后续的体内实验证明了我们丰富的多组学数据集的实用性，这些实验证实了通过NAD（+）或烟酰胺核苷补充剂增强NAD（+）会导致ZIKV感染小鼠大脑中的细胞死亡并增加皮质厚度。补充烟酰胺核苷增加了ZIKV感染小鼠的脑和体重，并提高了存活率。我们的研究提供了全面的生物学数据资源，以支持ZIKV诱导的小头畸形的未来研究，并表明代谢改变可以潜在地用于开发治疗策略。ZIKA病毒感染小鼠大脑的多组学表征揭示了代谢重编程事件，包括NAD（+）代谢的失调，其校正被证明可以减轻ZIKA病毒诱导的小头畸形。
Zika virus (ZIKV) infection during pregnancy can cause microcephaly in newborns, yet the underlying mechanisms remain largely unexplored. Here, we reveal extensive and large-scale metabolic reprogramming events in ZIKV-infected mouse brains by performing a multi-omics study comprising transcriptomics, proteomics, phosphoproteomics and metabolomics approaches. Our proteomics and metabolomics analyses uncover dramatic alteration of nicotinamide adenine dinucleotide (NAD(+))-related metabolic pathways, including oxidative phosphorylation, TCA cycle and tryptophan metabolism. Phosphoproteomics analysis indicates that MAPK and cyclic GMP-protein kinase G signaling may be associated with ZIKV-induced microcephaly. Notably, we demonstrate the utility of our rich multi-omics datasets with follow-up in vivo experiments, which confirm that boosting NAD(+) by NAD(+) or nicotinamide riboside supplementation alleviates cell death and increases cortex thickness in ZIKV-infected mouse brains. Nicotinamide riboside supplementation increases the brain and body weight as well as improves the survival in ZIKV-infected mice. Our study provides a comprehensive resource of biological data to support future investigations of ZIKV-induced microcephaly and demonstrates that metabolic alterations can be potentially exploited for developing therapeutic strategies.Multi-omics characterization of ZIKA virus-infected mouse brains reveals metabolic reprogramming events, including dysregulation of NAD(+) metabolism, the correction of which is shown to alleviate ZIKA virus-induced microcephaly.