Zika Virus Infection Induced Apoptosis by Modulating the Recruitment and Activation of Proapoptotic Protein Bax
Zika Virus Infection Induced Apoptosis by Modulating the Recruitment and Activation of Proapoptotic Protein Bax
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DOI：
10.1128/jvi.01445-20
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发表时间：
2021-04-01
影响因子：
5.4
通讯作者：
Cong, Haolong
中科院分区：
文献类型：
--
作者：
Han, Xiaodong;Wang, Jiuqiang;Cong, Haolong
寨卡病毒 (ZIKV) 感染与新生儿小头畸形和成人严重神经系统并发症有关。 ZIKV 感染诱导的神经祖细胞凋亡被认为是 ZIKV 感染相关小头畸形的主要原因。然而，ZIKV感染诱导细胞凋亡的详细机制仍有待阐明。在本报告中，ZIKV 感染诱导促凋亡蛋白 Bax 的构象激活，随后在线粒体中形成 Bax 寡聚体。 Bax 敲低后 SY5Y 细胞的细胞凋亡显着减少。此外，虽然减少 Bax 表达会抑制线粒体释放细胞色素 c (Cyt c)，并降低 ZIKV 感染引起的线粒体膜电位损失率，但沉默 Bak、caspase-8 和/或 caspase-10 表达则不会。从未经处理的 ZIKV 感染细胞中分离出的线粒体表现出 Bax 结合能力以及随后释放的 Cyt c。这项研究还表明，ZIKV 的 NS4B 蛋白将 Bax 招募到线粒体并诱导 Bax 构象激活。过表达的 NS4B 定位于线粒体，并通过激活促凋亡蛋白 Bax 诱导细胞凋亡。上述结果均表明，寨卡病毒感染通过调节Bax的募集和激活，直接影响线粒体凋亡途径。 重要性 自2013年太平洋岛屿和拉丁美洲发生大规模疫情以来，寨卡病毒已被证实是一种神经致畸病原体，是感染母亲所生儿童小头畸形和其他中枢神经系统发育异常的病原体。由于细胞凋亡广泛存在于整个大脑中，动物模型研究强化了 ZIKV 感染引起的小头畸形与神经祖细胞 (NPC) 细胞凋亡之间的联系。目前，ZIKV感染诱导细胞凋亡的详细机制仍有待阐明。在这里，我们首先证明 ZIKV 感染通过调节 Bax 的招募和激活来激活线粒体凋亡途径的经典迹象。 ZIKV NS4B 代表一种新型病毒凋亡蛋白，可以调节 Bax 的招募和激活并触发细胞凋亡程序。这是了解细胞凋亡和 ZIKV 感染之间相互作用的新见解。
Zika virus (ZIKV) infection is associated with microcephaly in newborns and serious neurological complications in adults. Apoptosis of neural progenitor cells induced by ZIKV infection is believed to be a main reason for ZIKV infection-related microcephaly. However, the detailed mechanism of ZIKV infection-induced apoptosis remains to be elucidated. In this report, ZIKV infection induced the conformational activation of the proapoptotic protein Bax, with subsequent formation of oligomers of Bax in the mitochondria. Cell apoptosis was reduced significantly in SY5Y cells subjected to Bax knockdown. Additionally, while decreasing Bax expression inhibited the release of cytochrome c (Cyt c) from the mitochondria and reduced the rate of loss of mitochondrial membrane potential induced by ZIKV infection, silencing Bak, caspase-8, and/or caspase-10 expression did not. Mitochondria isolated from the untreated ZIKV-infected cells displayed Bax-binding ability and the subsequent release of Cyt c. This study also indicated that the NS4B protein of ZIKV recruited Bax to the mitochondria and induced Bax conformational activation. The overexpressed NS4B was localized to the mitochondria and induced cell apoptosis by activating the proapoptotic protein Bax. All the above results indicated that ZIKV infection directly affected the mitochondrial apoptotic pathway by modulating the recruitment and activation of Bax.IMPORTANCE Since the large outbreaks that occurred in the Pacific Islands and Latin America in 2013, Zika virus has been confirmed a neuroteratogenic pathogen and causative agent of microcephaly and other developmental anomalies of the central nervous system in children born to infected mothers. As apoptosis is widespread throughout the whole brain, studies in animal models have reinforced the link between microcephaly caused by ZIKV infection and neural progenitor cell (NPC) apoptosis. Currently, the detailed mechanism of ZIKV infection-induced apoptosis still remains to be elucidated. Here, we first demonstrate that ZIKV infection activated the classic signs of mitochondrial apoptotic pathway by modulating the recruitment and activation of Bax. ZIKV NS4B represents a novel viral apoptotic protein that can modulate the recruitment and activation of Bax and trigger the apoptotic program. This is a new insight into understanding the interplay between apoptosis and ZIKV infection.