Zika Virus Infection Induced Apoptosis by Modulating the Recruitment and Activation of Proapoptotic Protein Bax

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.

Automated summary

This study demonstrates that Zika virus infection activates the mitochondrial apoptotic pathway by modulating the recruitment and activation of Bax. The viral protein NS4B plays a key role in modulating Bax recruitment and activation, providing new insights into the interaction between apoptosis and Zika virus infection.