The Unique Cofactor Region of Zika Virus NS2B-NS3 Protease Facilitates Cleavage of Key Host Proteins
The Unique Cofactor Region of Zika Virus NS2B-NS3 Protease Facilitates Cleavage of Key Host Proteins
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DOI：
10.1021/acschembio.8b00508
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发表时间：
2018-09-01
影响因子：
4
通讯作者：
Hardy, Jeanne A.
中科院分区：
文献类型：
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作者：
Hill, Maureen E.;Kumar, Anil;Hardy, Jeanne A.
寨卡病毒是一种新兴的蚊媒病原体，能够严重损害发育中的胎儿，并导致成人神经异常。寨卡病毒如何引起黄病毒家族中独特的病理学的分子细节仍然知之甚少，并导致缺乏寨卡病毒抗病毒疗法。为了阐明寨卡病毒蛋白酶（ZVP）如何影响宿主细胞途径和随后的病理学，我们使用无偏N-末端组学来鉴定31种被NS 2B-NS 3蛋白酶切割的人类蛋白质。特别是，自噬相关蛋白16-1（ATG 16 L1）和真核翻译起始因子4 γ 1（eIF 4G 1）在寨卡病毒感染期间显著耗尽。ATG 16 L1和eIF 4G 1分别介导II型干扰素产生和宿主细胞翻译，可能有助于免疫系统逃避并推动寨卡病毒的生命周期。有趣的是，寨卡病毒蛋白酶的NS 2B辅因子区域对于识别宿主细胞底物至关重要。替换另一种黄病毒蛋白酶中的NS 2B区域能够通过杂合蛋白酶识别新型寨卡特异性底物，表明辅因子是ZVP底物选择的主要决定因素。
Zika virus is an emerging mosquito-borne pathogen capable of severely damaging developing fetuses as well as causing neurological abnormalities in adults. The molecular details of how Zika virus causes pathologies that are unique among the flavivirus family remain poorly understood and have contributed to the lack of Zika antiviral therapies. To elucidate how Zika virus protease (ZVP) affects host cellular pathways and consequent pathologies, we used unbiased N-terminomics to identify 31 human proteins cleaved by the NS2B-NS3 protease. In particular, autophagy-related protein 16-1 (ATG16L1) and eukaryotic translation initiation factor 4 gamma 1 (eIF4G1) are dramatically depleted during Zika virus infection. ATG16L1 and eIF4G1 mediate type-II interferon production and host-cell translation, respectively, likely aiding immune system evasion and driving the Zika life cycle. Intriguingly, the NS2B cofactor region from Zika virus protease is essential for recognition of host cell substrates. Replacing the NS2B region in another flavivirus protease enabled recognition of novel Zika-specific substrates by hybrid proteases, suggesting that the cofactor is the principal determinant in ZVP substrate selection.