The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support Infection
The ER Membrane Protein Complex Promotes Biogenesis of Dengue and Zika Virus Non-structural Multi-pass Transmembrane Proteins to Support Infection
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DOI：
10.1016/j.celrep.2019.04.051
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发表时间：
2019-05-07
期刊：
影响因子：
8.8
通讯作者：
Tai, Andrew W.
中科院分区：
文献类型：
--
作者：
Lin, David L.;Inoue, Takamasa;Tai, Andrew W.
尽管黄病毒在感染过程中会与宿主内质网（ER）膜蛋白复合物（EMC）发生作用，但对这一现象的机制解释仍不清楚。在这里，我们表明EMC促进登革病毒（DENV）和寨卡病毒（ZIKV）非结构性多通道跨膜蛋白NS 4A和NS 4 B的生物合成，这是病毒复制所必需的。EMC与NS 4 B结合并与DENV复制细胞器共定位。作图分析显示NS 4 B的两个N-末端边缘疏水结构域赋予EMC依赖性。此外，改变这两个边缘疏水结构域的疏水性减轻了NS 4 B的EMC依赖性。我们证明，NS 4 B的生物合成，但不是它的稳定性，减少在EMC耗尽的细胞。我们的数据表明，EMC作为一个多通道的跨膜分子伴侣所需的表达至少两个病毒编码的蛋白质黄病毒感染所必需的，并指出在病毒的生命周期，可以利用抗病毒治疗的共享漏洞。
Although flaviviruses co-opt the function of the host endoplasmic reticulum (ER) membrane protein complex (EMC) during infection, a mechanistic explanation for this observation remains unclear. Here, we show that the EMC promotes biogenesis of dengue virus (DENV) and Zika virus (ZIKV) non-structural multi-pass transmembrane proteins NS4A and NS4B, which are necessary for viral replication. The EMC binds to NS4B and colocalizes with the DENV replication organelle. Mapping analysis reveals that the two N-terminal marginally hydrophobic domains of NS4B confer EMC dependency. Furthermore, altering the hydrophobicity of these two marginally hydrophobic domains relieves NS4B's EMC dependency. We demonstrate that NS4B biogenesis, but not its stability, is reduced in EMC-depleted cells. Our data suggest that the EMC acts as a multi-pass transmembrane chaperone required for expression of at least two virally encoded proteins essential for flavivirus infection and point to a shared vulnerability during the viral life cycle that could be exploited for antiviral therapy.