Department of Virology, Paul-Ehrlich-Institut, Langen, Germany.
Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
J Virol. 2022 Feb 23;96(4):e0211721. doi: 10.1128/jvi.02117-21. Epub 2021 Dec 22.
Zika virus (ZIKV) is a flavivirus that is mainly transmitted by mosquitos and normally causes mild symptoms. During the outbreak in the Americas in 2015, it was associated with more severe implications, like microcephaly in newborns and the Guillain-Barré syndrome. The lack of specific vaccines and cures strengthens the need for a deeper understanding of the virus life cycle and virus-host interactions. The restriction factor tetherin (THN) is an interferon-inducible cellular protein with broad antiviral properties. It is known to inhibit the release of various enveloped viruses by tethering them to each other and the cell membrane, thereby preventing their further spread. On the other hand, different viruses have developed various escape strategies against THN. Analysis of the cross-talk between ZIKV and THN revealed that, despite a strong induction of THN mRNA expression in ZIKV-infected cells, this is not reflected by an elevated protein level of THN. Contrariwise, the THN protein level is decreased due to a reduced half-life. The increased degradation of THN in ZIKV infected cells involves the endo-lysosomal system but does not depend on the early steps of autophagy. Enrichment of THN by depletion of the ESCRT-0 protein HRS diminishes ZIKV release and spread, which points out the capacity of THN to restrict ZIKV and explains the enhanced THN degradation in infected cells as an effective viral escape strategy. Although tetherin expression is strongly induced by ZIKV infection there is a reduction in the amount of tetherin protein. This is due to enhanced lysosomal degradation. However, if the tetherin level is rescued then the release of ZIKV is impaired. This shows that tetherin is a restriction factor for ZIKV, and the induction of an efficient degradation represents a viral escape strategy. To our knowledge, this is the first study that describes and characterizes tetherin as a restriction factor for the ZIKV life cycle.
Zika 病毒（ZIKV）是一种黄病毒，主要通过蚊子传播，通常引起轻微症状。在 2015 年美洲的疫情中，它与更严重的后果有关，例如新生儿小头畸形和格林-巴利综合征。缺乏特定的疫苗和治疗方法加强了对病毒生命周期和病毒-宿主相互作用的深入了解。限制因子 tetherin（THN）是一种干扰素诱导的细胞蛋白，具有广泛的抗病毒特性。它通过将包膜病毒彼此束缚在细胞膜上，从而抑制它们的释放，从而阻止它们的进一步传播。另一方面，不同的病毒已经开发出各种针对 THN 的逃逸策略。对 ZIKV 和 THN 之间的串扰进行分析表明，尽管 ZIKV 感染细胞中 THN mRNA 的表达强烈诱导，但这并没有反映在 THN 蛋白水平的升高上。相反，由于半衰期缩短，THN 蛋白水平降低。ZIKV 感染细胞中 THN 的降解增加涉及内体-溶酶体系统，但不依赖于自噬的早期步骤。通过耗尽 ESCRT-0 蛋白 HRS 来富集 THN 可减少 ZIKV 的释放和传播，这表明 THN 具有限制 ZIKV 的能力，并解释了感染细胞中 THN 降解增强作为一种有效的病毒逃逸策略。虽然 ZIKV 感染强烈诱导 tetherin 表达，但 tetherin 蛋白的数量减少。这是由于溶酶体降解增强。然而，如果恢复 tetherin 水平，则会损害 ZIKV 的释放。这表明 tetherin 是 ZIKV 的一种限制因子，诱导有效的降解代表了一种病毒逃逸策略。据我们所知，这是第一项描述和表征 tetherin 作为 ZIKV 生命周期的限制因子的研究。
