HIV/AIDS and Global Health Research Program, Department of Microbiology, University of Venda, Thohoyandou, Limpopo, South Africa.
Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908.
J Biol Chem. 2019 Oct 4;294(40):14591-14602. doi: 10.1074/jbc.RA119.007555. Epub 2019 Aug 2.
Zika virus (ZIKV) is an enveloped, single-stranded, positive-sense RNA virus of the Flaviviridae family that has emerged as a public health threat because of its global transmission and link to microcephaly. Currently there is no vaccine for this virus. Conversion of cholesterol to 25-hydroxycholesterol by cholesterol 25-hydroxylase (CH25H) has been shown to have broad antiviral properties. However, the molecular basis of induction of CH25H in humans is not known. Elucidation of signaling and transcriptional events for induction of CH25H expression is critical for designing therapeutic antiviral agents. In this study, we show that CH25H is induced by ZIKV infection or Toll-like receptor stimulation. Interestingly, CH25H is induced by pro-inflammatory cytokines, including IL-1β, tumor necrosis factor α, and IL-6, and this induction depends on the STAT1 transcription factor. Additionally, we observed that cAMP-dependent transcription factor (ATF3) weakly binds to the CH25H promoter, suggesting cooperation with STAT1. However, ZIKV-induced CH25H was independent of type I interferon. These findings provide important information for understanding how the Zika virus induces innate inflammatory responses and promotes the expression of anti-viral CH25H protein.
寨卡病毒（ZIKV）是黄病毒科的一种包膜、单链、正链 RNA 病毒，由于其在全球的传播及其与小头症的联系，已成为公共卫生威胁。目前尚无针对该病毒的疫苗。胆固醇 25-羟化酶（CH25H）将胆固醇转化为 25-羟胆固醇已被证明具有广泛的抗病毒特性。然而，人类中诱导 CH25H 的分子基础尚不清楚。阐明诱导 CH25H 表达的信号和转录事件对于设计治疗性抗病毒药物至关重要。在这项研究中，我们表明 ZIKV 感染或 Toll 样受体刺激可诱导 CH25H。有趣的是，促炎细胞因子，包括白细胞介素 1β、肿瘤坏死因子α和白细胞介素 6，可诱导 CH25H 的产生，这种诱导依赖于 STAT1 转录因子。此外，我们观察到 cAMP 依赖性转录因子（ATF3）与 CH25H 启动子弱结合，表明与 STAT1 合作。然而，ZIKV 诱导的 CH25H 不依赖于 I 型干扰素。这些发现为理解寨卡病毒如何诱导先天炎症反应并促进抗病毒 CH25H 蛋白的表达提供了重要信息。
