Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 40, Pages 14591-14602Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.007555
Keywords
flavivirus; infection; inflammation; innate immunity; macrophage; cholesterol 25-hydroxylase
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Funding
- Global Infectious Diseases Research Training Programme of the Fogarty International Center/National Institute of Health [D43 TW006578]
- Research and Publication Committee of the University of Venda, South Africa
- Global Infectious Diseases Institute of University of Virginia, Seed Grant
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Zika virus (ZIKV)(3) 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-1 beta, tumor necrosis factor alpha, 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.
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