2019 ; Vol.29-10: 1665~1674
|Author||Thi Thuy Ngan Ngueyen, Seong-Jun Kim, Jeong Yoon Lee, Jinjong Myoung|
|Place of duty||Korea Zoonosis Research Institute, Department of Bioactive Material Science and Genetic Engineering Research Institute, Chonbuk National University, Jeonju 54531, Republic of Korea|
|Title||Zika Virus Proteins NS2A and NS4A Are Major Antagonists that Reduce IFN-β Promoter Activity Induced by the MDA5/RIG-I Signaling Pathway|
J. Microbiol. Biotechnol.2019 ;
|Abstract||Zika virus (ZIKV) is a mosquito-transmitted, emerging Flavivirus that causes Guillain-Barré
syndrome and microcephaly in adults and fetuses, respectively. Since ZIKV was first isolated
in 1947, severe outbreaks have occurred at various places worldwide, including Yap Island in
2007, French Polynesia in 2013, and Brazil in 2015. Although incidences of ZIKV infection and
dissemination have drastically increased, the mechanisms underlying the pathogenesis of
ZIKV have not been sufficiently studied. In addition, despite extensive research, the exact
roles of individual ZIKV genes in the viral evasion of the host innate immune responses
remain elusive. Besides, it is still possible that more than one ZIKV-encoded protein may
negatively affect type I interferon (IFN) induction. Hence, in this study, we aimed to
determine the modulations of the IFN promoter activity, induced by the MDA5/RIG-I
signaling pathway, by over-expressing individual ZIKV genes. Our results show that two
nonstructural proteins, NS2A and NS4A, significantly down-regulated the promoter activity
of IFN-β by inhibiting multiple signaling molecules involved in the activation of IFN-β.
Interestingly, while NS2A suppressed both full-length and constitutively active RIG-I, NS4A
had inhibitory activity only on full-length RIG-I. In addition, while NS2A inhibited all forms
of IRF3 (full-length, regulatory domain-deficient, and constitutively active), NS4A could not
inhibit constitutively active IRF3-5D. Taken together, our results showed that NS2A and NS4A
play major roles as antagonists of MDA5/RIG-I-mediated IFN-β induction and more
importantly, these two viral proteins seem to inhibit induction of the type I IFN responses in
differential mechanisms. We believe this study expands our understanding regarding the
mechanisms via which ZIKV controls the innate immune responses in cells and may pave the
way to development of ZIKV-specific therapeutics.|
|Key_word||Zika virus, interferon, evasion|
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