Journal of Biological Chemistry
Volume 294, Issue 48, 29 November 2019, Pages 18168-18180
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Microbiology
Double-stranded RNA deaminase ADAR1 promotes the Zika virus replication by inhibiting the activation of protein kinase PKRADAR1 role in ZIKV replication

https://doi.org/10.1074/jbc.RA119.009113Get rights and content
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Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged as a threat to global health. The family of adenosine deaminases acting on dsRNA (ADARs) are human host factors important for the genetic diversity and evolution of ZIKV. Here, we further investigated the role of ADAR1 in ZIKV replication by utilizing CRISPR/Cas9-based gene editing and RNAi-based gene knockdown techniques. Both ADAR1 knockout and knockdown significantly reduced ZIKV RNA synthesis, protein levels, and viral titers in several human cell lines. Trans-complementation with the full-length ADAR1 form p150 or the shorter form p110 lacking the Zα domain restored viral replication levels suppressed by the ADAR1 knockout. Moreover, we observed that the nuclear p110 form was redistributed to the cytoplasm in response to ZIKV infection. ADAR1 was not involved in viral entry but promoted viral protein translation by impairing ZIKV-induced activation of protein kinase regulated by dsRNA (PKR). Of note, the RNA-editing activity of ADAR1 was not required to promote ZIKV replication. We also found that the proviral role of ADAR1 was partially mediated through its ability to suppress IFN production and PKR activation. Our work identifies ADAR1 as a proviral factor involved in ZIKV replication, suggesting that ADAR1 could be a potential antiviral target.

viral replication
interferon
flavivirus
RNA editing
host-pathogen interaction
post-transcriptional regulation
adenosine deaminase
host factor
positive stranded RNA virus
protein kinase regulated by dsRNA
Zika virus
arbovirus

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This work was supported by National Natural Science Foundation of China Grant 31970887, Guangdong Science and Technology Program Grants 2017A050501012 and 2018A050506029, and Natural Science Foundation of Guangdong Province Grant 2017A030313504. The authors declare that they have no conflicts of interest with the contents of this article.

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The abbreviations used are:

    ZIKV

    Zika virus

    E

    ZIKV envelope protein

    ADAR

    adenosine deaminase acting on dsRNA

    dsRBD

    dsRNA-binding domain

    IFN

    interferon

    VSV

    vesicular stomatitis virus

    PKR

    dsRNA-regulated protein kinase

    MOI

    multiplicity of infection

    qRT-PCR

    quantitative reverse transcription PCR

    p.i.

    postinfection

    siNC

    negative control siRNA

    GAPDH

    glyceraldehyde-3-phosphate dehydrogenase

    sgRNA

    single guide RNA

    aa

    amino acid(s)

    PMSF

    phenylmethanesulfonyl fluoride

    DAPI

    4′,6-diamidino-2-phenylindole.