The Unique Cofactor Region of Zika Virus NS2B–NS3 Protease Facilitates Cleavage of Key Host Proteins
datasetposted on 2018-08-06, 00:00 authored by Maureen E. Hill, Anil Kumar, James A. Wells, Tom C. Hobman, Olivier Julien, Jeanne A. Hardy
Zika virus is an emerging mosquito-borne pathogen capable of severely damaging developing fetuses as well as causing neurological abnormalities in adults. The molecular details of how Zika virus causes pathologies that are unique among the flavivirus family remain poorly understood and have contributed to the lack of Zika antiviral therapies. To elucidate how Zika virus protease (ZVP) affects host cellular pathways and consequent pathologies, we used unbiased N-terminomics to identify 31 human proteins cleaved by the NS2B–NS3 protease. In particular, autophagy-related protein 16-1 (ATG16L1) and eukaryotic translation initiation factor 4 gamma 1 (eIF4G1) are dramatically depleted during Zika virus infection. ATG16L1 and eIF4G1 mediate type-II interferon production and host-cell translation, respectively, likely aiding immune system evasion and driving the Zika life cycle. Intriguingly, the NS2B cofactor region from Zika virus protease is essential for recognition of host cell substrates. Replacing the NS2B region in another flavivirus protease enabled recognition of novel Zika-specific substrates by hybrid proteases, suggesting that the cofactor is the principal determinant in ZVP substrate selection.
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Zika virus proteaseNS 2B regiontype-II interferon productionUnique Cofactor RegionATG 16LNS 2B proteaseZika life cycleZika virus causes pathologieseIF 4GZika virus infectionNS 2B cofactor regionnovel Zika-specific substrateseukaryotic translation initiation factor 4 gamma 1Zika Virus NS 2B Protease Facilitates CleavageKey Host Proteins Zika virusautophagy-related protein 16-1ZVP substrate selectionhost cell substrates