posted on 2018-08-06, 00:00authored byMaureen
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.