Abstract
Zika virus (ZIKV) is a mosquito-transmitted virus that has caused significant public health concerns around the world, partly because of an association with microcephaly in babies born to mothers who were infected with ZIKV during pregnancy. As a recently emerging virus, little is known as to how the virus interacts with the host cell machinery. A yeast-2-hybrid screen for proteins capable of interacting with the ZIKV E protein domain III, the domain responsible for receptor binding, identified 21 proteins, one of which was the predominantly ER resident chaperone protein GRP78. The interaction of GRP78 and ZIKV E was confirmed by co-immunoprecipitation and reciprocal co-immunoprecipitation, and indirect immunofluorescence staining showed intracellular and extracellular co-localization between GRP78 and ZIKV E. Antibodies directed against the N-terminus of GRP78 were able to inhibit ZIKV entry to host cells, resulting in significant reductions in the levels of ZIKV infection and viral production. Consistently, these reductions were also observed after down-regulation of GRP78 by siRNA. These results indicate that GRP78 can play a role mediating ZIKV binding, internalization and replication in cells. GRP78 is a main regulator of the unfolded protein response (UPR), and the study showed that expression of GRP78 was up-regulated, and the UPR was activated. Increases in CHOP expression, and activation of caspases 7 and 9 were also shown in response to ZIKV infection. Overall these results indicate that the interaction between GRP78 and ZIKV E protein plays an important role in ZIKV infection and replication, and may be a potential therapeutic target.
Highlights
Zika virus (ZIKV) is an enveloped virus classified in the genus Flavivirus, family Flaviviridae[1] that is predominantly transmitted to humans by the bite of an infected Aedes species m osquito[2,3], other transmission routes including sexual t ransmission[4,5] and mother to fetus transmission[6,7] exist
ZIKV E protein contains three distinct domain, an N-terminal domain, an elongated finger-like structure which is responsible for dimerization of E protein and contains a hydrophobic fusion loop involved in membrane fusion, and immunoglobulin-like domain which plays a key role in receptor binding during virus entry to host c ell[16]
The major role of envelope protein of ZIKV is receptor binding for virus entry to the host cell, ZIKV E protein might have a functional role in manipulating host cellular pathways through interacting with host cell proteins to generate a favorable environment for viral replication[20]
Summary
Zika virus (ZIKV) is an enveloped virus classified in the genus Flavivirus, family Flaviviridae[1] that is predominantly transmitted to humans by the bite of an infected Aedes species m osquito[2,3], other transmission routes including sexual t ransmission[4,5] and mother to fetus transmission[6,7] exist. The envelope (E) protein is a major component of the ZIKV virion surface, and plays an essential role in receptor binding during virus entry. ZIKV E protein contains three distinct domain, an N-terminal domain (domain I), an elongated finger-like structure (domain II) which is responsible for dimerization of E protein and contains a hydrophobic fusion loop involved in membrane fusion, and immunoglobulin-like domain (domain III) which plays a key role in receptor binding during virus entry to host c ell[16]. The major role of envelope protein of ZIKV is receptor binding for virus entry to the host cell, ZIKV E protein might have a functional role in manipulating host cellular pathways through interacting with host cell proteins to generate a favorable environment for viral replication[20]. The second objective of this study was to investigate the activation of the UPR and apoptosis induction during ZIKV infection
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