Abstract
Flavivirus genus includes numerous arthropod-borne human pathogens that are clinically important. Flaviviruses are notorious for their ability to antagonize host interferon (IFN) induced anti-viral signalling. It has been documented that NS5s of flaviviruses mediate proteasome degradation of STAT2 to evade IFN signalling. Deciphering the molecular mechanism of the IFN antagonism by the viruses and reversing this antagonism may dictate anti-viral responses and provide novel antiviral approaches. In this report, by using Zika virus (ZIKV) as a model, we first demonstrated that ZIKV antagonized interferon signalling in an infectious dose-dependent manner; in other words, the virus antagonized interferon signalling at a high multiple of infection (MOI) and was sensitive to interferon signalling at a low MOI. Mechanistically, we found that ZIKV infection triggered degradation of ubiquitinated STAT2 and host short-lived proteins while didn't affect the proteasome activity per se. ZIKV infection resulted in suppression of host de novo protein synthesis. Overexpression of NS5 alone only marginally reduced STAT2 and had no effect on the host de novo protein synthesis. Ectopically expressed murine STAT2 that was resistant to NS5- and ZIKV-induced ablation exaggerated the IFN-induced anti-viral signalling. These data favour a new model of the innate immune evasion of ZIKV in which the viral infection triggers suppression of host de novo protein synthesis to accelerate the degradation of short-lived, ubiquitinated STAT2. As flaviviruses share a very conserved replication strategy, the mechanisms of IFN antagonism elucidated here might also be employed by other flaviviruses.