Enterovirus 71 (EV71) has emerged as one of the most important enteroviruses since the eradication of poliovirus, and causes severe neurological symptoms for which no effective antiviral drugs are available. Type I interferons (IFN-α/β) have been used clinically as antiviral therapy as the first line of defense against virus infections successfully for decades. However, treatment with Type I interferons has not been effective in patients with EV71 infection. In this study, we found that in cells pre-treated with IFN-β, EV71 infection could still lead to a cytopathic effect and the viral replication was not affected. The mechanism by which EV71 antagonizes interferon signaling, however, has been controversial. Our study indicated that EV71 infection did not inhibit phosphorylation of STAT1/2 induced by IFN-β stimulation, but p-STAT1/2 transport into the nucleus was significantly blocked. We showed that EV71 infection reduced the formation of STAT1/ karyopherin-α1 (KPNA1) complex upon interferon stimulation, and that the virus downregulated the expression of KPNA1, a nuclear localization signal receptor for p-STAT1. Using specific caspase inhibitors and siRNA for caspase-3, we demonstrated that EV71 infection induced degradation of cellular KPNA1 in a caspase-3 dependent manner, which led to decreased induction of ISGs and IFN response. Viral 2A and 3C proteases did not degrade KPNA1, inhibit the activity of ISRE, or suppress the transcription of ISGs induced by IFN-β. Our study demonstrates a novel mechanism by which antiviral signaling is suppressed through degradation of KPNA1 by activated caspase-3 induced in an enteroviral infection.
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