Enterovirus 71 (EV71) has emerged as one of the most important enteroviruses since the eradication of poliovirus, and it 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 pretreated 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 STAT/
karyopherin-α1 (KPNA1) complex upon
interferon stimulation and that the virus down-regulated 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
interferon-inducible genes and IFN response. Viral 2A and
3C proteases did not degrade KPNA1, inhibit the activity of ISRE or suppress the transcription of
interferon-inducible genes 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.