Key result
Enterovirus 71 suppresses the interferon response by inducing caspase-3-dependent degradation of KPNA1, which blocks the nuclear translocation of phosphorylated STAT1/2.
EV71 evades the antiviral effects of type I interferons by activating caspase-3 to degrade KPNA1, thereby preventing the nuclear translocation of phosphorylated STAT1/2 and suppressing the interferon response.
EV71 interferon evasion mechanism shown in animals; leaves open whether caspase-3 or KPNA1 targeting alters human outcomes.
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.
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Wang et al. (2017) studied Enterovirus 71 infection. Enterovirus 71 infection vs. Uninfected cells was evaluated on Mechanism of interferon response suppression. Enterovirus 71 suppresses the interferon response by inducing caspase-3-dependent degradation of KPNA1, which blocks the nuclear translocation of phosphorylated STAT1/2.