Abstract
Zika virus (ZIKV) is a re-emerging flavivirus. Similar to other flaviviruses, ZIKV antagonizes the host interferon (IFN) signaling pathway to establish infection. Understanding the molecular mechanism by which ZIKV antagonizes IFN-induced antiviral signaling may lead to a new antiviral strategy by cracking the IFN antagonism. Flaviviruses have been reported to employ NS5-dependent and -independent mechanisms to block STAT2-mediated signaling, whereas whether flaviviruses target STAT1 remains controversial. Herein, we found that ZIKV infection triggered caspase-dependent cleavage of STAT1 at the aspartic acid 694 during late infection, whereas murine STAT1 (mSTAT1) was resistant to cleavage. Intriguingly, ectopically expressed cleavage-resistant human STAT1.D694A or complementation of cleavable mSTAT1.D695G exerted comparable anti-ZIKV activity with their counterparts, challenging the role of caspase-mediated STAT1 cleavage in the IFN antagonism in ZIKV-infected cells. These data may also imply a dominant role of the antagonism of STAT2 but not STAT1 in ZIKV-infected cells.