ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I mediated control of Dengue and Zika virus replication

The establishment of a virus infection is the result of the pathogen9s ability to replicate in a hostile environment generated by the host9s immune system. Here, we found that ISG15 restricts Dengue and Zika viruses9 replication through the stabilization of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signaling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the cells9 immune response and restrict virus growth, suggesting that the IFNAR-mediated ISG15 activity is also antiviral. Our results add a novel layer of complexity in the virus/host interaction interface and suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing host9s IFN-I mediated response and promoting virus replication.