AUTHOR=Espada Constanza Eleonora , da Rocha Edroaldo Lummertz , Ricciardi-Jorge Taissa , dos Santos Adara Aurea , Soares Zamira Guerra , Malaquias Greicy , Patrício Daniel Oliveira , Gonzalez Kozlova Edgar , dos Santos Paula Fernandes , Bordignon Juliano , Sanford Thomas J. , Fajardo Teodoro , Sweeney Trevor R. , Báfica André , Mansur Daniel Santos TITLE=ISG15/USP18/STAT2 is a molecular hub regulating IFN I-mediated control of Dengue and Zika virus replication JOURNAL=Frontiers in Immunology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1331731 DOI=10.3389/fimmu.2024.1331731 ISSN=1664-3224 ABSTRACT=

The establishment of a virus infection is the result of the pathogen's ability to replicate in a hostile environment generated by the host's immune system. Here, we found that ISG15 restricts Dengue and Zika viruses' 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 STAT2's stability 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 host's IFN-I mediated response and promoting virus replication.