PT  - JOURNAL ARTICLE
AU  - Constanza Eleonora Espada
AU  - Edroaldo Lummertz da Rocha
AU  - Adara Aurea dos Santos
AU  - Zamira Guerra Soares
AU  - Greicy Malaquias
AU  - Daniel Oliveira Patrício
AU  - Edgar Gonzalez Kozlova
AU  - Paula Fernandes dos Santos
AU  - Juliano Bordignon
AU  - Thomas J. Sanford
AU  - Teodoro Fajardo
AU  - Trevor R. Sweeney
AU  - André Báfica
AU  - Daniel Santos Mansur
TI  - ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication
AID  - 10.1101/784678
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 784678
4099  - http://biorxiv.org/content/early/2019/12/28/784678.short
4100  - http://biorxiv.org/content/early/2019/12/28/784678.full
AB  - 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 cells’ 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 host’s IFN-I mediated response and promoting virus replication.