RT Journal Article
SR Electronic
T1 Flaviviruses exploit fine-tuning of the interferon response to promote replication
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 784678
DO 10.1101/784678
A1 Constanza Eleonora Espada
A1 Edroaldo Lummertz da Rocha
A1 Adara Aurea dos Santos
A1 Zamira Guerra Soares
A1 Greicy Malaquias
A1 Daniel Oliveira Patrício
A1 Edgar Gonzalez Kozlova
A1 Paula Fernandes dos Santos
A1 Juliano Bordignon
A1 Thomas J. Sanford
A1 Teodoro Fajardo
A1 Trevor R. Sweeney
A1 André Báfica
A1 Daniel Santos Mansur
YR 2019
UL http://biorxiv.org/content/early/2019/09/30/784678.abstract
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 regulatory function of ISG15 is also antiviral. Our results suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing host’s IFN-I mediated response and promoting virus replication, adding another layer of complexity in the virus/host interaction interface.