| Literature DB >> 26159719 |
Kirk J Lubick1, Shelly J Robertson1, Kristin L McNally1, Brett A Freedman1, Angela L Rasmussen2, R Travis Taylor3, Avram D Walts4, Seitaro Tsuruda5, Mizuki Sakai5, Mariko Ishizuka5, Elena F Boer1, Erin C Foster1, Abhilash I Chiramel1, Conrad B Addison1, Richard Green2, Daniel L Kastner6, Michael G Katze2, Steven M Holland7, Antonella Forlino8, Alexandra F Freeman7, Manfred Boehm4, Kentaro Yoshii5, Sonja M Best9.
Abstract
Type I interferon (IFN-α/β or IFN-I) signals through two receptor subunits, IFNAR1 and IFNAR2, to orchestrate sterile and infectious immunity. Cellular pathways that regulate IFNAR1 are often targeted by viruses to suppress the antiviral effects of IFN-I. Here we report that encephalitic flaviviruses, including tick-borne encephalitis virus and West Nile virus, antagonize IFN-I signaling by inhibiting IFNAR1 surface expression. Loss of IFNAR1 was associated with binding of the viral IFN-I antagonist, NS5, to prolidase (PEPD), a cellular dipeptidase implicated in primary immune deficiencies in humans. Prolidase was required for IFNAR1 maturation and accumulation, activation of IFNβ-stimulated gene induction, and IFN-I-dependent viral control. Human fibroblasts derived from patients with genetic prolidase deficiency exhibited decreased IFNAR1 surface expression and reduced IFNβ-stimulated signaling. Thus, by understanding flavivirus IFN-I antagonism, prolidase is revealed as a central regulator of IFN-I responses.Entities:
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Year: 2015 PMID： 26159719 PMCID： PMC4505794 DOI： 10.1016/j.chom.2015.06.007
Source DB: PubMed Journal: Cell Host Microbe ISSN： 1931-3128 Impact factor: 21.023