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Flavivirus antagonism of type I interferon signaling reveals prolidase as a regulator of IFNAR1 trafficking and expression

ABSTRACT: Type I interferon (IFN-I) signals through two receptor subunits, IFNAR1 and IFNAR2, to regulate sterile and infectious immunity. IFNAR1 expression is tightly regulated to prevent autoimmunity although the mechanisms governing this are incompletely understood. We investigated the strategies used by two flaviviruses, tick-borne encephalitis virus and West Nile virus, to antagonize IFN-I signaling. Infection with these viruses resulted in depletion of IFNAR1 associated with the function of the viral IFN-I antagonist, NS5. NS5 function was dependent on its ability to associate with prolidase (PEPD), a cellular dipeptidase. PEPD was required for IFNAR1 maturation and accumulation, as well as gene induction following IFNAR1 stimulation. The relevance of PEPD to human biology was confirmed in fibroblasts derived from patients with genetic prolidase deficiency that expressed low IFNAR1 and exhibited reduced responses to IFNAR1. Thus, by understanding flavivirus IFN-I antagonism, PEPD is revealed as a central regulator of IFN-I responses in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE64387 | GEO | 2015/07/08

SECONDARY ACCESSION(S): PRJNA270870

REPOSITORIES: GEO

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Flavivirus antagonism of type I interferon signaling reveals prolidase as a regulator of IFNAR1 trafficking and expression

Project description:Type I interferon (IFN-I) signals through two receptor subunits, IFNAR1 and IFNAR2, to regulate sterile and infectious immunity. IFNAR1 expression is tightly regulated to prevent autoimmunity although the mechanisms governing this are incompletely understood. We investigated the strategies used by two flaviviruses, tick-borne encephalitis virus and West Nile virus, to antagonize IFN-I signaling. Infection with these viruses resulted in depletion of IFNAR1 associated with the function of the viral IFN-I antagonist, NS5. NS5 function was dependent on its ability to associate with prolidase (PEPD), a cellular dipeptidase. PEPD was required for IFNAR1 maturation and accumulation, as well as gene induction following IFNAR1 stimulation. The relevance of PEPD to human biology was confirmed in fibroblasts derived from patients with genetic prolidase deficiency that expressed low IFNAR1 and exhibited reduced responses to IFNAR1. Thus, by understanding flavivirus IFN-I antagonism, PEPD is revealed as a central regulator of IFN-I responses in humans. RNA was isolated from replicates of 4 cultured dermal fibroblast lines derived from patients with genetic prolidase deficiency (PEPD), as well as from 4 cultured dermal fibroblast lines derived from normal healthy donors. These were run on Agilent microarrays to compare differences in gene expression observed in PEPD fibroblasts compared with normal fibroblasts.

2015-07-08 | E-GEOD-64387 | biostudies-arrayexpress

Structural basis of a novel Interferon b signaling axis mediated via the ifnar1 receptor

Project description:Type I interferons (IFNs) are a family of cytokines that play an important role in regulating immune responses to pathogens and tumors and are used therapeutically. All IFNs are considered to signal via the heterodimeric IFNAR1-IFNAR2 complex, yet some subtypes such as IFN? can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN uniquely and specifically ligates to IFNAR1 in an IFNAR2-independent manner and provide the structural basis of the IFNAR1-IFN interaction. We show that the IFNAR1-IFN complex transduces signals to modulate the expression of a set of genes independently of IFNAR2. Moreover, we show the in vivo importance of the IFNAR1-IFN signaling axis in a murine model of LPS-induced septic shock. Thus, we provide a molecular basis for understanding specific functions of IFN?. Interferon b induced gene expression in peritoneal exudate cells was measured 3hr post intra-peritoneal injection of 10,000IU/ml of interferon beta or saline into wildtype and Ifnar2-/- mice. Three independant experiments were performed for each treatment in both genotypes using different mice for each sample.

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IFNAR1 Signaling in NK Cells Promotes Persistent Virus Infection

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Genome-wide RNA-seq transcriptional analysis of splenocyte responses to Dengue virus infection in WT, Irf3(-/-)×Irf7(-/-) (DKO), Irf3-/-xIrf5-/-xIrf7-/- (TKO), and Ifnar1-/- (AB6) mice.

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Project description:Flavivirus, Zika virus Genome sequencing and assembly

| PRJNA394139 | ENA