Microarray analysis reveals that Type I interferon strongly increases the expression of immune-response related genes in Ubp43 (Usp18) deficient macrophages

Abstract

Type I interferon (IFN) contributes significantly to innate immune responses to pathogen infections in macrophages. Our previous studies demonstrate that Ubp43, an ISG15-specific isopeptidase, is highly expressed in macrophages and noncatalytically inhibits Type I IFN signaling. To understand the effect of Type I IFN and Ubp43 in macrophage activation, we analyzed the expression of IFN-β stimulated genes in wild-type and Ubp43 −/− bone marrow derived macrophages (BMMs). Here, we show that Ubp43 regulates IFN-β stimulated genes at genome level. IFN hypersensitivity of Ubp43 −/− BMMs resulted in the identification of 749 unique genes that are upregulated by IFN-β, including a large group of previously unidentified IFN-stimulated genes. Functional analyses of these genes showed that Type I IFN strongly induced the expression of a group of immune response related genes, including genes for antigen presentation, antiviral responses, and chemokine and cytokine production. These results provide excellent biochemical support for the high resistance of viral and bacterial infection of Ubp43 knockout mice, suggesting that Ubp43 is a potential therapeutic target for the enhancement of immune responses against infections.

Gene expression changes in the host response between resistant and susceptible inbred mouse strains after influenza A infection

“…Interferoninduced genes were activated in both groups to a similar extent [16]. Furthermore, Zou et al [21] described the activation of genes in interferon-treated macrophages of wild type and Ubp43 mutant mice. Of the 749 genes described in their analysis for the Ubp43 mutant after treatment, 235 were also regulated in our data set.…”

Identification of USP18 as an Important Regulator of the Susceptibility to IFN-α and Drug-Induced Apoptosis

“…mRNA profile studies using cells from USP18/Ubp43 −/− mice indicate that USP18 modulates the expression of many IFN-α-regulated genes (21). To evaluate the effect of USP18 silencing on the transcriptional response to IFN-α, we used a promoter containing repeated ISRE-binding sequences.…”

The Level of Hepatitis B Virus Replication Is Not Affected by Protein ISG15 Modification but Is Reduced by Inhibition of UBP43 (USP18) Expression

“…We observed previously that the lack of UBP43 results in enhanced and prolonged STAT1 phosphorylation (25) and increased induction of hundreds of ISG (26). More recently, we reported that UBP43 specifically binds to the IFNAR2 subunit and inhibits the activity of receptor-associated JAK1 by blocking the interaction between JAK and IFN receptor (28).…”

“…Importantly, UBP43-deficient cells are hypersensitive to type I IFN and undergo apoptosis upon IFN stimulation (25). Furthermore, lack of UBP43 results in enhanced and prolonged STAT1 phosphorylation and increased induction of hundreds of ISG, as confirmed by gene expression microarray studies (26). Loss of UBP43 in mice results in resistance to the cytopathic effects caused by a number of viruses including lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), and Sindbis virus (27).…”