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RNA-binding protein RBM47 stabilizes IFNAR1 mRNA to potentiate host antiviral activity.

ABSTRACT: The type I interferon (IFN-I, IFN-α/β)-mediated immune response is the first line of host defense against invading viruses. IFN-α/β binds to IFN-α/β receptors (IFNARs) and triggers the expression of IFN-stimulated genes (ISGs). Thus, stabilization of IFNARs is important for prolonging antiviral activity. Here, we report the induction of an RNA-binding motif-containing protein, RBM47, upon viral infection or interferon stimulation. Using multiple virus infection models, we demonstrate that RBM47 has broad-spectrum antiviral activity in vitro and in vivo. RBM47 has no noticeable impact on IFN production, but significantly activates the IFN-stimulated response element (ISRE) and enhances the expression of interferon-stimulated genes (ISGs). Mechanistically, RBM47 binds to the 3'UTR of IFNAR1 mRNA, increases mRNA stability, and retards the degradation of IFNAR1. In summary, this study suggests that RBM47 is an interferon-inducible RNA-binding protein that plays an essential role in enhancing host IFN downstream signaling.

SUBMITTER: Wang K

PROVIDER: S-EPMC8339671 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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RNA-binding protein RBM47 stabilizes IFNAR1 mRNA to potentiate host antiviral activity.

Wang Kezhen K Huang Chenxiao C Jiang Tao T Chen Zhiqiang Z Xue Minfei M Zhang Qi Q Zhang Jinyu J Dai Jianfeng J

EMBO reports 20210623 8

The type I interferon (IFN-I, IFN-α/β)-mediated immune response is the first line of host defense against invading viruses. IFN-α/β binds to IFN-α/β receptors (IFNARs) and triggers the expression of IFN-stimulated genes (ISGs). Thus, stabilization of IFNARs is important for prolonging antiviral activity. Here, we report the induction of an RNA-binding motif-containing protein, RBM47, upon viral infection or interferon stimulation. Using multiple virus infection models, we demonstrate that RBM47 ...[more]

PMID: 34160127

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Project description:Feline calicivirus (FCV) belongs to the Caliciviridae, which comprises small RNA viruses of both medical and veterinary importance. Once infection has occurred, FCV can persist in the cat population, but the molecular mechanism of how it escapes the innate immune response is still unknown. In this study, we found FCV strain 2280 to be relatively resistant to treatment with IFN-β. FCV 2280 infection inhibited IFN-induced activation of the ISRE (Interferon-stimulated response element) promoter and transcription of ISGs (Interferon-stimulated genes). The mechanistic analysis showed that the expression of IFNAR1, but not IFNAR2, was markedly reduced in FCV 2280-infected cells by inducing the degradation of IFNAR1 mRNA, which inhibited the phosphorylation of downstream adaptors. Further, overexpression of the FCV 2280 nonstructural protein p30, but not p30 of the attenuated strain F9, downregulated the expression of IFNAR1 mRNA. His-p30 fusion proteins were produced in Escherichia coli and purified, and an in vitro digestion assay was performed. The results showed that 2280 His-p30 could directly degrade IFNAR1 RNA but not IFNAR2 RNA. Moreover, the 5'UTR of IFNAR1 mRNA renders it directly susceptible to cleavage by 2280 p30. Next, we constructed two chimeric viruses: rFCV 2280-F9 p30 and rFCV F9-2280 p30. Compared to infection with the parental virus, rFCV 2280-F9 p30 infection displayed attenuated activities in reducing the level of IFNAR1 and inhibiting the phosphorylation of STAT1 and STAT2, whereas rFCV F9-2280 p30 displayed enhanced activities. Animal experiments showed that the virulence of rFCV 2280-F9 p30 infection was attenuated but that the virulence of rFCV F9-2280 p30 was increased compared to that of the parental viruses. Collectively, these data show that FCV 2280 p30 could directly and selectively degrade IFNAR1 mRNA, thus blocking the type I interferon-induced activation of the JAK-STAT signalling pathway, which may contribute to the pathogenesis of FCV infection.

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RNA-binding protein RBM47 stabilizes IFNAR1 mRNA to potentiate host antiviral activity.

Publications

RNA-binding protein RBM47 stabilizes IFNAR1 mRNA to potentiate host antiviral activity.

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