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Degradation of WTAP blocks antiviral responses by reducing the m⁶ A levels of IRF3 and IFNAR1 mRNA.

ABSTRACT: N⁶ -methyladenosine (m⁶ A) is a chemical modification present in multiple RNA species and is most abundant in mRNAs. Studies on m⁶ A reveal its comprehensive roles in almost every aspect of mRNA metabolism, as well as in a variety of physiological processes. Although some recent discoveries indicate that m⁶ A can affect the life cycles of numerous viruses as well as the cellular antiviral immune response, the roles of m⁶ A modification in type I interferon (IFN-I) signaling are still largely unknown. Here, we reveal that WT1-associated protein (WTAP), one of the m⁶ A "writers", is degraded via the ubiquitination-proteasome pathway upon activation of IFN-I signaling. With the degradation of WTAP, the m⁶ A levels of IFN-regulatory factor 3 (IRF3) and interferon alpha/beta receptor subunit 1 (IFNAR1) mRNAs are reduced, leading to translational suppression of IRF3 and instability of IFNAR1 mRNA. Thus, the WTAP-IRF3/IFNAR1 axis may serve as negative feedback pathway to fine-tune the activation of IFN-I signaling, which highlights the roles of m⁶ A in the antiviral response by dictating the fate of mRNAs associated with IFN-I signaling.

SUBMITTER: Ge Y

PROVIDER: S-EPMC8567250 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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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Degradation of WTAP blocks antiviral responses by reducing the m⁶ A levels of IRF3 and IFNAR1 mRNA.

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Degradation of WTAP blocks antiviral responses by reducing the m⁶ A levels of IRF3 and IFNAR1 mRNA.