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Inhibition of viral suppressor of RNAi proteins by designer peptides protects from enteroviral infection in vivo

ABSTRACT: RNA interference (RNAi) is an antiviral immunity conserved in diverse eukaryotes including mammals, while viruses encodes viral suppressors of RNAi (VSRs) as countermeasures. However, the physiological impact of RNAi on viral infection in mammals has not been fully assessed, and it also remains unknown whether antiviral RNAi can be therapeutically exploited. Here, we show that peptides designed to target enterovirus A71 (EV-A71)-encoded protein 3A, a well-characterized VSR, triggered an effective antiviral response. These VSR-targeting peptides, particularly ER-DRI, abrogated the VSR function of 3A, which enabled EV-A71-derived siRNA production and unlocked RNAi response that potently inhibited EV-A71 infection in mammals. ER-DRI treatment elicited a strong in vivo antiviral RNAi response that protected mice against lethal EV-A71 challenge. It also potently inhibited another enterovirus, Coxsackievirus-A16, dependently of RNAi. Our findings demonstrate that antiviral RNAi does have a physiologically important impact in mammals and targeting VSRs is a promising strategy for antiviral therapies.

ORGANISM(S): Enterovirus A71

PROVIDER: GSE179496 | GEO | 2021/07/31

REPOSITORIES: GEO

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Flavivirus induces and antagonizes antiviral RNA interference in both mammals and mosquitoes

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2020-02-24 | GSE133284 | GEO

STUB1 regulates antiviral RNAi through inducing ubiquitination and degradation of Dicer and AGO2 in mammals

Project description:RNA interference (RNAi) is a cell-intrinsic antiviral defense conserved in diverse organisms. However, the mechanism by which mammalian antiviral RNAi is regulated is largely unknown. Herein, we uncover that STUB1, an E3 ubiquitin ligase, interacts with and ubiquitinates AGO2, the core component of RNAi pathway, resulting in the degradation of AGO2 via ubiquitin-proteasome system. Additionally, STUB1 can induce the degradation of the other mammalian AGO proteins including AGO1, AGO3, and AGO4. Our further study reveals that STUB1 also interacts with and mediates the ubiquitination of Dicer, the endoribonuclease responsible for siRNA or miRNA biogenesis, via K48-linked poly-ubiquitin, which induces the degradation of Dicer and its specialized form, termed antiviral Dicer (aviDicer) that usually expresses in stem cells. Loss of STUB1 upregulated Dicer and AGO2, thereby enhancing antiviral RNAi to effectively inhibit viral RNA replication in mammalian cells. In vivo, the STUB1 deficiency markedly enhanced the production of virus-derived siRNAs and elicited a potent antiviral effect against Enterovirus-A71 (EV-A71) infection in newborn mouse. Our findings demonstrate STUB1 as a novel negative regulator of RNAi by mediating the ubiquitination and degradation of Dicer and AGO proteins, and provide novel insights into the regulatory mechanism of antiviral RNAi in mammals.

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Human virus-derived small RNAs can confer antiviral immunity in mammals

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2022-07-26 | GSE208611 | GEO

Homo sapiens

Project description:antiviral RNAi in mammals

| PRJNA397310 | ENA

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