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Dengue virus targets RBM10 deregulating host cell splicing and innate immune response.

ABSTRACT: RNA-seq experiments previously performed by our laboratories showed enrichment in intronic sequences and alterations in alternative splicing in dengue-infected human cells. The transcript of the SAT1 gene, of well-known antiviral action, displayed higher inclusion of exon 4 in infected cells, leading to an mRNA isoform that is degraded by non-sense mediated decay. SAT1 is a spermidine/spermine acetyl-transferase enzyme that decreases the reservoir of cellular polyamines, limiting viral replication. Delving into the molecular mechanism underlying SAT1 pre-mRNA splicing changes upon viral infection, we observed lower protein levels of RBM10, a splicing factor responsible for SAT1 exon 4 skipping. We found that the dengue polymerase NS5 interacts with RBM10 and its sole expression triggers RBM10 proteasome-mediated degradation. RBM10 over-expression in infected cells prevents SAT1 splicing changes and limits viral replication, while its knock-down enhances the splicing switch and also benefits viral replication, revealing an anti-viral role for RBM10. Consistently, RBM10 depletion attenuates expression of interferon and pro-inflammatory cytokines. In particular, we found that RBM10 interacts with viral RNA and RIG-I, and even promotes the ubiquitination of the latter, a crucial step for its activation. We propose RBM10 fulfills diverse pro-inflammatory, anti-viral tasks, besides its well-documented role in splicing regulation of apoptotic genes.

SUBMITTER: Pozzi B

PROVIDER: S-EPMC7337517 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Dengue virus targets RBM10 deregulating host cell splicing and innate immune response.

Pozzi Berta B Bragado Laureano L Mammi Pablo P Torti María Florencia MF Gaioli Nicolás N Gebhard Leopoldo G LG García Solá Martín E ME Vaz-Drago Rita R Iglesias Néstor G NG García Cybele C CC Gamarnik Andrea V AV Srebrow Anabella A

Nucleic acids research 20200701 12

RNA-seq experiments previously performed by our laboratories showed enrichment in intronic sequences and alterations in alternative splicing in dengue-infected human cells. The transcript of the SAT1 gene, of well-known antiviral action, displayed higher inclusion of exon 4 in infected cells, leading to an mRNA isoform that is degraded by non-sense mediated decay. SAT1 is a spermidine/spermine acetyl-transferase enzyme that decreases the reservoir of cellular polyamines, limiting viral replicati ...[more]

PMID: 32432721

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Dengue virus targets RBM10 deregulating host cell splicing and innate immune response.

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Dengue virus targets RBM10 deregulating host cell splicing and innate immune response.

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