RESUMO
[This corrects the article DOI: 10.1371/journal.ppat.1005772.].
RESUMO
Spliceosomal SNRNP200 is a Ski2-like RNA helicase that is associated with retinitis pigmentosa 33 (RP33). Here we found that SNRNP200 promotes viral RNA sensing and IRF3 activation through the ability of its amino-terminal Sec63 domain (Sec63-1) to bind RNA and to interact with TBK1. We show that SNRNP200 relocalizes into TBK1-containing cytoplasmic structures upon infection, in contrast to the RP33-associated S1087L mutant, which is also unable to rescue antiviral response of SNRNP200 knockdown cells. This functional rescue correlates with the Sec63-1-mediated binding of viral RNA. The hindered IFN-ß production of knockdown cells was further confirmed in peripheral blood cells of RP33 patients bearing missense mutation in SNRNP200 upon infection with Sendai virus (SeV). This work identifies a novel immunoregulatory role of the spliceosomal SNRNP200 helicase as an RNA sensor and TBK1 adaptor for the activation of IRF3-mediated antiviral innate response.
Assuntos
Imunidade Inata/imunologia , Fator Regulador 3 de Interferon/imunologia , RNA Viral/imunologia , Ribonucleoproteínas Nucleares Pequenas/imunologia , Viroses/imunologia , Western Blotting , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Técnicas de Silenciamento de Genes , Humanos , Imunoprecipitação , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Proteínas Serina-Treonina Quinases/imunologia , Transdução de Sinais/imunologia , Spliceossomos/imunologiaRESUMO
To identify new regulators of antiviral innate immunity, we completed the first genome-wide gene silencing screen assessing the transcriptional response at the interferon-ß (IFNB1) promoter following Sendai virus (SeV) infection. We now report a novel link between WNT signaling pathway and the modulation of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-dependent innate immune responses. Here we show that secretion of WNT2B and WNT9B and stabilization of ß-catenin (CTNNB1) upon virus infection negatively regulate expression of representative inducible genes IFNB1, IFIT1 and TNF in a CTNNB1-dependent effector mechanism. The antiviral response is drastically reduced by glycogen synthase kinase 3 (GSK3) inhibitors but restored in CTNNB1 knockdown cells. The findings confirm a novel regulation of antiviral innate immunity by a canonical-like WNT/CTNNB1 signaling pathway. The study identifies novel avenues for broad-spectrum antiviral targets and preventing immune-mediated diseases upon viral infection.
Assuntos
Glicoproteínas/imunologia , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Infecções por Respirovirus/imunologia , Vírus Sendai/imunologia , Proteínas Wnt/imunologia , Via de Sinalização Wnt/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Linhagem Celular , Proteína DEAD-box 58 , RNA Helicases DEAD-box/imunologia , RNA Helicases DEAD-box/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Estudo de Associação Genômica Ampla , Glicoproteínas/metabolismo , Humanos , Interferon beta/imunologia , Interferon beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Interferência de RNA , Proteínas de Ligação a RNA , Receptores Imunológicos , Infecções por Respirovirus/metabolismo , Infecções por Respirovirus/patologia , Vírus Sendai/metabolismo , Proteínas Wnt/metabolismoRESUMO
Interferons (IFNs) have long been used as an immunomodulatory therapy for a large array of acute and chronic viral infections. However, IFN therapies have been plagued by severe side effects. The discovery of pathogen recognition receptors (PRR) rejuvenated the interest for immunomodulatory therapies. The successes obtained with Toll-like receptor (TLR) agonists in activating immune cells and as adjuvant for prophylactic vaccines against different viruses paved the way to targeted immunomodulatory therapy. Better characterization of pathogen-induced immune disorders and newly discovered regulators of innate immunity have now the potential to specifically withdraw prevailing subversion mechanisms and to transform antiviral treatments by introducing panviral therapeutics with less adverse effects than IFN therapies.