RESUMEN
As influenza-A viruses (IAV) replicate in the host cell nucleus, intranuclear pathways are usurped for viral gene expression. The eight genomic viral ribonucleoproteins (vRNPs) segments of IAV are transcribed and two generate viral mRNAs (M and NS) that undergo alternative splicing followed by export from the nucleus. The focus of this review is on viral RNA splicing and nuclear export. Recent mechanistic advances on M and NS splicing show differential regulation by RNA-binding proteins as well as distinct intranuclear localization. After a review of IAV splicing, we will discuss the nuclear export of viral mRNAs, which occur by interacting with specific constituents of the host mRNA export machinery that translocate viral mRNAs through the nuclear pore complex for translation in the cytoplasm.
Asunto(s)
Interacciones Microbiota-Huesped , Virus de la Influenza A , Transporte Activo de Núcleo Celular , Núcleo Celular , Virus de la Influenza A/genética , Empalme del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Viral/genética , Replicación ViralRESUMEN
Viral infection induces the expression of numerous host genes that impact the outcome of infection. Here, we show that infection of human lung epithelial cells with influenza A virus (IAV) also induces a broad program of alternative splicing of host genes. Although these splicing-regulated genes are not enriched for canonical regulators of viral infection, we find that many of these genes do impact replication of IAV. Moreover, in several cases, specific inhibition of the IAV-induced splicing pattern also attenuates viral infection. We further show that approximately a quarter of the IAV-induced splicing events are regulated by hnRNP K, a host protein required for efficient splicing of the IAV M transcript in nuclear speckles. Finally, we find an increase in hnRNP K in nuclear speckles upon IAV infection, which may alter accessibility of hnRNP K for host transcripts thereby leading to a program of host splicing changes that promote IAV replication.
Asunto(s)
Empalme Alternativo , Núcleo Celular/virología , Células Epiteliales/virología , Virus de la Influenza A/crecimiento & desarrollo , Pulmón/virología , Replicación Viral , Células A549 , Núcleo Celular/genética , Núcleo Celular/metabolismo , Células Epiteliales/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo K/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , Interacciones Huésped-Patógeno , Humanos , Virus de la Influenza A/genética , Virus de la Influenza A/patogenicidad , Pulmón/metabolismoRESUMEN
Viruses have been invaluable tools for discovering key pathways of nucleocytoplasmic transport. Conversely, disruption of specific nuclear transport pathways, are crucial for the productive life cycle of some viruses. The major cellular mRNA export pathway, which uses TAP (NXF1)/p15(NXT) as receptor, was discovered as a result of TAP interaction with CTE-containing RNAs from Mason-Pfizer Monkey Virus. In addition, CRM1 or exportin 1, which is a transport receptor that mediates nuclear export of proteins, snRNAs, rRNAs and a small subset of mRNAs, was discovered as an interacting partner of the Rev protein of HIV1. Viruses may disrupt the nuclear transport machinery to prevent host antiviral response. VSV Matrix (M) protein inhibits mRNA export by forming a complex with the mRNA export factor Rae1 whereas poliovirus inhibits nuclear import of proteins by probably degrading Nup62 and Nup153. Hence, this review focuses on viruses as tools and as disruptors of nucleocytoplasmic trafficking.