RESUMO
Antiviral responses must rapidly defend against infection while minimizing inflammatory damage, but the mechanisms that regulate the magnitude of response within an infected cell are not well understood. miRNAs are small non-coding RNAs that suppress protein levels by binding target sequences on their cognate mRNA. Here, we identify miR-144 as a negative regulator of the host antiviral response. Ectopic expression of miR-144 resulted in increased replication of three RNA viruses in primary mouse lung epithelial cells: influenza virus, EMCV, and VSV. We identified the transcriptional network regulated by miR-144 and demonstrate that miR-144 post-transcriptionally suppresses TRAF6 levels. In vivo ablation of miR-144 reduced influenza virus replication in the lung and disease severity. These data suggest that miR-144 reduces the antiviral response by attenuating the TRAF6-IRF7 pathway to alter the cellular antiviral transcriptional landscape.
Assuntos
Influenza Humana/imunologia , MicroRNAs/metabolismo , Orthomyxoviridae/genética , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Animais , Linhagem Celular , Células Epiteliais/virologia , Perfilação da Expressão Gênica , Genes Reporter , Humanos , Influenza Humana/virologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Orthomyxoviridae/imunologia , Orthomyxoviridae/fisiologia , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Carga Viral , Replicação ViralRESUMO
Independent lines of investigation have documented effects of both transposable elements (TEs) and gene length (GL) on gene expression. However, TE gene fractions are highly correlated with GL, suggesting that they cannot be considered independently. We evaluated the TE environment of human genes and GL jointly in an attempt to tease apart their relative effects. TE gene fractions and GL were compared with the overall level of gene expression and the breadth of expression across tissues. GL is strongly correlated with overall expression level but weakly correlated with the breadth of expression, confirming the selection hypothesis that attributes the compactness of highly expressed genes to selection for economy of transcription. However, TE gene fractions overall, and for the L1 family in particular, show stronger anticorrelations with expression level than GL, indicating that GL may not be the most important target of selection for transcriptional economy. These results suggest a specific mechanism, removal of TEs, by which highly expressed genes are selectively tuned for efficiency. MIR elements are the only family of TEs with gene fractions that show a positive correlation with tissue-specific expression, suggesting that they may provide regulatory sequences that help to control human gene expression. Consistent with this notion, MIR fractions are relatively enriched close to transcription start sites and associated with coexpression in specific sets of related tissues. Our results confirm the overall relevance of the TE environment to gene expression and point to distinct mechanisms by which different TE families may contribute to gene regulation.
