(HCV) is a single-stranded positive-sense RNA hepatotropic virus. Despite cellular defenses, HCV is able to replicate in hepatocytes and to establish a chronic infection that could lead to severe complications and hepatocellular carcinoma. An important player in subverting the host response to HCV infection is the viral nonstructural protein NS5A, which, in addition to its role in replication and assembly, targets several pathways involved in the cellular response to viral infection. Several unbiased screens identified nucleosome assembly protein 1-like 1 (NAP1L1) as an interaction partner of HCV NS5A. Here we confirmed this interaction and mapped it to the C terminus of NS5A of both genotype 1 and 2. NS5A sequesters NAP1L1 in the cytoplasm, blocking its nuclear translocation. However, only NS5A from genotype 2 HCV, and not that from genotype 1, targets NAP1L1 for proteosome-mediated degradation. NAP1L1 is a nuclear chaperone involved in chromatin remodeling, and we demonstrated the NAP1L1-dependent regulation of specific pathways involved in cellular responses to viral infection and cell survival. Among those, we showed that lack of NAP1L1 leads to a decrease of RELA protein levels and a strong defect of IRF3 TBK1/IKKε-mediated phosphorylation, leading to inefficient RIG-I and Toll-like receptor 3 (TLR3) responses. Hence, HCV is able to modulate the host cell environment by targeting NAP1L1 through NS5A. Viruses have evolved to replicate and to overcome antiviral countermeasures of the infected cell. Hepatitis C virus is capable of establishing a lifelong chronic infection in the liver, which could develop into cirrhosis and cancer. Chronic viruses are particularly able to interfere with the cellular antiviral pathways by several different mechanisms. In this study, we identified a novel cellular target of the viral nonstructural protein NS5A and demonstrated its role in antiviral signaling. This factor, called nucleosome assembly protein 1-like 1 (NAP1L1), is a nuclear chaperone involved in the remodeling of chromatin during transcription. When it is depleted, specific signaling pathways leading to antiviral effectors are affected. Therefore, we provide evidence for both a novel strategy of virus evasion from cellular immunity and a novel role for a cellular protein, which has not been described to date.
Viruses use miRNAs to enable efficient replication, control host defense mechanisms, and regulate latent infection. Herpes simplex virus 1 (HSV-1) expresses multiple miRNAs, whose functions are largely unknown. The evolutionary conservation of many HSV-1 miRNAs in the closely related HSV-2 suggests their functional importance. miRNAs, similar to other transcripts, can undergo various posttranscriptional modifications that may affect their biogenesis, stability and targeting. To investigate whether ADAR mediated editing occurs in HSV-1 miRNAs, we sequenced samples from latently infected human ganglia. We show that one of the six HSV-1 miRNAs (miR-H2-H8) that define HSV-1 latency, miR-H2, exhibits A-to-I hyperediting within the miRNA seed sequence. We observed the same specific miR-H2 hyperediting phenomenon in miRNAs isolated from the ganglia of latently infected mice and, to a lesser extent, during productive infection in cultured cells. Curiously, we found no evidence of editing of the encoded HSV-2 homolog in latently infected mice or in cultured cells. The efficient loading of the edited miRNAs onto the RISC complex, indicates their ability to function as miRNAs. Therefore, to investigate the potential of the edited miRNA to alter mRNA targeting, we predicted the host and viral targets. Nucleotide substitution in the seed region significantly increased the number of potential host and viral targets. Most notably, ICP4, an essential viral protein, was predicted to be an additional target. Using transfection assays, we demonstrated that edited miRNAs have the potential to regulate ICP4 in addition to the previously identified target ICP0. Our study identifies a specific hyperedited HSV-1 mRNA, miR-H2, and highlights how the virus can use a single miRNA to target multiple transcripts during persistent, latent infection.
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