Human Herpesvirus 6A Tegument Protein U14 Induces NF-κB Signaling by Interacting with p65

Abstract

Viral infection induces host cells to mount a variety of immune responses, which may either limit viral propagation or create conditions conducive to virus replication in some instances. In this regard, activation of the NF-κB transcription factor is known to modulate virus replication. Human herpesvirus 6A (HHV-6A), which belongs to the Betaherpesvirinae subfamily, is frequently found in patients with neuro-inflammatory diseases, although its role in disease pathogenesis has not been elucidated. In this study, we found that the HHV-6A-encoded U14 protein activates NF-κB signaling following interaction with the NF-κB complex protein, p65. Through induction of nuclear translocation of p65, U14 increases the expression of IL-6, IL-8 and MCP-1 transcripts. We also demonstrated that activation of NF-κB signaling is important for HHV-6A replication, as inhibition of this pathway reduced virus protein accumulation and viral genome copy number. Taken together, our results suggest that HHV-6A infection activates the NF-κB pathway and promotes viral gene expression via late gene products including U14. IMPORTANCE Human herpesvirus 6A (HHV-6A) is frequently found in patients with neuro-inflammation, although its role in the pathogenesis of this disease has not been elucidated. Most viral infections activate the NF-κB pathway, which causes the transactivation of various genes, including those encoding pro-inflammatory cytokines. Our results indicate that HHV-6A U14 activates the NF-κB pathway, leading to upregulation of pro-inflammatory cytokines. We also found that activation of the NF-κB transcription factor is important for efficient viral replication. This study provides new insight into HHV-6A U14 function in host cell signaling, and identifies potential cellular targets involved in HHV-6A pathogenesis and replication.

The Cytomegalovirus M35 Protein Modulates Transcription ofIfnb1and Other IRF3-Driven Genes by Direct Promoter Binding

“…The MCMV M35 crystal structure is highly similar to that of HHV6B U14, but our investigations suggest that the immunomodulatory function is not generally conserved in the members of the pp85 protein superfamily. In line with our observations, a recent study shows that HHV6A U14 does not significantly modulate the activity of the 125 bp human Ifnb1 promoter in the absence of PRR stimulation, although it interacts with p65 and increases expression of NF-κB dependent promoters (84). Still, down-modulation of Ifnb1 promoter induction by HHV7 U14 indicates that at least one further homologue might share M35’s immunomodulatory activity.…”

The Cytomegalovirus M35 Protein Directly Binds to the Interferon-β Enhancer and Modulates Transcription of Ifnb1 and Other IRF3-Driven Genes

“…Consistently, our investigations suggest that the immunomodulatory function is not generally conserved in the members of the pp85 protein superfamily. In line with our observations, a recent study shows that HHV6A U14 does not significantly modulate the activity of the 125-bp human Ifnb1 promoter in the absence of PRR stimulation, although it interacts with p65 and increases expression of NF-κB dependent promoters ( 77 ). Still, downmodulation of Ifnb1 promoter induction by HHV7 U14 indicates that at least one further homolog might share M35’s immunomodulatory activity.…”

Effect of FXR agonist GW4064 in the treatment of hilar cholangiocarcinoma in rats

“…Third, it regulates NF-κB signaling pathway affects the development of inflammation 16,17 , when NF-κB rises, this signal pathway is obviously activated, which leads to more significant inflammatory reaction, promotes the edema, destruction and repeated proliferation of cells, and increases the probability of cells with malignant phenotype, thus further promoting the progress of tumors. Therefore, in the experimental results, we found that in the model group, NF-κB increased significantly with obvious inflammatory cell infiltration, but it not emerge in normal tissues [18][19][20][21] . Previous studies have shown that the expression level of FXR in hepatocellular carcinoma was significantly decreased, and the incidence of liver tumours in FXR gene knockout mice was 100%.…”