Abstract
Non-coding small RNAs are involved in many physiological responses including viral life cycles. Adenovirus-encoding small RNAs, known as virus-associated RNAs (VA RNAs), are transcribed throughout the replication process in the host cells, and their transcript levels depend on the copy numbers of the viral genome. Therefore, VA RNAs are abundant in infected cells after genome replication, i.e. during the late phase of viral infection. Their function during the late phase is the inhibition of interferon-inducible protein kinase R (PKR) activity to prevent antiviral responses; recently, mivaRNAs, the microRNAs processed from VA RNAs, have been reported to inhibit cellular gene expression. Although VA RNA transcription starts during the early phase, little is known about its function. The reason may be because much smaller amount of VA RNAs are transcribed during the early phase than the late phase. In this study, we applied replication-deficient adenovirus vectors (AdVs) and novel AdVs lacking VA RNA genes to analyze the expression changes in cellular genes mediated by VA RNAs using microarray analysis. AdVs are suitable to examine the function of VA RNAs during the early phase, since they constitutively express VA RNAs but do not replicate except in 293 cells. We found that the expression level of hepatoma-derived growth factor (HDGF) significantly decreased in response to the VA RNAs under replication-deficient condition, and this suppression was also observed during the early phase under replication-competent conditions. The suppression was independent of mivaRNA-induced downregulation, suggesting that the function of VA RNAs during the early phase differs from that during the late phase. Notably, overexpression of HDGF inhibited AdV growth. This is the first report to show the function, in part, of VA RNAs during the early phase that may be contribute to efficient viral growth.
Highlights
It has become increasingly clear over the past decade that noncoding small RNAs play roles in viral life cycles at various ways [1,2,3]
To determine whether virus-associated RNAs (VA RNAs) expressed from FG adenovirus vectors (AdVs) disturb cellular gene expression, a microarray analysis was performed
The numbers of VA-(+) specific genes and VA-(2) specific genes were found to be 300 and 100, respectively (Figure 1B). These results indicated that the VA RNAs expressed from AdV do not have a major impact on the expressions of whole genes
Summary
It has become increasingly clear over the past decade that noncoding small RNAs play roles in viral life cycles at various ways [1,2,3]. Epstein-Barr virus (EBV) encodes two small RNAs, EBER-1 and EBER-2 [7,8,9], which modulate the interferon-mediated antiviral response [10]. Adenoviruses (Ads) encode two kinds of non-coding smallRNAs, known as virus-associated (VA) RNAs, VAI and VAII, that consist of 157–160 nucleotides (nts). After Ad infection, the transcription of VA RNAs starts at the same time as the E1A gene and lasts until the late phase. Since the transcription level of VA RNAs increases depending on the number of viral genome copies, VA RNAs in Ad-infected cells are abundant during the late phase, and this is one reason why the functional analysis of VA RNAs during the late phase has been investigated much more frequently than during the early phase
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