title: Adenovirus-encoding virus-associated RNAs suppress HDGF gene expression to support efficient viral replication.
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.
authors.affiliation: Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Kondo
authors.affiliation: Regenerative and Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd., Minatojima Minamimachi, Chuo-ku, Kobe, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
authors.forename: Izumu
authors.initials: I
authors.lastname: Saito
authors.affiliation: Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kanegae
mesh_terms: D000256:Adenoviridae / Q000254:growth & development / Q000502:physiology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D039102:Poly(A)-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism*; D000074019:T-Cell Intracellular Antigen-1; D015854:Up-Regulation; D014779:Virus Replication
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D039102:Poly(A)-Binding Proteins; D012367:RNA, Viral; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; C052835:adenovirus associated RNA; C051610:hepatoma-derived growth factor