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Activating transcription factor 4 (ATF4) is upregulated by human herpesvirus 8 infection, increases virus replication and promotes proangiogenic properties

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Abstract

Human herpesvirus 8 (HHV-8) triggers proangiogenic behaviour in endothelial cells by inducing monocyte chemoattractant protein 1 (MCP-1) through activation of Nuclear Factor κB (NF-κB). However, NF-κB inhibition still results in partial MCP-1 induction and consequent angiogenesis, suggesting the involvement of another transcriptional pathway. We analysed activating transcription factor 4 (ATF4), since it is central in the cellular response to stress and is involved in angiogenesis. The results show that HHV-8 upregulates ATF4 expression, which in turn promotes HHV-8 infection, and induces MCP-1 production and proangiogenic properties in endothelial cells. By contrast, ATF4 silencing decreases virus replication and inhibits virus-induced MCP-1 production and induction of tube-like structures. Therefore, ATF4 plays a role in HHV-8 replication and associated virus-induced angiogenesis. The elucidation of molecular pathways involved in this process will result in a better understanding of the virus-induced angiogenic process and might help in designing novel therapies to reduce tumour growth.

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Acknowledgments

This work was supported by the Italian Ministry of University and Scientific Research (PRIN projects), FAR (University of Ferrara) and Istituto Superiore di Sanità (ISS; AIDS project). We thank Dr. T. Hai (Department of Molecular and Cellular Biochemistry, Neurobiotechnology Center, Ohio State University, Columbus, USA) for providing the pCG-ATF4 plasmid. We thank Annalisa Peverati for excellent technical assistance, and Linda M. Sartor for revising the English manuscript

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The authors declare that they have no conflicting interests.

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Authors and Affiliations

  1. Section of Microbiology, Department of Experimental and Diagnostic Medicine, University of Ferrara, via L. Borsari 46, 44100, Ferrara, Italy

    Elisabetta Caselli, Sabrina Benedetti, Jessica Grigolato & Dario Di Luca

  2. Section of Microbiology, University of Brescia, Brescia, Italy

    Arnaldo Caruso

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  1. Elisabetta Caselli
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  2. Sabrina Benedetti
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Correspondence to Elisabetta Caselli.

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Caselli, E., Benedetti, S., Grigolato, J. et al. Activating transcription factor 4 (ATF4) is upregulated by human herpesvirus 8 infection, increases virus replication and promotes proangiogenic properties. Arch Virol 157, 63–74 (2012). https://doi.org/10.1007/s00705-011-1144-3

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