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  • U20 is responsible for human herpesvirus 6B inhibition of tumor necrosis factor receptor-dependent signaling and apoptosis.

U20 is responsible for human herpesvirus 6B inhibition of tumor necrosis factor receptor-dependent signaling and apoptosis.

Journal of virology (2012-08-17)
Emil Kofod-Olsen, Katrine Ross-Hansen, Mariane Høgsbjerg Schleimann, Dea Kejlberg Jensen, Janni Michelle Lund Møller, Bettina Bundgaard, Jacob Giehm Mikkelsen, Per Höllsberg
ABSTRACT

The immune system targets virus-infected cells by different means. One of the essential antiviral mechanisms is apoptosis induced by ligation of tumor necrosis factor receptor 1 (TNFR1). This receptor can be activated by tumor necrosis factor alpha (TNF-α), which upon binding to TNFR1 induces the assembly of first an inflammatory and later a proapoptotic signaling complex. Here, we report that infection by human herpesvirus 6B (HHV-6B) inhibited poly(ADP-ribose) polymerase (PARP) cleavage, caspase 3 and 8 activation, and IκBα Ser-32 phosphorylation downstream of TNFR1, indicating inhibition of both the inflammatory and apoptotic signaling pathways. We identified a hitherto uncharacterized viral protein, U20, as sufficient for mediating this inhibition. U20 was shown to locate to the cell membrane, and overexpression inhibited PARP cleavage, caspase 3 and 8 activation, IκBα Ser-32 phosphorylation, and NF-κB transcriptional activity. Moreover, small interfering RNA (siRNA) knockdown of U20 demonstrated that the protein is necessary for HHV-6B-mediated inhibition of TNFR signaling during infection. These results suggest an important novel function of U20 as a viral immune evasion protein during HHV-6B infection.

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Mouse IgG2a Isotype Control from murine myeloma, clone UPC-10, purified immunoglobulin, buffered aqueous solution