U20 is responsible for human herpesvirus 6B inhibition of tumor necrosis factor receptor-dependent signaling and apoptosis.
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.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Emil
E
Kofod-Olsen
Katrine
K
Ross-Hansen
Mariane Høgsbjerg
MH
Schleimann
Dea Kejlberg
DK
Jensen
Janni Michelle Lund
JM
Møller
Bettina
B
Bundgaard
Jacob Giehm
JG
Mikkelsen
Per
P
Höllsberg
D017209:Apoptosis; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D015654:Herpesvirus 6, Human / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D057131:Immune Evasion; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014764:Viral Proteins / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*
D047888:Receptors, Tumor Necrosis Factor, Type I; D014764:Viral Proteins; D037521:Virulence Factors