Latently expressed human herpesvirus 8-encoded interferon regulatory factor 2 inhibits double-stranded RNA-activated protein kinase.
Human herpesvirus 8 (HHV-8; Kaposi's sarcoma herpesvirus) encodes four open reading frames with homology to cellular proteins of interferon regulatory factor (IRF) family. Three of them, viral IRF-1 (vIRF-1), vIRF-2, and vIRF-3, have been cloned and found, when overexpressed, to down-regulate the transcriptional activity of interferon type I gene promoters in infected cells by interfering with the transactivating activity of cellular IRFs. In this study, we have further characterized vIRF-2 and shown that it is a nuclear protein which is constitutively expressed in HHV-8-positive pleural effusion lymphoma cell lines. Nuclear localization of vIRF-2 was confirmed by in situ detection of ectopically expressed enhanced green fluorescent protein/vIRF-2 fusion protein. We found that the expression of vIRF-2 in HEK293 cells inhibited the antiviral effect of interferon and rescued translation of vesicular stomatitis virus mRNA from interferon-induced translational block. To provide insight into the mechanism of this effect we have demonstrated that vIRF-2 physically interacts with PKR consequently inhibiting autophosphorylation of double-stranded RNA-activated protein kinase (PKR) and blocking phosphorylation of PKR substrates histone 2A and eukaryotic translation initiation factor 2alpha. These results suggest that the latently expressed vIRF-2 has a role in viral mimicry which targets the activity of interferon-induced PKR kinase. By inhibiting the kinase activity of PKR and consequent down-modulation of protein synthesis, HHV-8 has evolved a mechanism by which it can overcome the interferon-mediated antiviral effect. Thus, the anti-interferon functions of vIRF-2 may contribute to the establishment of a chronic or latent infection.
Burýsek
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Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Pitha
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PM
D000818:Animals; D002417:Cattle; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D006566:Herpesviridae Infections / Q000821:virology*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D050836:Interferon Regulatory Factor-2; D016898:Interferon-alpha / Q000037:antagonists & inhibitors; D016393:Lymphoma, B-Cell / Q000821:virology; D016366:Open Reading Frames / Q000235:genetics; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D017735:Virus Latency; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D006657:Histones; C494229:IRF2 protein, human; D050836:Interferon Regulatory Factor-2; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D019892:eIF-2 Kinase