HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators

Abstract

Human herpes virus 8 (HHV-8) has developed unique mechanisms for altering cellular proliferative and apoptotic control pathways by incorporating viral homologs to several cellular regulatory genes into its genome. One of the important pirated genes encoded by the ORF K9 reading frame is a viral homolog of the interferon regulatory factors (IRF), a family of cellular transcription proteins that regulates expression of genes involved in pathogen response, immune modulation and cell proliferation. vIRF-1 has been shown to downregulate the interferon-and IRF-mediated transcriptional activation of ISG and murine IFNA4 gene promoters. In this study we demonstrate that vIRF-1 e ciently inhibited virus-induced expression of endogenous interferon B, CC chemokine RANTES and CXC chemokine IP-10 genes. Co-expression analysis revealed that vIRF-1 selectively blocked IRF-3 but not IRF-7-mediated transactivation. vIRF-1 was able to bind to both IRF-3 and IRF-7 in vivo as detected by coimmunoprecipitation analysis, but did not a ect IRF-3 dimerization, nuclear translocation and DNA binding activity. Rather, vIRF-1 interacted with the CBP/p300 coactivators and e ciently inhibited the formation of transcriptionally competent IRF-3-CBP/p300 complexes. These results illustrate that vIRF-1 is able to block the early stages of the IFN response to virus infection by interfering with the activation of IRF-3 responsive, immediate early IFN genes. Oncogene (2001) 20, 800 ± 811.

Oncogenic Potential of a Dominant Negative Mutant of Interferon Regulatory Factor 3

“…However, several viral oncoproteins, including human papillomavirus 16 E6 and adenovirus E1A, can inhibit the activation of IRF3 as well as p53 (18,34). The v-IRF protein from Kaposi's sarcoma-associated herpes virus is shown to inhibit IRF3 transcriptional activity by blocking the interaction of CBP (CREB-binding protein)/p300 coactivator with IRF3 (35). On the basis of the present studies, the interaction of these oncoproteins with IRF3 and the inhibition of its transcriptional activation function could contribute directly to the oncogenic potential of these viruses by altering cell growth control pathways.…”

Human Bocavirus NP1 Inhibits IFN-β Production by Blocking Association of IFN Regulatory Factor 3 with IFNB Promoter

“…Several viral proteins were also reported to modulate the function of activated IRF-3. For instance, ICP0 of bovine herpes virus 1, ORF 61 of varicella-zoster virus, and vIRF-2 of Kaposi's sarcoma-associated herpesvirus (KSHV) cause IRF-3 degradation (39,42,44); E1A of adenovirus 5 and vIRF-1/vIRF-2 of KSHV inhibit recruitment of CBP/p300 coactivators by IRF-3, decreasing the transcription efficiency (38,40,46,49); IE1 of HSV-1 disrupts IRF-3 dimer in the nucleus (41); NSs of La Crosse encephalitis virus (a bunyavirus) targets downstream of IRF-3 by specifically inducing proteasomal degradation of RNA polymerase II subunit RPB1 293T cells were cotransfected with HA-tagged NP1 and Flag-tagged IRF-3 or deletion mutant expression plasmids for 24 h. Cells were lysed and subjected to IP using mouse anti-FLAG tag (upper panel) or mouse anti-HA tag (middle panel). Mouse IgG was used as negative control.…”

“…36,37). Only a limited number of viral proteins was reported to interfere with the function of activated IRF-3 in the nucleus (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51).…”

A requirement for NF-κB induction in the production of replication-competent HHV-8 virions

“…These HHV-8-encoded cellular homologues include: cytokine and signal transduction intermediates , a cell-cycle regulator (v-cyclin D, encoded by open-reading frame (ORF) 72) and inhibitors of apoptosis , v-IL-6) (Gwack et al, 2001;Montaner et al, 2001;Means et al, 2002). Among the vIRFs, vIRF-1 (ORF K9) has been shown to disrupt the formation of transcriptionally active IRF-3-CBP/p300 complexes, thus blocking the early steps of the IFN response (Lin et al, 2001). Recently, lymphoma cells infected with HHV-8 were shown to be autocrine dependent on vIL-6 (ORF K2) for growth but not cellular IL-6 (Chatterjee et al, 2002).…”