Kaposi’s Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor Confers Resistance to the Antiproliferative Effect of Interferon-α

Flowers, C. Clay; Flowers, Scarlett P.; Nabel, Gary J.

doi:10.1007/bf03401747

Cited by 45 publications

(32 citation statements)

References 57 publications

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“…Human B lymphocytes expressing vIRF1 are resistant to the antiproliferative effects of IFN-␣, and vIRF1 expression inhibits p53-induced apoptosis (12,33,41). MCF-7 cells expressing vIRF1 are also resistant to IFN/RA-induced cell death, possibly through interactions between vIRF1 and GRIM19 (Fig.…”

Section: Discussionmentioning

confidence: 98%

Viral Interferon Regulatory Factor 1 of Kaposi's Sarcoma-Associated Herpesvirus Interacts with a Cell Death Regulator, GRIM19, and Inhibits Interferon/Retinoic Acid-Induced Cell Death

Seo

Lee

Shim

et al. 2002

J Virol

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Section: Discussionmentioning

confidence: 98%

Viral Interferon Regulatory Factor 1 of Kaposi's Sarcoma-Associated Herpesvirus Interacts with a Cell Death Regulator, GRIM19, and Inhibits Interferon/Retinoic Acid-Induced Cell Death

Seo

Lee

Shim

et al. 2002

J Virol

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“…As described above, KSHV carries an additional battery of vIRF genes, vIRF1 to -4 (6, 18, 34). These vIRFs have been shown to primarily attack the IFN-␣/␤ signaling pathway (3,14,16,41). Thus, KSHV may utilize K3, K5, and vIRFs to comprehensively suppress host IFN-mediated antiviral activity, which ultimately creates a favorable milieu for the establishment and/or maintenance of persistent viral infection.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Gamma Interferon Receptor 1 by Kaposi's Sarcoma-Associated Herpesvirus K3 and K5

Means

Lang

et al. 2007

J Virol

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Upon viral infection, the major defense mounted by the host immune system is activation of the interferon (IFN)-mediated antiviral pathway. In order to complete their life cycles, viruses must modulate the host IFN-mediated immune response. The K3 and K5 proteins of a human tumor-inducing herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV), have been shown to downregulate the surface expression of host immune modulatory receptors by increasing their endocytosis rates, which leads to suppression of cellmediated immunity. In this report, we demonstrate that K3 and K5 both specifically target gamma interferon receptor 1 (IFN-␥R1) and induce its ubiquitination, endocytosis, and degradation, resulting in downregulation of IFN-␥R1 surface expression and, thereby, inhibition of IFN-␥ action. Mutational analysis indicated that K5 appeared to downregulate IFN-␥R1 more strongly than K3 and that the amino-terminal ring finger motif and the carboxyl-terminal region of K5 were necessary for IFN-␥R1 downregulation. These results suggest that KSHV K3 and K5 suppress both cytokine-mediated and cell-mediated immunity, which ensures efficient viral avoidance of host immune controls.Interferons (IFNs) are a family of cytokines that exhibit such diverse biological effects as the inhibition of cell growth and protection against viral infection. There are two major subtypes of IFNs: type I IFNs (alpha IFN [IFN-␣] and IFN-␤) and type II IFN (IFN-␥). Both subtypes elicit similar yet distinct biological activities. IFN-␣/␤ are vital signals for the host immune system to initiate an antiviral response, provide the first front line of innate immune defense against virus infection, and additionally modulate adaptive immune response (29). IFN-␥, which is produced by activated T cells and natural killer cells, is primarily involved in the regulation of specific immune responses, immune surveillance, and tumor suppression (1, 4). IFNs carry out their responses through activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signal pathway. Activation of the STAT pathway leads to the formation of two major complexes: gamma-activated factor (GAF), which is composed of STAT1 dimers and induced by IFN-␥, and IFN-stimulated gene factor 3, which consists of STAT1 (p84/91), STAT2 (p113), and a DNA binding protein, p48 (IRF9), and is mainly induced by IFN-␣/␤. IRF9 and GAF complexes translocate to the nucleus, bind to the interferon-stimulated response element (ISRE) and the gamma-activated sequence (GAS), respectively, and modulate gene transcription (12,13,15,47,48).Most viruses have evolved immune evasion strategies to protect themselves against host IFN responses, elaborating viral proteins as a counterdefense against the host IFN defenses. Recently, the IFN antagonist strategies used by many viruses have been revealed; these strategies include blocking IFN signaling by downregulation of JAK-STAT signal molecule basal levels, suppression of particular molecule modifications, and prevention of molecule tra...

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“…They consist of a conserved N-terminal DNA-binding domain and a C-terminal regulatory domain. The DNA-binding domain is also partially conserved in vIRF-1, although the protein appears to inhibit interferon-induced transcription in reporter transfection studies by mechanisms other than binding directly to DNA (Gao et al, 1997;Li et al, 1998;Zimring et al, 1998;Flowers et al, 1998;Burysek et al, 1999a). These mechanisms involve binding to some of the cellular IRFs and to coadaptors that link transcription factors to the RNA polymerase holoenzyme (Jayachandra et al, 1999;Burysek et al, 1999a;Seo et al, 2000;Li et al, 2000;Lin et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…The gene is assigned to the early kinetic class since its expression is resistant to inhibition of DNA replication (Wang et al, 2001). The mRNA is 1?5 kb in size Sarid et al, 1998) , 1997;Li et al, 1998;Zimring et al, 1998;Flowers et al, 1998;Burysek et al, 1999a). These mechanisms involve binding to some of the cellular IRFs and to coadaptors that link transcription factors to the RNA polymerase holoenzyme (Jayachandra et al, 1999;Burysek et al, 1999a;Seo et al, 2000;Li et al, 2000; Lin et al, 2001).…”

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confidence: 99%

Transcription mapping of human herpesvirus 8 genes encoding viral interferon regulatory factors

Cunningham

Barnard

Blackbourn

et al. 2003

Journal of General Virology

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The human herpesvirus 8 (HHV-8) genome contains four tandemly arranged genes encoding viral interferon regulatory factors (vIRF-1 to 4) located between genes 57 and 58. Transcript mapping techniques were employed to determine the sizes, ends and splicing patterns of mRNAs specified by these genes in HHV-8-infected cell lines untreated or chemically induced into the lytic growth cycle. Depending on the cell line used, vIRF-3 transcription was minimally or not induced (i.e. expressed with latent kinetics), whereas the other vIRFs were inducible (i.e. expressed with lytic kinetics). Each gene possessed its own promoter (or promoters) and polyadenylation sites, and all but vIRF-1 were spliced from two exons. vIRF-1 was transcribed in uninduced and induced cells from a single initiation site preceded by a TATA box, with the possible use of an additional TATA box and initiation site in uninduced cells. In induced cells, vIRF-2 was transcribed from a single major initiation site preceded by a TATA box, and vIRF-4 was expressed from two sites each preceded by a TATA box. Transcripts for these genes were insufficiently abundant in uninduced cells to map the 59-ends. vIRF-3 lacks an obvious TATA box and exhibited heterogeneous 59-ends in uninduced and induced cells. These data clarify and extend our understanding of the structure and transcription of the HHV-8 vIRF genes. INTRODUCTIONGenome sequences have been published for two strains of human herpesvirus 8 [HHV-8; also known as Kaposi's sarcoma-associated herpesvirus (KSHV)] by Russo et al. (1996) (accession no. U75698) and Neipel et al. (1997) (U93872). In addition to genes that are common to the members of the genus Rhadinovirus, several genes are unique to HHV-8 or found only in closely related species (for reviews, see Schulz, 1998;. A cluster of such genes is located in a 10 kbp region between open reading frames (ORFs) 57 and 58. Russo et al. (1996) described this region as containing an ORF (K9) whose encoded protein is related to cellular interferon regulatory factors (IRFs), plus two other protein-coding regions (K10 and K11), as illustrated in the upper part of Fig. 1. Other regions bearing amino acid similarity to IRFs were also noted, two upstream from K10 and one upstream from K11. Neipel et al. (1997) identified another ORF between K10 and K11, termed K10.1 (or K10.5), which corresponds closely to one of the IRF-like regions identified by Russo et al. (1996). Data from several groups subsequently indicated that this region of the genome contains four vIRF genes, one unspliced (vIRF-1 from K9) and three spliced (vIRF-2 from K11, vIRF-3 from K10.5 and vIRF4 from K10), as illustrated in the lower part of Fig. 1. The vIRF genes presumably arose by capture of cellular sequences followed by gene duplication events. The only other herpesvirus known to possess vIRFs is rhesus rhadinovirus (RRV), a close relative of HHV-8 (Searles et al., 1999;Alexander et al., 2000). RRV possesses eight tandem vIRFs, none of which appears to be spliced.Expression of HHV-8 genes is...

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Kaposi’s Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor Confers Resistance to the Antiproliferative Effect of Interferon-α

Cited by 45 publications

References 57 publications

Viral Interferon Regulatory Factor 1 of Kaposi's Sarcoma-Associated Herpesvirus Interacts with a Cell Death Regulator, GRIM19, and Inhibits Interferon/Retinoic Acid-Induced Cell Death

Viral Interferon Regulatory Factor 1 of Kaposi's Sarcoma-Associated Herpesvirus Interacts with a Cell Death Regulator, GRIM19, and Inhibits Interferon/Retinoic Acid-Induced Cell Death

Downregulation of Gamma Interferon Receptor 1 by Kaposi's Sarcoma-Associated Herpesvirus K3 and K5

Transcription mapping of human herpesvirus 8 genes encoding viral interferon regulatory factors

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