Characterization of a Novel Human Herpesvirus 8-Encoded Protein, vIRF-3, That Shows Homology to Viral and Cellular Interferon Regulatory Factors

Lubyová, Barbora; Pitha, Paula M.

doi:10.1128/jvi.74.17.8194-8201.2000

Cited by 153 publications

(109 citation statements)

References 45 publications

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“…The putative TATA box identified by Lubyova & Pitha (2000) is located 500 bp further upstream and appears not to direct initiation. The 59-ends of another latent mRNA, encoding LANA-1, have been Residues that are conserved in at least eight of the nine human sequences and corresponding residues conserved in the viral sequences, and residues that are conserved in all of the viral sequences, are shown in bold.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, Rivas et al (2001) and Fakhari & Dittmer (2002) showed that the gene is expressed constitutively. Lubyova & Pitha (2000) noted a potential TATA box and polyadenylation signal in the DNA sequence, but the 59-end of a single cDNA clone analysed by Rivas et al (2001) does not correspond with use of this TATA box. The vIRF-3 protein (LANA-2) is expressed in the nuclei of PEL cell lines but not in KS tissue, and appears to be involved in inhibiting p53-mediated apoptosis (Rivas et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Lubyova & Pitha (2000) and Jenner et al (2001) characterized vIRF-3 as inducible. In contrast, Rivas et al (2001) and Fakhari & Dittmer (2002) showed that the gene is expressed constitutively.…”

Section: Introductionmentioning

confidence: 99%

“…vIRF-3 specifies a spliced mRNA of 2?2 or 1?8 kb (Lubyova & Pitha, 2000;Rivas et al, 2001;Jenner et al, 2001). Lubyova & Pitha (2000) and Jenner et al (2001) characterized vIRF-3 as inducible.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Finally, the ORFK10.5 encodes the LANA2 protein (previously called vIRF 3 ) with homology to cellular IRF-4 and KSHV vIRF2 (Rivas et al, 2001). LANA2 functions as a dominant-negative mutant of both IRF-3 and IRF-7 and inhibits virus-mediated transcriptional activity of the IFNA promoter (Lubyova & Pitha, 2000).KSHV has thus developed strategies to counteract IFN through the synthesis of several viral proteins with homology to the IRF-like proteins. However, only one KSHV protein (vIRF2) has been identified so far that specifically counteracts PKR action, the most common target of virus action to block IFN signalling pathways.…”

mentioning

confidence: 99%

The latency protein LANA2 from Kaposi's sarcoma-associated herpesvirus inhibits apoptosis induced by dsRNA-activated protein kinase but not RNase L activation

Esteban

García

Domingo-Gil

et al. 2003

Journal of General Virology

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Kaposi's sarcoma-associated herpesvirus (KSHV) uses several strategies to counteract the interferon (IFN) system. In this study, the relationship of the protein LANA2 from KSHV to the IFN-activated protein kinase (PKR) and 2-5A system was analysed. It was found that LANA2 could not abrogate apoptosis or RNA degradation mediated by the 2-5A system. However, expression of LANA2 inhibited apoptosis triggered by PKR. LANA2 also counteracted the PKR-mediated inhibition of protein synthesis and partially blocked PKR-induced phosphorylation of eIF-2a. Analysis of PKR-induced activation of caspases 3 and 9 revealed that LANA2 abrogated activation of caspase 3 but not of caspase 9. These findings show that LANA2 is able to interfere with downstream events triggered by PKR. Hence, LANA2 should be considered as a KSHV defence protein against IFN. INTRODUCTIONVirus infection induces expression of a group of proteins, the interferons (IFNs), which play major roles as a first-line host defence response against pathogens. IFNs are multifunctional cytokines with important roles in the induction of antiviral, cell growth, differentiation and immunomodulatory functions (Harada et al., 1998;Stark et al., 1998). There are two types of IFN, type I (IFN-a/b) and type II (IFN-c). Type I IFNs are produced by virus-infected cells and constitute the primary response against virus infection, whereas type II IFN is a Th1 cytokine produced by activated T cells and natural killer cells and is involved in immune regulation (Vilcek & Sen, 1996;Stark et al., 1998). Induction of IFN is highly regulated through IFN regulatory factors (IRFs), a family of transcription factors with a broad range of activities (Nguyen et al., 1997;Mamane et al., 1999;Taniguchi et al., 2001). The different biological actions of IFN are mediated by the products of specifically induced cellular genes in target cells. Two of these IFN-regulated cellular products are the dsRNA-activated protein kinase (PKR) and the 2-5A system. PKR controls cell growth (Chong et al., 1992), cell differentiation (Petryshyn et al., 1984), virus clearance (Lee & Esteban, 1993;Lee et al., 1996) and induction of apoptosis (Lee & Esteban, 1994). PKR is a serine/threonine kinase activated by dsRNA binding and exerts its effect on subsequent autophosphorylation. Some targets of the activated PKR are the phosphorylation of the eukaryotic translation initiation factor 2 (eIF-2a) and NFkB activation, events that mediate the induction of apoptosis by PKR. Activation of the caspase 9 pathway together with the fas-associated death domain (FADD)/caspase 8 pathway are also events downstream of PKR-induced apoptosis, although this activation is not required for the induction of apoptosis (Gil et al., 2002). The 2-5A pathway is constituted by the IFN-induced proteins 2-5A synthetase and 2-5A-dependent RNase L, together with 2-5A phosphodiesterase. dsRNA activates the 2-5A synthetases that, in the presence of ATP, synthesize a complex mixture (referred to as 2-5AS) of 2959-triphosphorylated oligoadenylic a...

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Interferon Regulatory Factors

Pitha

Alce

2002

Wiley Encyclopedia of Molecular Medicine

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Characterization of a Novel Human Herpesvirus 8-Encoded Protein, vIRF-3, That Shows Homology to Viral and Cellular Interferon Regulatory Factors

Cited by 153 publications

References 45 publications

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

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

The latency protein LANA2 from Kaposi's sarcoma-associated herpesvirus inhibits apoptosis induced by dsRNA-activated protein kinase but not RNase L activation

Interferon Regulatory Factors

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