A Complete Genomic DNA Sequence of Marek’s Disease Virus Type 2, Strain HPRS24

Izumiya, Yoshihiro; Jang, Hyung Kwan; Ono, M.; Mikami, Takeshi

doi:10.1007/978-3-642-56863-3_8

Cited by 59 publications

(38 citation statements)

References 107 publications

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“…The HSV UL56 gene is an accessory gene that most members of the Alphaherpesvirinae family possess homologs for (except bovine herpes virus-1 and -5) (1,17,19,22,29,34,37,46,53,(65)(66)(67)(68)(69)(70); M. Schwyzer, V. Paces, G. J. Letchworth, V. Misra, H. J. Buhk, D. E. Lowery, C. Simard, L. J. Bello, E. Thiry, and C. Vlcek, 1995, complete DNA sequence of bovine herpesvirus 1. GenBank database [http://www.ncbi.nlm.nih.gov/Genbank/index .html] accession number NC_001847) and has been shown to play an important role in HSV type 1 (HSV-1) pathogenicity in vivo.…”

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confidence: 99%

Herpes Simplex Virus Type 2 UL56 Interacts with the Ubiquitin Ligase Nedd4 and Increases Its Ubiquitination

Ushijima

Koshizuka

Goshima

et al. 2008

J Virol

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The herpes simplex virus UL56 gene is conserved among most members of the Alphaherpesvirinae family and plays a critical role in viral pathogenicity in vivo. The HSV-2 UL56 protein (UL56) is a C-terminally anchored type II membrane protein that is predicted to be inserted into the virion envelope, leaving its N-terminal domain in the tegument. UL56 interacts with KIF1A and UL11. Here we report that UL56 also interacts with the ubiquitin ligase Nedd4 and increases its ubiquitination. Nedd4 was identified as a UL56-interacting protein by a yeast two-hybrid screen. UL56 bound to Nedd4 via its PY motifs. Nedd4 was phosphorylated and degraded in wild-type HSV-2-infected cells but not in cells infected with a UL56-deficient mutant. Ubiquitination assays revealed that UL56 increased ubiquitinated Nedd4, which was actively degraded in infected cells. UL56 also caused a decrease in Nedd4 protein levels and the increased ubiquitination in cotransfected cells. However, UL56 itself was not ubiquitinated, despite its interaction with Nedd4. Based on these findings, we propose that UL56 regulates Nedd4 in HSV-2-infected cells, although deletion of UL56 had no apparent effect on viral growth in vitro.Herpes simplex virus (HSV) is a large, enveloped DNA virus with a genome possessing at least 74 different genes (19,46). Although approximately half of the HSV genes are not essential for replication in vitro, all of these accessory gene products are predicted to play indispensable roles in viral replication and dissemination in vivo (57).The HSV UL56 gene is an accessory gene that most members of the Alphaherpesvirinae family possess homologs for (except bovine herpes virus-1 and -5) (1,17,19,22,29,34,37,46,53,(65)(66)(67)(68)(69)(70); M. Schwyzer, V. Paces, G. J. Letchworth, V. Misra, H. J. Buhk, D. E. Lowery, C. Simard, L. J. Bello, E. Thiry, and C. Vlcek, 1995, complete DNA sequence of bovine herpesvirus 1. GenBank database [http://www.ncbi.nlm.nih.gov/Genbank/index .html] accession number NC_001847) and has been shown to play an important role in HSV type 1 (HSV-1) pathogenicity in vivo. UL56-deficient HSV-1 mutants are substantially less neuroinvasive (4, 58), although little is known molecularly about how this attenuation occurs. HSV-2 UL56 is a 235-amino-acid, C-terminally anchored, type II membrane protein (39) that is predicted to be inserted into the viral envelope so that the N-terminal domain is located in the virion tegument. In this topology, UL56 is predicted to have a 216-amino-acid cytoplasmic domain. UL56 associates with the neuron-specific kinesin KIF1A (41) and the HSV-2 protein UL11 (40). KIF1A is involved in the axonal transport of synaptic vesicle precursors (51), and its association with UL56 suggests that UL56 may affect vesicular transport in infected neurons. UL11 is a tegument protein that is involved in the envelopment and egress of viral nucleocapsids (3) and has dynamic membrane-trafficking properties (45). UL56 may specifically promote UL11 function in virion envelopment and egress in infected neur...

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confidence: 99%

Herpes Simplex Virus Type 2 UL56 Interacts with the Ubiquitin Ligase Nedd4 and Increases Its Ubiquitination

Ushijima

Koshizuka

Goshima

et al. 2008

J Virol

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“…Within these regions there are limited number of genes, including viral telomerase RNA (5), viral IL-8 (6,7), meq (8), pp38 (9), and ICP4 (10). Of these genes, only Meq was consistently expressed in all MDV lymphoblast tumor cells (7,8) and it is present in serotype 1 strains but not in nononcogenic serotypes 2 and 3 (11)(12)(13).…”

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Marek's disease virus-encoded Meq gene is involved in transformation of lymphocytes but is dispensable for replication

Lupiani

Lee

Chen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

201

149

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Marek's disease virus (MDV) causes an acute lymphoproliferative disease in chickens, resulting in T cell lymphomas in visceral organs and peripheral nerves. Earlier studies have determined that the repeat regions of oncogenic serotype 1 MDV encode a basic leucine zipper protein, Meq, which structurally resembles the Jun͞Fos family of transcriptional activators. Meq is consistently expressed in MDV-induced tumor cells and has been suggested as the MDVassociated oncogene. To study the function of Meq, we have generated an rMd5⌬Meq virus by deleting both copies of the meq gene from the genome of a very virulent strain of MDV. Growth curves in cultured fibroblasts indicated that Meq is dispensable for in vitro virus replication. In vivo replication in lymphoid organs and feather follicular epithelium was also not impaired, suggesting that Meq is dispensable for lytic infection in chickens. Reactivation of the rMd5⌬Meq virus from peripheral blood lymphocytes was reduced, suggesting that Meq is involved but not essential for latency. Pathogenesis experiments showed that the rMd5⌬Meq virus was fully attenuated in chickens because none of the infected chickens developed Marek's disease-associated lymphomas, suggesting that Meq is involved in lymphocyte transformation. A revertant virus that restored the expression of the meq gene, showed properties similar to those of the parental virus, confirming that Meq is involved in transformation but not in lytic replication in chickens.

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“…The genes residing in UL and US, mostly encoding components for genome replication and virus assembly, are highly conserved. By contrast, the genes in RL and RS are significantly divergent between MDV and herpes simplex virus, as well as among different serotypes of MDV (4,24,29). It was postulated that the genes in the repeat regions are likely to account for the unique lymphotropic and oncogenic properties of MDV.…”

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Characterization of the Chromosomal Binding Sites andDimerization Partners of the Viral Oncoprotein Meq in Marek'sDisease Virus-Transformed TCells

Levy

Izumiya

Brunovskis

et al. 2003

J Virol

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Marek's disease virus (MDV) is an acute transforming alphaherpesvirus that causes T-cell lymphomas in chickens.We previously reported the identification of a putative oncogene, meq, that is encoded only by the oncogenic serotype of MDV. The gene product, Meq, is a latent protein that is consistently expressed in MDV-transformed lymphoblastoid cells and tumor cells. Meq has a bZIP (basic leucine zipper) structure resembling the family of Jun/Fos. The mechanism whereby Meq transforms T cells remains poorly understood. In this study, we explored the properties of Meq as a transcriptional factor. We analyzed Meq's dimerization partners and its target genes in MSB-1, an MDV-transformed T-cell line. By using in vitro assays, we first demonstrated Meq's potential to dimerize with a variety of bZIP proteins. We then identified c-Jun as the primary dimerization partner of Meq. Both are found to be colocalized in the nucleus and corecruited to promoters with AP-1 sequences. By using chromatin immunoprecipitation (ChIP), we scanned the entire MDV genome for Meq binding sites and found three regions that were enriched with Meq binding: the MDV lytic replication origin, the promoter for Meq, and the promoter for ICP4. Transactivation assays using the above promoters showed that Meq/Meq homodimers exhibited repression activity, whereas Meq/Jun heterodimers showed activation. Finally, we were able to show by ChIP that Meq is recruited to the interleukin-2 promoter in a region encompassing an AP-1 site. Thus, in addition to providing general knowledge about the transcriptional properties of Meq, our studies revealed for the first time the ability of Meq to interact with the latent MDV and host genomes. Our data suggest, therefore, a role for Meq in viral genome regulation during latency, in addition to its putative causal role in T-cell transformation.Marek's disease (MD) is a communicable viral lymphoproliferative disease of chickens (13). The signs associated with MD are paralysis, depression, tremors, blindness, widespread T-cell lymphomas, and death. The costs of controlling MD and the associated loss make MD one of the most costly infectious diseases affecting the poultry industry. MD is caused by MD virus (MDV) (13). MDVs are composed of three antigenically related viruses, serotypes 1, 2, and 3, of which only serotype 1 MDVs are oncogenic. MDV is the only acute transforming alphaherpesvirus that causes tumors in its host. MDV was classified as an alphaherpesvirus on the basis of DNA sequence homology and genome organization (29, 55; P. Brunovskis, Z.

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A Complete Genomic DNA Sequence of Marek’s Disease Virus Type 2, Strain HPRS24

Cited by 59 publications

References 107 publications

Herpes Simplex Virus Type 2 UL56 Interacts with the Ubiquitin Ligase Nedd4 and Increases Its Ubiquitination

Herpes Simplex Virus Type 2 UL56 Interacts with the Ubiquitin Ligase Nedd4 and Increases Its Ubiquitination

Marek's disease virus-encoded Meq gene is involved in transformation of lymphocytes but is dispensable for replication

Characterization of the Chromosomal Binding Sites andDimerization Partners of the Viral Oncoprotein Meq in Marek'sDisease Virus-Transformed TCells

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