Human Herpesvirus 6 Immediate-Early 1 Protein Is a Sumoylated Nuclear Phosphoprotein Colocalizing with Promyelocytic Leukemia Protein-associated Nuclear Bodies

Gravel, Annie; Gosselin, Jean; Flamand, Louis

doi:10.1074/jbc.m200836200

Cited by 55 publications

(96 citation statements)

References 75 publications

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“…The ND10s are nuclear bodies that contain promyelocytic leukemia (PML) protein as a structural marker and are implicated in the regulation of transcription, apoptosis, tumor suppression, and the antiviral response (reviewed in reference 7). PML is frequently targeted and degraded by some IE proteins encoded by herpesviruses such as herpes simplex virus type 1 ICP0 (10), Epstein-Barr virus EBNA-5 (50), BZLF1 (1), HCMV IE1 and IE2 (2,23), and HHV-6 IE1 (14,48). Recently, it has been demonstrated that the HCMV tegument pp71 protein also targets PML (16,17,26) and recruits the UL35 protein, a homolog of HHV-6 U14, to the ND10 structures (43).…”

Section: Discussionmentioning

confidence: 99%

Human Herpesvirus 6 Open Reading Frame U14 Protein and Cellular p53 Interact with Each Other and Are Contained in the Virion

Takemoto

Koike

Mori

et al. 2005

J Virol

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A mass spectroscopic analysis of proteins from human herpesvirus 6 (HHV-6)-infected cells showed that the HHV-6 U14 protein coimmunoprecipitated with the tumor suppressor p53. The binding of U14 to p53 was verified by coimmunoprecipitation experiments in both Molt-3 cells infected with HHV-6 and 293 cells cotransfected with U14 and p53 expression vectors. Indirect immunofluorescence assays (IFAs) showed that by 18 h postinfection (hpi) U14 localized to the dot-like structures observed in both the nucleus and cytoplasm where p53 was partly accumulated. Despite Northern blotting evidence that U14 follows late kinetics, the U14 protein was detected immediately after infection (at 3 hpi) by IFA. In addition, by Western blotting, U14 was detected at 0 hpi or in the presence of cycloheximide which completely abolished the expression of IE1 protein.In addition to U14, p53 was detected at 0 hpi although it was not detected in mock-infected cells. Furthermore, both U14 and p53 were clearly detected in the viral particles by Western blotting and immunoelectron microscopy, supporting the idea that U14 and p53 are incorporated into virions. Our study provides the first evidence of the incorporation of cellular p53 into viral particles and suggests that p53 may play an important role in viral infection.

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Section: Discussionmentioning

confidence: 99%

Human Herpesvirus 6 Open Reading Frame U14 Protein and Cellular p53 Interact with Each Other and Are Contained in the Virion

Takemoto

Koike

Mori

et al. 2005

J Virol

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“…Cell-free virus inoculum was prepared by using the freeze-thawing method as described by Mirandola et al (1998) with modifications (Supplementary Methods). HHV-6 infectivity was determined as described by Gravel et al (2002) with modifications. Briefly, three independent infections were performed whereby 5610 6 SupT1 cells were exposed to 1 ml virus inoculum for 1 h, washed and incubated at 37 uC for 60 h. Infected cells were fixed in cold acetone for 10 min, air-dried IP: 13.66.222.141…”

Section: Methodsmentioning

confidence: 99%

Microarray-based determination of the lytic cascade of human herpesvirus 6B

Tsao

Kellam

Sin

et al. 2009

Journal of General Virology

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The lytic gene expression of several members of the human herpesvirus family has been profiled by using gene-expression microarrays; however, the lytic cascade of roseoloviruses has not been studied in similar depth. Based on the complete DNA genome sequences of human herpesvirus 6 variant A (HHV-6A) and variant B (HHV-6B), we constructed a cDNA microarray containing DNA probes to their predicted open reading frames, plus 914 human genes. Gene-expression profiling of HHV-6B strain Z29 in SupT1 cells over a 60 h time-course post-infection, together with kinetic classification of the HHV-6B genes in the presence of either cycloheximide or phosphonoacetic acid, allowed the placement of HHV-6B genes into defined kinetic classes. Eighty-nine HHV-6B genes were divided into four different expression kinetic classes: eight immediate-early, 44 early, 33 late and four biphasic. Clustering of genes with similar expression profiles implied a shared function, thus revealing possible roles of previously uncharacterized HHV-6B genes. INTRODUCTIONHuman herpesvirus 6 (HHV-6) is a betaherpesvirus, first isolated in 1986 from individuals with lymphoproliferative disorders (Salahuddin et al., 1986). Primary infection occurs in early childhood (Hall et al., 1994), when it can cause febrile illnesses including exanthem subitum (ES) (Yamanishi et al., 1988;Zerr et al., 2005). Following initial infection, HHV-6 establishes lifelong latency in the host, with monocytes (Kondo et al., 1991) and bone-marrow progenitor cells (Luppi et al., 1999) being suggested as the sites of latency. HHV-6 reactivation in immunocompromised hosts can be pathogenic, particularly in the transplant setting, and has been associated with encephalitis, bone-marrow suppression and graft rejection (Clark & Griffiths, 2003).Two variants of HHV-6 exist (-6A and -6B), each with distinct genetic, antigenic and biological properties (Pellett & Black, 1996; Schirmer et al., 1991). HHV-6A is not associated consistently with disease, but HHV-6B is the cause of ES in childhood (Dewhurst et al., 1993;Yamanishi et al., 1988;Zerr et al., 2005). Publication of the complete DNA genome sequences of HHV-6A and -6B (Dominguez et al., 1999;Gompels et al., 1995;Isegawa et al., 1999) confirmed the close relatedness of the two variants.However, significant sequence variations observed at the right end of the unique region, plus the existence of variant-specific open reading frames (ORFs), may explain the differential properties described for HHV-6A and -6B (Clark, 2000).As HHV-6 replicates predominantly in CD4 + T cells in vitro and in vivo (Lopez et al., 1988;Lusso et al., 1988), there is interest in the regulation of viral gene expression in its target cell type. We have previously described the use of DNA microarrays for expression profiling of two gammaherpesviruses, Kaposi's sarcoma-associated herpesvirus (Jenner et al., 2001) and murine gammaherpesvirus 68 (Ahn et al., 2002), and demonstrated the functional predictions of uncharacterized viral genes and transcription from inte...

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“…Equal amounts of proteins were loaded in all lanes as confirmed by actin blotting. Viral Preparation-The HHV-6 (type B, Z29 strain) used in this study was propagated on Molt-3 cells as described (39). After 7 days of infection, virus was concentrated from culture supernatant by centrifugation (38,800 ϫ g, 2 h 40 min) and resuspended in a minimal volume of complete culture medium.…”

Section: Figmentioning

confidence: 99%

Activation of Monocyte Cyclooxygenase-2 Gene Expression by Human Herpesvirus 6

Janelle¹,

Gravel²,

Gosselin³

et al. 2002

Journal of Biological Chemistry

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Prostaglandin E 2 (PGE 2 ) is an arachidonic acid metabolite mainly produced by activated monocytes/macrophages (Mo/M) that display broad immunomodulatory activities. Several viruses capable of infecting Mo/M modulate PGE 2 synthesis in a way that favors the infection processes and the spread of virions. In the present work, we studied the effect of human herpesvirus 6 (HHV-6) infection of Mo/M on PGE 2 synthesis. Our results indicate that HHV-6 induces COX-2 gene expression and PGE 2 synthesis within a few hours of infection. We mapped the different promoter elements associated with COX-2 gene activation by HHV-6 to two cis-acting elements: a cyclic AMP-responsive element and an activator protein-1 element. HHV-6 immediate-early protein 2 was identified as a modulator of COX-2 gene expression in Mo/M. Finally, addition of PGE 2 to HHV-6-infected peripheral blood mononuclear cells cultures was found to increase significantly viral replication. Overall, these results further contribute to the immunomodulatory properties of HHV-6 and highlight a potential role for eicosanoids in the replication process of this virus.

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Human Herpesvirus 6 Immediate-Early 1 Protein Is a Sumoylated Nuclear Phosphoprotein Colocalizing with Promyelocytic Leukemia Protein-associated Nuclear Bodies

Cited by 55 publications

References 75 publications

Human Herpesvirus 6 Open Reading Frame U14 Protein and Cellular p53 Interact with Each Other and Are Contained in the Virion

Human Herpesvirus 6 Open Reading Frame U14 Protein and Cellular p53 Interact with Each Other and Are Contained in the Virion

Microarray-based determination of the lytic cascade of human herpesvirus 6B

Activation of Monocyte Cyclooxygenase-2 Gene Expression by Human Herpesvirus 6

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