Sμbp-2 Represses the Epstein–Barr Virus Lytic Switch Promoter

Zhang, Qin; Wang, Yi-Chun James; Montalvo, Eduardo A.

doi:10.1006/viro.1998.9588

Cited by 32 publications

(20 citation statements)

References 46 publications

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“…Negative regulatory elements of the BZLF1 promoter lie both within (36,43,60) and outside (42,43,49) the Ϫ221 to ϩ 20 region. We showed here that ZVR does not bind any of the known proximal negative elements (Fig.…”

Section: Vol 75 2001mentioning

confidence: 99%

“…Unfortunately, the authors failed to detect a specific protein complex that recognized this sequence. Recently, Zhang et al (60) showed that the ubiquitous factor Sbp-2 represses transcription of the BZLF1 promoter, with this repression being significantly affected by an element located between nt Ϫ93 and Ϫ79. Whether this or the ZIIR element is an Sbp-2 DNAbinding site remains unclear.…”

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confidence: 99%

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Identification of a Novel Element Involved in Regulation of the Lytic Switch BZLF1 Gene Promoter of Epstein-Barr Virus

Kraus

Mirocha

Stephany

et al. 2001

J Virol

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Epstein-Barr virus (EBV) isEpstein-Barr virus (EBV) is a human herpesvirus that is estimated to infect up to 90% of the world's population (28,29). EBV infection is associated with several human diseases, including infectious mononucleosis, nasopharyngeal carcinoma, Burkitt's lymphoma, and, in immunosuppressed patients, B-cell and T-cell lymphomas (28,29). Thus, EBV is a serious pathogen and poses a significant threat to human health.Like other herpesviruses, primary infection with EBV is followed by a persistent infection of the human host. Oropharyngeal epithelium is thought to be the primary site of EBV infection and replication and of viral spread (28-30, 51), while B cells are the major site of persistent latency (28-31). Eleven of EBV's approximately 100 viral genes are expressed during latency. These include ones encoding the EBV-encoded nuclear antigens (EBNAs 1 to 6), the latent membrane proteins (LMPs 1 and 2), two EBV-encoded small nuclear RNAs, and the BamHIA transcripts (28, 29). Expression of a subset of the latter genes is sufficient to immortalize B cells and to maintain steady-state levels of the viral genome (31). Treatment of certain latently infected B-cell populations with reagents such as phorbol esters (5, 17, 64), Ca 2ϩ ionophores (15), sodium butyrate (26, 38), and serum factors (2) or cross-linking of surface anti-immunoglobulin (12, 21, 50, 53) leads to cellular differentiation and the concomitant induction of the rest of EBV's genes, followed by viral genome replication to higher copy number and production of infectious virus particles (28-30).Two immediate-early genes, BZLF1 and BRLF1, are the first to be expressed during induction of EBV out of latency (11,23,32,52). The protein products of both of these genes are strong transcriptional transactivators (9, 16). The product of the BZLF1 gene, referred to as Zta, ZEBRA, or EB1, plays a crucial role in the disruption of latency and initiation of the viral infectious cycle (10,11,41,46,52). Thus, regulation of Zta expression is critical to the state of EBV in cells.The transcriptional regulation of the BZLF1 promoter (also referred to as Zp) has been studied extensively. Zp exhibits very low basal activity and is readily activated by inducers of the viral infectious cycle. The cis-acting elements necessary both for basal activity and for response to exogenous inducers lie within the nucleotide (nt) Ϫ221 to ϩ12 region of the promoter relative to the transcriptional initiation site (12,17,18). These elements have been divided into three classes ( Fig. 1; also, see reference 36 and references therein). Four AT-rich elements, termed ZIA to ZID, are dispersed throughout the promoter. They can bind the transcription factors Sp1 and Sp3 (34) and myocyte enhancer factor 2D (37, 44). A second type of element, ZII, shares significant homology with the consensus CRE/AP-1 binding site (1,13,25,54). Finally, a region called ZIII contains multiple binding sites for the Zta protein itself (18). It has been proposed that activation of the BZLF1 gene oc...

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Section: Vol 75 2001mentioning

confidence: 99%

mentioning

confidence: 99%

Identification of a Novel Element Involved in Regulation of the Lytic Switch BZLF1 Gene Promoter of Epstein-Barr Virus

Kraus

Mirocha

Stephany

et al. 2001

J Virol

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“…Besides JDP2, several factors have been reported to suppress the BZLF1 promoter. SMUBP-2, a transcription factor first identified through its interaction with the immunoglobulin Smu region, represses Zp activation by TPA (37). ZEB proteins restrict BZLF1 expression by binding to the ZV element of the promoter (38 -40).…”

Section: Discussionmentioning

confidence: 99%

Involvement of Jun Dimerization Protein 2 (JDP2) in the Maintenance of Epstein-Barr Virus Latency

Murata

Noda

Saito

et al. 2011

Journal of Biological Chemistry

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Reactivation of the Epstein-Barr virus from latency is dependent on expression of the BZLF1 viral immediate-early protein.The BZLF1 promoter (Zp) normally exhibits only low basal activity but is activated in response to chemical inducers such as 12-O-tetradecanoylphorbol-13-acetate and calcium ionophore. We found that Jun dimerization protein 2 (JDP2) plays a significant role in suppressing Zp activity. Reporter, EMSA, and ChIP assays of a Zp mutant virus revealed JDP2 association with Zp at the ZII cis-element, a binding site for CREB/ATF/AP-1. Suppression of Zp activity by JDP2 correlated with HDAC3 association and reduced levels of histone acetylation. Although introduction of point mutations into the ZII element of the viral genome did not increase the level of BZLF1 production, silencing of endogenous JDP2 gene expression by RNA interference increased the levels of viral early gene products and viral DNA replication. These results indicate that JDP2 plays a role as a repressor of Zp and that its replacement by CREB/ ATF/AP-1 at ZII is crucial to triggering reactivation from latency to lytic replication.The Epstein-Barr virus (EBV) 2 is a human ␥-herpesvirus that predominantly establishes latent infection in B lymphocytes. Only a small percentage of infected cells switch from the latent stage into the lytic cycle to produce progeny viruses. Although the mechanism of EBV reactivation in vivo is not fully understood, it is known to be elicited by treatment of latently infected B cells with chemical or biological reagents, such as 12-O-tetradecanoylphorbol 13-acetate (TPA), calcium ionophore, sodium butyrate, or anti-immunoglobulin, at least in cultured cells. Stimulation of the EBV lytic cascade by any of these leads to expression of two immediate-early genes, BZLF1 and BRLF1.The BZLF1 protein is a transcriptional activator that shares structural similarities to basic leucine zipper (b-Zip) family transcriptional factors and acts as an oriLyt binding protein essential for lytic viral DNA replication. BZLF1 expression alone can trigger the entire reactivation cascade (1-3).Expression of the BZLF1 gene is tightly controlled at the transcriptional level. The BZLF1 promoter (Zp) normally exhibits low basal activity and is activated in response to TPA or the other reagents described above. The minimal sequence of Zp necessary for activation by the inducers is 233 bp in length (4). The region harbors at least three types of cis regulatory elements, referred to as ZI, ZII, and ZIII. Four copies of the ZI element (ZIA-D) are distributed within the minimal Zp. The myocyte enhancer factor 2D binds to ZIA, ZIB, and ZID (5), whereas Sp1 or Sp3 can bind to ZIA, ZIC, and ZID (6). A single ZII element is located near TATA, sharing homology with binding sites for the cyclic AMP-response element-binding protein (CREB), activating transcription factor (ATF), and activator protein-1 (AP-1) family transcriptional factors such as JunB and JunD (7,8). Two copies of the ZIII element (ZIII-A and -B) bind to the BZLF1 protein. Previou...

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“…IGHMBP2 is ubiquitously expressed and consists of 15 exons encoding a protein of 993 amino acids that possesses a putative DNA helicase region, an R3H motif, and a zinc-finger AN1-like domain. Although the physiological function of IGHMBP2 is not known in detail, the protein is suspected to be involved in immunoglobulin-class switching, pre-mRNA processing, and regulation of transcription through DNA-binding or interaction with TATA-binding proteins (Fukita et al 1993;Molnar et al 1997;Zhang et al 1999;Miao et al 2000;Liepinsh 2003). Fukita et al (1993) first showed that IGHMBP2 binds to singlestranded DNA with 5¢-phosphorylated guanine-rich sequences related to the immunoglobulin l-chain switch (Sm) region.…”

Section: Discussionmentioning

confidence: 99%

Association of a single-nucleotide polymorphism in the immunoglobulin μ-binding protein 2 gene with immunoglobulin A nephropathy

et al. 2004

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Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis worldwide. The pathogenesis of IgA nephropathy is unknown, but it is certain that some genetic factors are involved in susceptibility to the disease. Employing a large-scale, case-control association study using genebased single-nucleotide polymorphism (SNP) markers, we previously reported four candidate genes. We report here an additional significant association between IgA nephropathy and an SNP located in the gene encoding immunoglobulin l-binding protein 2 (IGHMBP2) at chromosome 11q13.2-q13.4. The association (v 2 =17.1, p=0.00003; odds ratio of 1.85 with 95% confidence interval of 1.39-2.50 in a dominant association model) was found using DNA from 465 affected individuals and 634 controls. The SNP (G34448A) caused an amino acid substitution from glutamine to lysine (E928K). As the gene product is involved in immunoglobulin-class switching and patients with the A allele revealed higher serum levels of IgA (p=0.048), the amino acid change might influence a class switch to increase serum IgA levels, resulting in a higher risk of IgA nephropathy.

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Sμbp-2 Represses the Epstein–Barr Virus Lytic Switch Promoter

Cited by 32 publications

References 46 publications

Identification of a Novel Element Involved in Regulation of the Lytic Switch BZLF1 Gene Promoter of Epstein-Barr Virus

Identification of a Novel Element Involved in Regulation of the Lytic Switch BZLF1 Gene Promoter of Epstein-Barr Virus

Involvement of Jun Dimerization Protein 2 (JDP2) in the Maintenance of Epstein-Barr Virus Latency

Association of a single-nucleotide polymorphism in the immunoglobulin μ-binding protein 2 gene with immunoglobulin A nephropathy

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