The bZIP transactivator of Epstein-Barr virus, BZLF1, functionally and physically interacts with the p65 subunit of NF-kappa B.

Gutsch, David; Holley-Guthrie, Elizabeth; Zhang, Qin; Stein, Bernd; Blanar, Michael A.; Baldwin, Albert S.; Kenney, Shannon C.

doi:10.1128/mcb.14.3.1939

Cited by 115 publications

(79 citation statements)

References 74 publications

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“…Equal amounts of proteins were incubated with 2 ,u of either a hRARa-specific monoclonal antibody (RalO) (Dianova, Hamburg, Germany) or an unrelated anti-Gal4-specific antibody (Santa Cruz Biotechnology) for 4 h at 4°C. Protein complexes were precipitated with 10 ,ul of protein G-Sepharose (Pharmacia) for 1 h at 4°C, washed, and analyzed as described (18).…”

Section: Methodsmentioning

confidence: 99%

Functional antagonism between the retinoic acid receptor and the viral transactivator BZLF1 is mediated by protein-protein interactions.

Pfitzner¹,

Becker²,

Rolke³

et al. 1995

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

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The Epstein-Barr virus-encoded protein BZLF1 is a member of the basic leucine zipper (bZip) Epstein-Barr virus is a human herpesvirus that infects B lymphocytes and epithelial cells of the nasopharynx (1). Infection of B cells typically results in a latent state, whereas infection of epithelial cells leads to viral replication and cytolysis (2). The switch from latency to the productive (replicative) cycle is induced by various agents such as calcium ionophores, sodium butyrate, and tumor promoters like phorbol 12-myristate 13-acetate, all of which activate expression of the Epstein-Barr virus immediate-early gene product BZLF1 (2). Overexpression of BZLF1 is sufficient to trigger the switch to the lytic cycle (2). Like the c-Jun/c-Fos proteins BZLF1 is a member of the basic leucine zipper (bZIP) transcription factor family (3, 4). BZLF1 binds as a homodimer to DNA (4) and transactivates several early viral promoters required in the cytolytic cycle of the virus. The BZLF1 response elements (ZREs) in these promoters are similar and sometimes identical to AP-1 binding sites (4).Retinoids play an important role in development and differentiation and are well-known inhibitors of cell growth (for review, see ref. 5). Retinoic acid (RA) exerts biological effects by acting through at least two distinct classes of intracellular proteins including the RA receptors (RARs) and the retinoid X receptors (RXRs), both of which are members of the nuclear receptor superfamily (5). While both the RARs and RXRs are effective activators of some genes, RA is also known to repress expression of AP-1-dependent genes (6). RAR has beenThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.shown to inhibit transcriptional activity of the AP-1 complex by a mechanism that is not dependent on the receptor's ability to bind DNA and most likely reflects protein-protein interactions (6). This interaction of distinct regulatory pathways, termed "cross-talk," suggested a means by which nuclear hormone receptors could modulate the action of growthinducing factors. Recent data suggested that RARa is able to repress the BZLF1-mediated transcriptional activation of the BMFR1 promoter via direct protein-protein interactions between RARa and BZLF1 (7).To further extend our understanding of the cross-talk between RAR and members of the bZIP transcription factor family, we were interested in examining the mutual repression effects of RARa and BZLF1 in more detail. In this report, we show that RARa and BZLF1 repress each other's transcriptional activity. Transfection analysis of RARa and BZLF1 mutants reveals that the transactivation domain and the dimerization domain of the BZLF1 and the DNA binding domain (DBD) of RARa are required for repression. Glutathione S-transferase (GST)-pulldown assays and coimmunoprecipitation experiments demonstrate direct protein-protein interactions between BZ...

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Section: Methodsmentioning

confidence: 99%

Functional antagonism between the retinoic acid receptor and the viral transactivator BZLF1 is mediated by protein-protein interactions.

Pfitzner¹,

Becker²,

Rolke³

et al. 1995

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

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“…Generally, the regulation of cellular genes by Zta is at the RNA level. It has been demonstrated that Zta modulates the expression of the p65 subunit of NFκB, 67 transforming growth factor β (TGFβ) and Retinolmetabolizing Enzyme, DHRS9, 68 through directly binding to their promoter sequences. Zta can also interact with some cellular proteins, including the retinoic acid receptors RAR and RXR, 69 the TATA binding protein TFIID, 70 the C/EBP transcription factor 40 and tumor suppressor p53.…”

Section: Characterization Of Ztamentioning

confidence: 99%

Regulation of cellular and viral protein expression by the Epstein-Barr virus transcriptional regulator Zta: Implications for therapy of EBV associated tumors

Chen¹,

Li²,

Guo³

2009

Cancer Biology & Therapy

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“…It is reported that bZIP-containing proteins such as Fos, Jun, and BZLF interact with p65 through the bZIP domain. [13][14][15] Based on the fact that ICER also contains bZIP domain, we tested whether ICER associates with p65. Indeed, we recovered all four isoforms of HA-tagged ICER via immunoprecipitation (IP) with Flag-tagged p65 (Figure 3a).…”

Section: Icer Deficiency Promotes P65 Dna-binding and Inflammatory Rementioning

confidence: 99%

A negative feedback loop of ICER and NF-κB regulates TLR signaling in innate immune responses

Qiu

et al. 2016

Cell Death Differ

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The NF-κB pathway has important roles in innate immune responses and its regulation is critical to maintain immune homeostasis. Here, we report a newly discovered feedback mechanism for the regulation of this pathway by TLR ligands in macrophages. Lipopolysaccharide (LPS) induced the expression of ICER via p38-mediated activation of CREB in macrophages. ICER, in turn, inhibited the transcriptional activity of NF-κB by direct interaction with the p65 subunit of NF-κB. Deficiency in ICER elevated binding of NF-κB to promoters of pro-inflammatory genes and their subsequent gene expression. Mice deficient in ICER were hypersensitive to LPS-induced endotoxic shock and showed propagated inflammation. Whereas ICER expression in ICER KO bone marrow transplanted mice rescued the ultra-inflammation phenotype, expression of a p65 binding-deficient ICER mutant failed to do so. Our results thus establish p38-CREB-ICER as key components of a negative feedback mechanism necessary to regulate TLR-driven inflammation. Cell Death and Differentiation (2017) 24, 492-499; doi:10.1038/cdd.2016; published online 23 December 2016Activation of TLR4, a pattern recognition receptor used in the innate immune system, by lipopolysaccharide (LPS) leads to the transcription of pro-inflammatory mediators that promote innate immune responses.1 One critical pathway triggered by TLR4 is the NF-κB pathway.2 TLR4 initiates a signaling cascade through adapter molecules MyD88 and TRIF, resulting in TRAF6 activation. TRAF6 in turn triggers the phosphorylation of IκB by IKK and proteosomal degradation of IκB. Subsequently, NF-κB disassociates from IκB and translocates to the nucleus where it promotes the transcription of genes involved in pro-inflammatory responses.3,4 Activation of TRAF6 also leads to downstream activation of the MAPK cascade, including JNKs and p38 isoforms. 5 The p38 pathway has attracted considerable interest as a possible target for antiinflammatory drugs. Activation of p38 results in the activation of CREB, a transcription factor that regulates diverse cellular responses including proliferation, survival and immune responses. CREB is phosphorylated and activated by MSK1/2, a downstream kinase of p38, and subsequently mediates the transcription of genes containing a cAMP-responsive element. Several anti-inflammatory genes possess this cAMPresponsive element, including Dusp1 and IL-10. 6 In addition, phosphorylated CREB has been proposed to directly inhibit NF-κB activation by blocking the binding of CREB binding protein to the NF-κB complex, thereby limiting proinflammatory responses. 7Inducible cAMP early repressors (ICERs) are members of the cAMP-response element (CRE) modulator family and are induced by CREB.8 ICER is transcribed via an alternative internal promoter in the CREM gene and consists of four different isoforms generated by alternative splicing of its transcript (ICERI, ICERIγ, ICERII, ICERIIγ). 9 The isoforms encode either CREB-like (ICERI) or CREM-like (ICERII) DNA-binding domains (DBDs) with or without the alternat...

show abstract

The bZIP transactivator of Epstein-Barr virus, BZLF1, functionally and physically interacts with the p65 subunit of NF-kappa B.

Cited by 115 publications

References 74 publications

Functional antagonism between the retinoic acid receptor and the viral transactivator BZLF1 is mediated by protein-protein interactions.

Functional antagonism between the retinoic acid receptor and the viral transactivator BZLF1 is mediated by protein-protein interactions.

Regulation of cellular and viral protein expression by the Epstein-Barr virus transcriptional regulator Zta: Implications for therapy of EBV associated tumors

A negative feedback loop of ICER and NF-κB regulates TLR signaling in innate immune responses

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