Epstein‐Barr virus antagonizes the antiproliferative activity of transforming growth factor‐β but does not abolish its signaling

Horndasch, Manuela; Raschke, Eva; Bommer, Guido T.; Schuhmacher, Marino; Dumont, Elisabeth; Conny, Kuklik-Roos; Eick, Dirk; Kempkes, Bettina

doi:10.1002/ijc.10626

Cited by 7 publications

(6 citation statements)

References 28 publications

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“…Various mechanisms by which EBV confers resistance to TGF-␤ have been proposed (for a review, see reference 19), including a decrease in the level of TGF-␤ receptors (78,79,91). Elsewhere, however, it has been shown that the EBV Lat III program, but not c-MYC, preferentially protects P493-6 cells from the antiproliferative effect of TGF-␤1 (92). Furthermore, the same study ruled out the abolition of TGF-␤1 apoptotic signaling, cyclin D2, EBV lytic cycle activation, and secondary genetic events as potential contributory factors.…”

Section: Discussionmentioning

confidence: 99%

Repression of the Proapoptotic CellularBIK/NBKGene by Epstein-Barr Virus Antagonizes Transforming Growth Factor β1-Induced B-Cell Apoptosis

Campion

Hakimjavadi

Loughran

et al. 2014

J Virol

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The Epstein-Barr virus (EBV) establishes a lifelong latent infection in humans. EBV infection of primary B cells causes cell activation and proliferation, a process driven by the viral latency III gene expression program, which includes EBV nuclear proteins (EBNAs), latent membrane proteins, and untranslated RNAs, including microRNAs. Some latently infected cells enter the long-lived memory B-cell compartment and express only EBNA1 transiently (Lat I) or no EBV protein at all (Lat 0). Targeting the molecular machinery that controls B-cell fate decisions, including the Bcl-2 family of apoptosis-regulating proteins, is crucial to the EBV cycle of infection. Here, we show that BIK (also known as NBK), which encodes a proapoptotic "sensitizer" protein, is repressed by the EBNA2-driven Lat III program but not the Lat I program. BIK repression occurred soon after infection of primary B cells by EBV but not by a recombinant EBV in which the EBNA2 gene had been knocked out. Ectopic BIK induced apoptosis in Lat III cells by a mechanism dependent on its BH3 domain and the activation of caspases. We show that EBNA2 represses BIK in EBV-negative B-cell lymphoma-derived cell lines and that this host-virus interaction can inhibit the proapoptotic effect of transforming growth factor ␤1 (TGF-␤1), a key physiological mediator of B-cell homeostasis. Reduced levels of TGF-␤1-associated regulatory SMAD proteins were bound to the BIK promoter in response to EBV Lat III or ectopic EBNA2. These data are evidence of an additional mechanism used by EBV to promote Bcell survival, namely, the transcriptional repression of the BH3-only sensitizer BIK. IMPORTANCEOver 90% of adult humans are infected with the Epstein-Barr virus (EBV). EBV establishes a lifelong silent infection, with its DNA residing in small numbers of blood B cells that are a reservoir from which low-level virus reactivation and shedding in saliva intermittently occur. Importantly, EBV DNA is found in some B-cell-derived tumors in which viral genes play a key role in tumor cell emergence and progression. Here, we report for the first time that EBV can shut off a B-cell gene called BIK. When activated by a molecular signal called transforming growth factor ␤1 (TGF-␤1), BIK plays an important role in killing unwanted B cells, including those infected by viruses. We describe the key EBV-B-cell molecular interactions that lead to BIK shutoff. These findings further our knowledge of how EBV prevents the death of its host cell during infection. They are also relevant to certain posttransplant lymphomas where unregulated cell growth is caused by EBV genes. E pstein-Barr virus (EBV) is a B lymphotropic human herpesvirus with oncogenic potential (for reviews, see references 1 and 2). Following primary infection, EBV establishes a lifelong latent infection in more than 90% of all adults, with intermittent virus shedding in very low levels in saliva. EBV persists in a quiescent state in circulating, resting, memory B cells. EBV is a potent transforming virus in vitro and eff...

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Section: Discussionmentioning

confidence: 99%

Repression of the Proapoptotic CellularBIK/NBKGene by Epstein-Barr Virus Antagonizes Transforming Growth Factor β1-Induced B-Cell Apoptosis

Campion

Hakimjavadi

Loughran

et al. 2014

J Virol

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“…EBNA-2 transactivates the anti-apoptotic gene BFL-1 (BCL2A1, GenBank: NM_004049) in complex with RBP-Jj [22]. EBNA-2 can also inhibit the pro-apoptotic and anti-proliferative functions of the transforming growth factor beta 1 (TGFB1, GenBank: NP_000651) cytokine, as shown in the EBNA-2 inducible EREB system [23]. The EBNA3 family proteins are also increasingly involved in protection against apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes

Yenamandra

Hellman

Kempkes³

et al. 2010

Cell. Mol. Life Sci.

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Epstein-Barr virus (EBV) is a human gamma herpes virus that infects B cells and induces their transformation into immortalized lymphoblasts that can grow as cell lines (LCLs) in vitro. EBNA-3 is a member of the EBNA-3-protein family that can regulate transcription of cellular and viral genes. The identification of EBNA-3 cellular partners and a study of its influence on cellular pathways are important for understanding the transforming action of the virus. In this work, we have identified the vitamin D receptor (VDR) protein as a binding partner of EBNA-3. We found that EBNA3 blocks the activation of VDR-dependent genes and protects LCLs against vitamin-D3-induced growth arrest and/or apoptosis. The presented data shed some light on the anti-apoptotic EBV program and the role of the EBNA-3-VDR interaction in the viral strategy.

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“…HCMV miR-UL22A Downregulates SMAD3 to Allow Viral Reactivation in CD34 + HPCs Although HCMV-induced TGF-b exhibits myelosuppressive effects on uninfected CD34 + HPCs, the effects of the cytokine on latently infected HPCs are unknown. Since TGF-b can negatively affect the growth of other viruses (Campion et al, 2014;Chiu et al, 2012;Choi et al, 2015;Di Bartolo et al, 2008;DiMaio et al, 2014;Fukuda et al, 2002;Fukuda and Longnecker, 2004;Horndasch et al, 2002;Inman and Allday, 2000;Lei et al, 2012;Lo et al, 2010;Mori et al, 2003;Morris et al, 2016;Prokova et al, 2002;Seo et al, 2005;Tomita et al, 2004;Wood et al, 2007), we hypothesized that HCMV protects infected cells from the negative effects of TGF-b signaling by manipulating components of the TGF-b signaling pathway. To test this hypothesis, we mock-or HCMV-infected primary CD34 + HPCs for 48 h and isolated a pure population of viable, CD34 + , GFP + HPCs.…”

Section: Hcmv Mir-us5-2 Is Sufficient To Induce Expression Of Tgf-b and Myelosuppression In Cd34 + Hpcsmentioning

confidence: 99%

Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34+ Hematopoietic Progenitor Cells

Hancock

Crawford

Pham

et al. 2020

Cell Host & Microbe

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Epstein‐Barr virus antagonizes the antiproliferative activity of transforming growth factor‐β but does not abolish its signaling

Cited by 7 publications

References 28 publications

Repression of the Proapoptotic CellularBIK/NBKGene by Epstein-Barr Virus Antagonizes Transforming Growth Factor β1-Induced B-Cell Apoptosis

Repression of the Proapoptotic CellularBIK/NBKGene by Epstein-Barr Virus Antagonizes Transforming Growth Factor β1-Induced B-Cell Apoptosis

Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes

Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34+ Hematopoietic Progenitor Cells

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