A herpesvirus transactivator and cellular POU proteins extensively regulate DNA binding of the host Notch signaling protein RBP-Jκ to the virus genome

González‐López, Olga; DeCotiis, Jennifer; Goyeneche, Corey; Mello, Helena Flores; Vicente-Ortiz, Bryan Alexis; Shin, Hye Jin; Driscoll, Kyla E.; Du, Peicheng; Palmeri, Diana; Lukac, David M.

doi:10.1074/jbc.ra118.007331

Cited by 6 publications

(17 citation statements)

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“…The copyright holder for this preprint this version posted October 22, 2022. ; https://doi.org/10.1101/2022.10.21.513206 doi: bioRxiv preprint Based on experimental data, we have published two mechanisms that describe how Rta regulates RBP-Jk DNA binding: (1) Rta directly binds to RBP-Jk, and (2) Rta induces expression of additional cellular proteins during reactivation which in turn bind to DNA adjacent to RBP-Jk (4,7,25,26). The latter mechanism is consistent with our work and others that demonstrated that de novo gene expression downstream of Rta is required for robust reactivation (25,86).…”

Section: Discussionmentioning

confidence: 99%

“…Knock-down of endogenous Notch1 was confirmed via Western ). We and others have demonstrated that RBP-Jk1 binds to many sites on KSHV DNA (4-27), and we have mapped eighty-two RBP-Jk1 binding sites to the viral genome during reactivation (55). We selected six RBP-Jk1 binding sites found within 1 kb upstream of transcription start sites for KSHV genes, ie.…”

Section: Notch1 Is Necessary For Optimal Viral Reactivationmentioning

confidence: 99%

“…Rta-dependent stimulation of RBP-Jk binding to the KSHV Mta promoter converts it to a Notch-responsive gene (4). Moreover, our ChIP/Seq studies demonstrated that RBP-Jk binding to the viral genome is dramatically redistributed during reactivation, but Rta and RBP-Jk do not co-occupy every newly identified RBP-Jk site (26). Taken together, these data suggest that Notch plays an essential and complementary role with Rta in KSHV reactivation.…”

Section: Introductionmentioning

confidence: 96%

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The cellular Notch1 Protein Promotes KSHV reactivation in an Rta-dependent manner

DeCotiis-Mauro

Han

Mello

et al. 2022

Preprint

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The cellular Notch signal transduction pathway is intimately associated with infections by Kaposi’s sarcoma-associated herpesvirus (KSHV) and other gamma-herpesviruses. RBP-Jk, the cellular DNA binding component of the canonical Notch pathway, is the key Notch downstream effector protein in virus-infected and uninfected animal cells. Reactivation of KSHV from latency requires the viral lytic switch protein, Rta, to form complexes with RBP-Jk on numerous sites within the viral DNA. Constitutive Notch activity is essential for KSHV pathophysiology in models of Kaposi’s sarcoma (KS) and Primary Effusion Lymphoma (PEL), and we demonstrate that Notch1 is also constitutively active in infected Vero cells. Although the KSHV genome contains >100 RBP-Jk DNA motifs, we show that none of the four isoforms of activated Notch can productively reactivate the virus from latency in a highly quantitative trans-complementing reporter virus system. Nevertheless, Notch contributed positively to reactivation because broad inhibition of Notch1-4 with gamma secretase inhibitor (GSI) or expression of dominant negative mastermind-like1 (dnMAML1) coactivators severely reduced production of infectious KSHV from Vero cells. In infected PEL cells, we show that reduction of vDNA synthesis by GSI is associated with gene specific reduction of viral transcription. Specific inhibition of Notch1 by siRNA partially reduces production of infectious KSHV, and ectopic activated Notch (NICD1) enhances virus production induced by Valproic Acid (VPA) treatment. We conclude that constitutive Notch activity is required for robust production of infectious KSHV, and our results implicate activated Notch1 as a pro-viral member of a MAML1/RBP-Jk complex during viral reactivation.ImportanceKaposi’s sarcoma-associated herpesvirus (KSHV) manipulates the host cell oncogenic Notch signaling pathway for viral reactivation from latency and cell pathogenesis. KSHV reactivation requires that the viral protein Rta functionally interacts with RBP-Jk, the DNA binding component of the Notch pathway, and with promoter DNA to drive transcription of productive cycle genes. We show that the Notch pathway is constitutively active during KSHV reactivation and is essential for robust production of infectious virus progeny. Inhibiting Notch during reactivation reduces expression of specific viral genes yet does not affect growth of the host cells. Although Notch cannot reactivate KSHV alone, the requisite expression of Rta reveals a previously unappreciated role for Notch in reactivation. We propose that activated Notch cooperates with Rta in a promoter-specific manner that is partially programmed by Rta’s ability to redistribute RBP-Jk DNA binding to the virus during reactivation.

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Section: Discussionmentioning

confidence: 99%

Section: Notch1 Is Necessary For Optimal Viral Reactivationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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The cellular Notch1 Protein Promotes KSHV reactivation in an Rta-dependent manner

DeCotiis-Mauro

Han

Mello

et al. 2022

Preprint

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“…Importantly, the expression of IE gene ORF50 encoding the replication and transcription activator protein RTA is necessary and sufficient to induce the lytic cycle of KSHV both in latently infected cells and following de novo infection [ 138 , 139 ]. RTA can induce lytic genes by binding to their promoters and recruiting epigenetic factors such as CBP/p300, SWI/SNF, mediator, and histone demethylases that can alter the viral chromatin to favor viral gene expression ( Figure 2 ) [ 140 , 141 , 142 , 143 ]. Since RTA has an E3 ubiquitin ligase activity, it can also promote lytic gene expression by inducing the degradation of host proteins repressing KSHV gene transcription [ 144 , 145 , 146 ].…”

Section: Impact Of Host Epigenetic Machinery On the Viral Life Cyclementioning

confidence: 99%

Clinical Manifestations and Epigenetic Regulation of Oral Herpesvirus Infections

Atyeo

Rodriguez

Papp

et al. 2021

Viruses

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The oral cavity is often the first site where viruses interact with the human body. The oral epithelium is a major site of viral entry, replication and spread to other cell types, where chronic infection can be established. In addition, saliva has been shown as a primary route of person-to-person transmission for many viruses. From a clinical perspective, viral infection can lead to several oral manifestations, ranging from common intraoral lesions to tumors. Despite the clinical and biological relevance of initial oral infection, little is known about the mechanism of regulation of the viral life cycle in the oral cavity. Several viruses utilize host epigenetic machinery to promote their own life cycle. Importantly, viral hijacking of host chromatin-modifying enzymes can also lead to the dysregulation of host factors and in the case of oncogenic viruses may ultimately play a role in promoting tumorigenesis. Given the known roles of epigenetic regulation of viral infection, epigenetic-targeted antiviral therapy has been recently explored as a therapeutic option for chronic viral infection. In this review, we highlight three herpesviruses with known roles in oral infection, including herpes simplex virus type 1, Epstein–Barr virus and Kaposi’s sarcoma-associated herpesvirus. We focus on the respective oral clinical manifestations of these viruses and their epigenetic regulation, with a specific emphasis on the viral life cycle in the oral epithelium.

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“…KSHV will enter the lytic cycle when its RTA protein is expressed. RTA is an immediate-early viral protein that is a potent viral transcription factor, which can directly induce the expression of several cellular and viral genes [ 9 , 10 , 11 , 12 , 13 ]. RTA is necessary and sufficient for the latent-lytic switch of KSHV where all viral lytic genes are expressed in a temporal, cascade-like manner: immediate-early (IE), early (E), and late (L) [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Protein Degradation by Gammaherpesvirus RTAs: More Than Just Viral Transactivators

Combs

McKenna

et al. 2023

Viruses

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Kaposi’s sarcoma-associated herpesvirus (KSHV) is a member of the Gammaherpesvirus subfamily that encodes several viral proteins with intrinsic E3 ubiquitin ligase activity or the ability to hijack host E3 ubiquitin ligases to modulate the host’s immune response and to support the viral life cycle. This review focuses specifically on how the immediate-early KSHV protein RTA (replication and transcription activator) hijacks the host’s ubiquitin–proteasome pathway (UPP) to target cellular and viral factors for protein degradation to allow for robust lytic reactivation. Notably, RTA’s targets are either potent transcription repressors or they are activators of the innate and adaptive immune response, which block the lytic cycle of the virus. This review mainly focuses on what is currently known about the role of the E3 ubiquitin ligase activity of KSHV RTA in the regulation of the KSHV life cycle, but we will also discuss the potential role of other gammaherpesviral RTA homologs in UPP-mediated protein degradation.

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A herpesvirus transactivator and cellular POU proteins extensively regulate DNA binding of the host Notch signaling protein RBP-Jκ to the virus genome

Cited by 6 publications

References 83 publications

The cellular Notch1 Protein Promotes KSHV reactivation in an Rta-dependent manner

The cellular Notch1 Protein Promotes KSHV reactivation in an Rta-dependent manner

Clinical Manifestations and Epigenetic Regulation of Oral Herpesvirus Infections

Protein Degradation by Gammaherpesvirus RTAs: More Than Just Viral Transactivators

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