Fine-Tuning of the Kaposi’s Sarcoma-Associated Herpesvirus Life Cycle in Neighboring Cells through the RTA-JAG1-Notch Pathway

Li, Shasha; Hu, Hao; He, Zhiheng; Liang, Deguang; Sun, Rui; Lan, Ke

doi:10.1371/journal.ppat.1005900

Cited by 24 publications

(28 citation statements)

References 76 publications

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“…While we were able to demonstrate Tet-driven expression of the RTA lytic switch gene in vivo by monitoring RFP expression in xenografted iSLK.219 cells, this was relatively inefficient. It is possible that the density of cells in the yolk sac could limit lytic reactivation through RTA-dependent activation of the NOTCH1 pathway that suppresses lytic gene expression in neighbouring cells [30]. To our knowledge, this is the first demonstration that Tet-regulated promoters in xenotransplanted cells can respond to doxycycline in the fish water, which may be useful in other studies requiring post-XT stimulation of gene expression.…”

Section: Discussionmentioning

confidence: 84%

The Zebrafish Xenograft Platform—A Novel Tool for Modeling KSHV-Associated Diseases

Pringle

Wertman

Melong

et al. 2019

Viruses

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Kaposi’s sarcoma associated-herpesvirus (KSHV, also known as human herpesvirus-8) is a gammaherpesvirus that establishes life-long infection in human B lymphocytes. KSHV infection is typically asymptomatic, but immunosuppression can predispose KSHV-infected individuals to primary effusion lymphoma (PEL); a malignancy driven by aberrant proliferation of latently infected B lymphocytes, and supported by pro-inflammatory cytokines and angiogenic factors produced by cells that succumb to lytic viral replication. Here, we report the development of the first in vivo model for a virally induced lymphoma in zebrafish, whereby KSHV-infected PEL tumor cells engraft and proliferate in the yolk sac of zebrafish larvae. Using a PEL cell line engineered to produce the viral lytic switch protein RTA in the presence of doxycycline, we demonstrate drug-inducible reactivation from KSHV latency in vivo, which enabled real-time observation and evaluation of latent and lytic phases of KSHV infection. In addition, we developed a sensitive droplet digital PCR method to monitor latent and lytic viral gene expression and host cell gene expression in xenografts. The zebrafish yolk sac is not well vascularized, and by using fluorogenic assays, we confirmed that this site provides a hypoxic environment that may mimic the microenvironment of some human tumors. We found that PEL cell proliferation in xenografts was dependent on the host hypoxia-dependent translation initiation factor, eukaryotic initiation factor 4E2 (eIF4E2). This demonstrates that the zebrafish yolk sac is a functionally hypoxic environment, and xenografted cells must switch to dedicated hypoxic gene expression machinery to survive and proliferate. The establishment of the PEL xenograft model enables future studies that exploit the innate advantages of the zebrafish as a model for genetic and pharmacologic screens.

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Section: Discussionmentioning

confidence: 84%

The Zebrafish Xenograft Platform—A Novel Tool for Modeling KSHV-Associated Diseases

Pringle

Wertman

Melong

et al. 2019

Viruses

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“…Our previous study has indicated that, following internalization into PEL cells, HIV-1 soluble Vpr protein inhibits KSHV lytic replication by activating NF-B signaling (23). Other studies have shown that KSHV can hijack the Notch signaling pathway to maintain the viral life cycle and determine the fate of adjacent cells (27,31). To determine whether Notch signaling is involved in Vpr inhibition of KSHV lytic replication, we incubated BC3 and BCBL-1 cells with soluble Vpr for 24, 48, and 72 h. Western blotting indicated that Vpr inhibited the expression of Notch1 and Hey1 proteins as well as the KSHV lytic proteins, including replication and transcription activator (RTA) and ORF65 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It is generally accepted that the highly conserved Notch signaling plays a fundamental role during embryonic development that is associated with cell fate determination, immune regulation, and neural stem cell survival (40,41), while aberrant Notch signaling contributes to angiogenesis, maintenance of cancer stem cells, epithelial-tomesenchymal transition (EMT)-mediated metastasis, and resistance to therapeutic agents in cancers progression, including KSHV-associated malignancies (27,42). Multiple Notch pathway components, such as Notch ligand (Jagged1), receptors (Notch1, Notch2, and Notch4), and the direct targets (Hes1 and Hey1) (43), are highly expressed in KS tumor cells, while increased expression of ICN has been found in KSHV latently infected PEL cells (42), indicating a critical role of the Notch pathway in KSHV life cycle and pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, through RBP-J transactivation of the LANA promoter and antagonizing ICN function, the Notch pathway mediates a LANA-RTA feedback loop to balance viral latent and lytic replication at the early stages of KSHV infection (31,48). A recent study showed that RTA induced the expression of Jagged1 during reactivation, which activated Notch signaling in the neighboring cells and prevented viral lytic replication (27). However, in this study, we have found that Vpr inactivation of Notch signaling promotes KSHV persistent latency, which might occur in the complex microenvironment of HIV-1 and KSHV coinfections.…”

Section: Discussionmentioning

confidence: 99%

“…The Notch pathway functions as a mediator of viral replication and host cellular microenvironment (27)(28)(29)(30). In this study, we investigated the role of the Notch pathway in HIV-1 Vpr-controlled balance between KSHV lytic replication and latency.…”

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Upregulation of MicroRNA 711 Mediates HIV-1 Vpr Promotion of Kaposi's Sarcoma-Associated Herpesvirus Latency and Induction of Pro-proliferation and Pro-survival Cytokines by Targeting the Notch/NF-κB-Signaling Axis

Yan

Zhao

Shen

et al. 2018

J Virol

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Coinfection with HIV-1 and Kaposi's sarcoma-associated herpesvirus (KSHV) often leads to AIDS-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The interaction between HIV and KSHV plays a pivotal role in the progression of these malignancies. We have previously demonstrated that, by upregulating miR-942-5p, HIV-1 viral protein R (Vpr) inhibits KSHV lytic replication by targeting IκBα to activate the NF-κB signaling (Q. Yan, C. Shen, J. Qin, W. Li, M. Hu, H. Lu, D. Qin, J. Zhu, S. J. Gao, C. Lu, J Virol 90:8739-8753, 2016). Here, we show that Vpr inactivates Notch signaling, resulting in inhibition of KSHV lytic replication and induction of pro-proliferative and -survival cytokines, including interleukin-2 (IL-2), TIMP-1, IGF-1, and NT-4. Mechanistically, Vpr upregulates miR-711, which directly targets the Notch1 3' untranslated region. Suppression of miR-711 relieved Notch1 and reduced Vpr inhibition of KSHV lytic replication and Vpr induction of pro-proliferation and -survival cytokines, while overexpression of miR-711 exhibited the opposite effect. Finally, overexpression of Notch1 reduced Vpr induction of NF-κB activity by promoting IκBα promoter activity. Our novel findings reveal that by upregulating miR-711 to target Notch1, Vpr silences Notch signaling to activate the NF-κB pathway by reducing IκBα expression, leading to inhibition of KSHV lytic replication and induction of pro-proliferation and -survival cytokines. Therefore, the miR-711/Notch/NF-κB axis is important in the pathogenesis of AIDS-related malignancies and could be an attractive therapeutic target. HIV-1 infection significantly increases the risk of KS and PEL in KSHV-infected individuals. Our previous study has shown that HIV-1 Vpr regulates the KSHV life cycle by targeting IκBα to activate NF-κB signaling through upregulating cellular miR-942-5p. In this study, we have further found that Vpr inactivates Notch signaling to promote KSHV latency and production of pro-proliferation and -survival cytokines. Another Vpr-upregulated cellular microRNA, miR-711, participates in this process by directly targeting Notch1. As a result, Notch1 upregulation of the IκBα promoter activity is attenuated, resulting in reduced levels of IκBα transcript and protein. Overall, these results illustrate an alternative mechanism of HIV-1 Vpr regulation of KSHV latency and aberrant cytokines through the miR-711/Notch/NF-κB axis. Our novel findings further demonstrate the role of an HIV-1-secreted regulatory protein in the KSHV life cycle and KSHV-related malignancies.

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The role of endogenous retroviruses‐K in human cancer

Salavatiha

Soleimani‐Jelodar

Jalilvand

2020

Reviews in Medical Virology

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It is known that human endogenous retroviruses (HERVs) constitute almost 8% of the human genome. Although the expression of HERVs from the human genome is tightly regulated, different exogenous and endogenous factors could trigger HERV activation. Aberrant expression of different HERVs may potentially cause a variety of diseases such as neurological and autoimmune diseases as well as cancer. It is suggested that HERV-K can induce cancer through different mechanisms that are discussed. The interplay between some tumor viruses and HERV-K seems to be a key player in progression of viral-associated cancers because elevated levels of Rec and Np9 proteins are observed in several cancers. The frequent over expression of HERV proteins and some specific antibodies in cancer cells could be considered as suitable prognostic and therapeutic biomarkers in diagnosis and treatment of cancers. The expression of HERV proteins in cancers and development of immune responses against them may also be used as targets for cancer immunotherapy. Further studies are warranted to evaluate the role of HERVs in cancer formation and use of different HERV proteins in developing new diagnostic and therapeutic approaches for cancer treatments.

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Fine-Tuning of the Kaposi’s Sarcoma-Associated Herpesvirus Life Cycle in Neighboring Cells through the RTA-JAG1-Notch Pathway

Cited by 24 publications

References 76 publications

The Zebrafish Xenograft Platform—A Novel Tool for Modeling KSHV-Associated Diseases

The Zebrafish Xenograft Platform—A Novel Tool for Modeling KSHV-Associated Diseases

Upregulation of MicroRNA 711 Mediates HIV-1 Vpr Promotion of Kaposi's Sarcoma-Associated Herpesvirus Latency and Induction of Pro-proliferation and Pro-survival Cytokines by Targeting the Notch/NF-κB-Signaling Axis

The role of endogenous retroviruses‐K in human cancer

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