Intracellular Tat of Human Immunodeficiency Virus Type 1 Activates Lytic Cycle Replication of Kaposi's Sarcoma-Associated Herpesvirus: Role of JAK/STAT Signaling

Zeng, Yi; Zhang, Xunhai; Huang, Zan; Cheng, Lin; Yao, Shuang; Qin, Di; Chen, Xiuying; Qiao, Tiankui; Lv, Zhigang; Zhang, Ling; Liu, Chun

doi:10.1128/jvi.02024-06

Cited by 111 publications

(106 citation statements)

References 68 publications

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“…ORF45 has been shown to work synergistically with the HIV-1-encoded protein Tat to potently increase LTR transcription activity in an RSK-dependent manner (47,54). Conversely, Tat has been found to increase KSHV lytic gene expression and infectivity (55)(56)(57). Third, Chang and Ganem recently discovered a unique transcriptional program consisting of both latency and limited expression of lytic genes in KSHV-infected lymphatic endothelial cells (LECs) but not in the similarly infected blood endothelial cells (BECs) (58).…”

Section: Discussionmentioning

confidence: 99%

Activation of p90 Ribosomal S6 Kinases by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Optimal Production of Infectious Viruses

Kuang

et al. 2015

J Virol

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We have previously shown that ORF45, an immediate-early and tegument protein of Kaposi's sarcoma-associated herpesvirus (KSHV), causes sustained activation of p90 ribosomal S6 kinases (RSKs) and extracellular regulated kinase (ERK) (E. Kuang, Q. Tang, G. G. Maul, and F. Zhu, J Virol 82:1838 -1850, 2008, http://dx.doi.org/10.1128/JVI.02119-07). We now have identified the critical region of ORF45 that is involved in RSK interaction and activation. Alanine scanning mutagenesis of this region revealed that a single F66A point mutation abolished binding of ORF45 to RSK or ERK and, consequently, its ability to activate the kinases. We introduced the F66A mutation into BAC16 (a bacterial artificial chromosome clone containing the entire infectious KSHV genome), producing BAC16-45F66A. In parallel, we also repaired the mutation and obtained a revertant, BAC16-45A66F. The reconstitution of these mutants in iSLK cells demonstrated that the ORF45-F66A mutant failed to cause sustained ERK and RSK activation during lytic reactivation, resulting in dramatic differences in the phosphoproteomic profile between the wildtype virus-infected cells and the mutant virus-infected cells. ORF45 mutation or deletion also was accompanied by a noticeable decreased in viral gene expression during lytic reactivation. Consequently, the ORF45-F66A mutant produced significantly fewer infectious progeny virions than the wild type or the revertant. These results suggest a critical role for ORF45-mediated RSK activation in KSHV lytic replication. IMPORTANCEKSHV is the causative agent of three human malignancies. KSHV pathogenesis is intimately linked to its ability to modulate the host cell microenvironment and to facilitate efficient production of progeny viral particles. We previously described the mechanism by which the KSHV lytic protein ORF45 activates the cellular kinases ERK and RSK. We now have mapped the critical region of ORF45 responsible for binding and activation of ERK/RSK to a single residue, F66. We mutated this amino acid of ORF45 (F66A) and introduced the mutation into a newly developed bacterial artificial chromosome containing the KSHV genome (BAC16). This system has provided us with a useful tool to characterize the functions of ORF45-activated RSK upon KSHV lytic reactivation. We show that viral gene expression and virion production are significantly reduced by F66A mutation, indicating a critical role for ORF45-activated RSK during KSHV lytic replication. K aposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), the most common malignancy in HIV-infected individuals (1, 2). Besides KS, KSHV is associated with two lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman's disease (3, 4). KSHV belongs to the Gammaherpesvirinae subfamily in the Herpesviridae family and is closely related to rhesus rhadinovirus (RRV), herpesvirus saimiri (HVS), and murine gammaherpesvirus 68 (MHV-68) in the Rhadinovirus genus (␥2). Its closest relative in humans is Epstein-...

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Section: Discussionmentioning

confidence: 99%

Activation of p90 Ribosomal S6 Kinases by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Optimal Production of Infectious Viruses

Kuang

et al. 2015

J Virol

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“…As an HIV accessory protein that can be released from HIV-1-infected cells, Vpr might be involved in the regulation of KSHV latency as Tat and Nef do (21,26). The recombinant Vpr (soluble Vpr) was purified by affinity chromatography (Fig.…”

Section: Resultsmentioning

confidence: 99%

HIV-1 Vpr Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by Inducing MicroRNA miR-942-5p and Activating NF-κB Signaling

Yan

Shen

Qin

et al. 2016

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) infection is required for the development of several AIDS-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The high incidence of AIDS-KS has been ascribed to the interaction of KSHV and HIV-1. We have previously shown that HIV-1-secreted proteins Tat and Nef regulate the KSHV life cycle and synergize with KSHV oncogenes to promote angiogenesis and tumorigenesis. Here, we examined the regulation of KSHV latency by HIV-1 viral protein R (Vpr). We found that soluble Vpr inhibits the expression of KSHV lytic transcripts and proteins, as well as viral particle production by activating NF-B signaling following internalization into PEL cells. By analyzing the expression profiles of microRNAs combined with target search by bioinformatics and luciferase reporter analyses, we identi- Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the causative agent of Kaposi's sarcoma (KS). AIDS-associated Kaposi's sarcoma (AIDS-KS) remains a clinical challenge in sub-Saharan Africa and the United States, including a subset of AIDS patients receiving highly active antiretroviral therapy (HAART) (1-4). KSHV infection is also linked to two B-cell lymphoproliferative disorders associated with AIDS, including primary effusion lymphoma (PEL) and a subset of multicentric Castleman's disease (MCD) (5, 6).KSHV displays two distinct replication phases: a latent phase and a productive lytic phase. Following acute infection, KSHV in general establishes lifetime persistence in the infected individuals. During the latent phase, only a limited number of viral genes are expressed, which serve to maintain the persistence of the viral genome, restrict host immune responses, and enhance cell survival. KSHV latently infected cells can be reactivated into lytic replication by several intracellular or extracellular stimuli, such as hypoxia, oxidative stress, and certain cytokines (7-10). Activation of viral lytic replication results in the expression of viral lytic genes and the production of infectious virions (11). Both latent and lytic replication phases are crucial for the long-term persistence of KSHV in the host, and their gene products play critical roles in the pathogenesis of KSHV-associated disease.As is true of infection with other human oncogenic viruses, KSHV infection alone is not sufficient to cause KSHV-associated malignancy (1, 12). Previously, we and others demonstrated that other cofactors, such as human herpesvirus 6 (HHV-6), herpes simplex virus 1 (HSV-1), human immunodeficiency virus type 1

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“…Total protein was separated by denaturing 12% SDS-polyacrylamide gel electrophoresis. Western blot analysis was performed as described (20). The primary antibodies for Bcl-2 and ß-actin were purchased from Santa Cruz Biotechnology.…”

Section: Transient Transfection and Western Blot Analysismentioning

confidence: 99%

MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2

Chen

Zhu²,

Shi³

et al. 2010

Oncol Rep

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Abstract. Radiotherapy is widely used in cancer treatment and biological studies. Multiple mechanisms induced by radiation, especially changes of the expression profile of genes, lead to the disruption of cellular homeostasis. MicroRNAs (miRNAs) are important post-transcriptional gene regulators and play an important role in response to cellular stress. Here we investigated the profiles of miRNA expression following exposure to radiation and the possible role of miRNAs in the modulation of radiosensitivity in the glioblastoma multiform U87MG cell line. MiRNA expression profiles revealed a limited set of miRNAs with altered expression in U87MG cells in response to radiation treatment. MiR-181a, a member of miR-181 family, was one of the down-regulated miRNAs, whose expression was further validated by qRT-PCR. The target mRNAs of radiation-responsive miRNAs were predicted with a target prediction tool. Transiently overexpressed miR-181a significantly sensitized malignant glioma cells to radiation treatment concurrent with the downregulation of the protein Bcl-2 (B cell lymphoma/lewkmia-2). It indicates that miR-181a may modulate radiosensitivity by targeting Bcl-2 in human malignant glioma cells. These data suggest that radiation can affect miRNA expression, which regulates the cellular response, and miR-181a could be a target for enhancing the effect of radiation treatment on malignant glioma cells.

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Intracellular Tat of Human Immunodeficiency Virus Type 1 Activates Lytic Cycle Replication of Kaposi's Sarcoma-Associated Herpesvirus: Role of JAK/STAT Signaling

Cited by 111 publications

References 68 publications

Activation of p90 Ribosomal S6 Kinases by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Optimal Production of Infectious Viruses

Activation of p90 Ribosomal S6 Kinases by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Optimal Production of Infectious Viruses

HIV-1 Vpr Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by Inducing MicroRNA miR-942-5p and Activating NF-κB Signaling

MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2

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