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Han C, Niu D, Lan K. Rewriting Viral Fate: Epigenetic and Transcriptional Dynamics in KSHV Infection. Viruses 2024; 16:1870. [PMID: 39772181 PMCID: PMC11680275 DOI: 10.3390/v16121870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 11/27/2024] [Accepted: 11/28/2024] [Indexed: 01/11/2025] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV), a γ-herpesvirus, is predominantly associated with Kaposi's sarcoma (KS) as well as two lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). Like other herpesviruses, KSHV employs two distinct life cycles: latency and lytic replication. To establish a lifelong persistent infection, KSHV has evolved various strategies to manipulate the epigenetic machinery of the host. In latently infected cells, most viral genes are epigenetically silenced by components of cellular chromatin, DNA methylation and histone post-translational modifications. However, some specific latent genes are preserved and actively expressed to maintain the virus's latent state within the host cell. Latency is not a dead end, but the virus has the ability to reactivate. This reactivation is a complex process that involves the removal of repressive chromatin modifications and increased accessibility for both viral and cellular factors, allowing the activation of the full transcriptional program necessary for the subsequent lytic replication. This review will introduce the roles of epigenetic modifications in KSHV latent and lytic life cycles, including DNA methylation, histone methylation and acetylation modifications, chromatin remodeling, genome conformation, and non-coding RNA expression. Additionally, we will also review the transcriptional regulation of viral genes and host factors in KSHV infection. This review aims to enhance our understanding of the molecular mechanisms of epigenetic modifications and transcriptional regulation in the KSHV life cycle, providing insights for future research.
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Affiliation(s)
- Chunyan Han
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; (C.H.); (D.N.)
| | - Danping Niu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; (C.H.); (D.N.)
| | - Ke Lan
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; (C.H.); (D.N.)
- Department of Infectious Diseases, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430072, China
- Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430072, China
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2
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Diggins NL, Hancock MH. Viral miRNA regulation of host gene expression. Semin Cell Dev Biol 2023; 146:2-19. [PMID: 36463091 PMCID: PMC10101914 DOI: 10.1016/j.semcdb.2022.11.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/16/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022]
Abstract
Viruses have evolved a multitude of mechanisms to combat barriers to productive infection in the host cell. Virally-encoded miRNAs are one such means to regulate host gene expression in ways that benefit the virus lifecycle. miRNAs are small non-coding RNAs that regulate protein expression but do not trigger the adaptive immune response, making them powerful tools encoded by viruses to regulate cellular processes. Diverse viruses encode for miRNAs but little sequence homology exists between miRNAs of different viral species. Despite this, common cellular pathways are targeted for regulation, including apoptosis, immune evasion, cell growth and differentiation. Herein we will highlight the viruses that encode miRNAs and provide mechanistic insight into how viral miRNAs aid in lytic and latent infection by targeting common cellular processes. We also highlight how viral miRNAs can mimic host cell miRNAs as well as how viral miRNAs have evolved to regulate host miRNA expression. These studies dispel the myth that viral miRNAs are subtle regulators of gene expression, and highlight the critical importance of viral miRNAs to the virus lifecycle.
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Affiliation(s)
- Nicole L Diggins
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, OR, USA
| | - Meaghan H Hancock
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, OR, USA.
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3
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Gorbea C, Elhakiem A, Cazalla D. Shaping the host cell environment with viral noncoding RNAs. Semin Cell Dev Biol 2023; 146:20-30. [PMID: 36581481 PMCID: PMC10101873 DOI: 10.1016/j.semcdb.2022.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/24/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022]
Abstract
Just like the cells they infect viruses express different classes of noncoding RNAs (ncRNAs). Viral ncRNAs come in all shapes and forms, and they usually associate with cellular proteins that are important for their functions. Viral ncRNAs have diverse functions, but they all contribute to the viral control of the cellular environment. Viruses utilize ncRNAs to regulate viral replication, to decide whether they should remain latent or reactivate, to evade the host immune responses, or to promote cellular transformation. In this review we describe the diverse functions played by different classes of ncRNAs expressed by adenoviruses and herpesviruses, how they contribute to the viral infection, and how their study led to insights into RNA-based mechanisms at play in host cells.
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Affiliation(s)
- Carlos Gorbea
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Abdalla Elhakiem
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Demián Cazalla
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
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Ruivinho C, Gama-Carvalho M. Small non-coding RNAs encoded by RNA viruses: old controversies and new lessons from the COVID-19 pandemic. Front Genet 2023; 14:1216890. [PMID: 37415603 PMCID: PMC10322155 DOI: 10.3389/fgene.2023.1216890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 06/07/2023] [Indexed: 07/08/2023] Open
Abstract
The recurring outbreaks caused by emerging RNA viruses have fostered an increased interest in the research of the mechanisms that regulate viral life cycles and the pathological outcomes associated with infections. Although interactions at the protein level are well-studied, interactions mediated by RNA molecules are less explored. RNA viruses can encode small non-coding RNAs molecules (sncRNAs), including viral miRNAs (v-miRNAs), that play important roles in modulating host immune responses and viral replication by targeting viral or host transcripts. Starting from the analysis of public databases compiling the known repertoire of viral ncRNA molecules and the evolution of publications and research interests on this topic in the wake of the COVID-19 pandemic, we provide an updated view on the current knowledge on viral sncRNAs, with a focus on v-miRNAs encoded by RNA viruses, and their mechanisms of action. We also discuss the potential of these molecules as diagnostic and prognostic biomarkers for viral infections and the development of antiviral therapies targeting v-miRNAs. This review emphasizes the importance of continued research efforts to characterize sncRNAs encoded by RNA viruses, identifies the most relevant pitfalls in the study of these molecules, and highlights the paradigm changes that have occurred in the last few years regarding their biogenesis, prevalence and functional relevance in the context of host-pathogen interactions.
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miRNAs in Herpesvirus Infection: Powerful Regulators in Small Packages. Viruses 2023; 15:v15020429. [PMID: 36851643 PMCID: PMC9965283 DOI: 10.3390/v15020429] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/29/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023] Open
Abstract
microRNAs are a class of small, single-stranded, noncoding RNAs that regulate gene expression. They can be significantly dysregulated upon exposure to any infection, serving as important biomarkers and therapeutic targets. Numerous human DNA viruses, along with several herpesviruses, have been found to encode and express functional viral microRNAs known as vmiRNAs, which can play a vital role in host-pathogen interactions by controlling the viral life cycle and altering host biological pathways. Viruses have also adopted a variety of strategies to prevent being targeted by cellular miRNAs. Cellular miRNAs can act as anti- or proviral components, and their dysregulation occurs during a wide range of infections, including herpesvirus infection. This demonstrates the significance of miRNAs in host herpesvirus infection. The current state of knowledge regarding microRNAs and their role in the different stages of herpes virus infection are discussed in this review. It also delineates the therapeutic and biomarker potential of these microRNAs in future research directions.
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6
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Toyoda K, Matsuoka M. Functional and Pathogenic Roles of Retroviral Antisense Transcripts. Front Immunol 2022; 13:875211. [PMID: 35572593 PMCID: PMC9100821 DOI: 10.3389/fimmu.2022.875211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 04/06/2022] [Indexed: 11/13/2022] Open
Abstract
Exogenous retroviruses such as human immunodeficiency virus type 1 (HIV-1), human T-cell leukemia virus type 1 (HTLV-1) and bovine leukemia virus (BLV) can cause various diseases including immunodeficiency, inflammatory diseases and hematologic malignancies. These retroviruses persistently infect their hosts. Therefore, they need to evade host immune surveillance. One way in which these viruses might avoid immune detection is to utilize functional RNAs, rather than proteins, for certain activities, because RNAs are not recognized by the host immune system. HTLV-1 encodes the HTLV-1 bZIP factor (HBZ) gene in the antisense strand of the provirus. The HBZ protein is constantly expressed in HTLV-1 carriers and patients with adult T-cell leukemia-lymphoma, and it plays critical roles in pathogenesis. However, HBZ not only encodes this protein, but also functions as mRNA. Thus, HBZ gene mRNA is bifunctional. HIV-1 and BLV also encode long non-coding RNAs as antisense transcripts. In this review, we reshape our current understanding of how these antisense transcripts function and how they influence disease pathogenesis.
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Yu Z, Zhu J, Wang H, Li H, Jin X. Function of BCLAF1 in human disease. Oncol Lett 2022; 23:58. [PMID: 34992690 PMCID: PMC8721854 DOI: 10.3892/ol.2021.13176] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 09/22/2021] [Indexed: 02/06/2023] Open
Abstract
Originally identified as a regulator of apoptosis and transcription, B-cell lymphoma-2-associated transcription factor 1 (BCLAF1) has since been shown to be associated with a multitude of biological processes, such as DNA damage response, splicing and processing of pre-mRNA, T-cell activation, lung development, muscle cell proliferation and differentiation, autophagy, ischemia-reperfusion injury, and viral infection. In recent years, an increasing amount of evidence has shown that BCLAF1 acts as either a tumor promoter or tumor suppressor in tumorigenesis depending on the cellular context and the type of cancer. Even in the same tumor type, BCLAF1 may have opposite effects. In the present review, the subcellular localization, structural features, mutations within BCLAF1 will be described, then the regulation of BCLAF1 and its downstream targets will be analyzed. Furthermore, the different roles and possible mechanisms of BCLAF1 in tumorigenesis will also be highlighted and discussed. Finally, BCLAF1 may be considered as a potential target for cancer therapy in the future.
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Affiliation(s)
- Zongdong Yu
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center of LiHuiLi Hospital, Ningbo University, Ningbo, Zhejiang 315040, P.R. China.,Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Jie Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center of LiHuiLi Hospital, Ningbo University, Ningbo, Zhejiang 315040, P.R. China.,Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Haibiao Wang
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Hong Li
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center of LiHuiLi Hospital, Ningbo University, Ningbo, Zhejiang 315040, P.R. China.,Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Xiaofeng Jin
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center of LiHuiLi Hospital, Ningbo University, Ningbo, Zhejiang 315040, P.R. China.,Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, P.R. China
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8
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Zhang R, Xue T, Shao A, Lang Y, Qin C, Zhao M, Kuang Y, Yu Z, Geng Y, Zhao C, Tang J. Bclaf1 regulates c-FLIP expression and protects cells from TNF-induced apoptosis and tissue injury. EMBO Rep 2022; 23:e52702. [PMID: 34693625 PMCID: PMC8728627 DOI: 10.15252/embr.202152702] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 09/27/2021] [Accepted: 10/06/2021] [Indexed: 01/07/2023] Open
Abstract
TNF stimulation generates pro-survival signals through activation of NF-κB that restrict the build-in death signaling triggered by TNF. The competition between TNF-induced survival and death signals ultimately determines the fate of a cell. Here, we report the identification of Bclaf1 as a novel component of the anti-apoptotic program of TNF. Bclaf1 depletion in multiple cells sensitizes cells to TNF-induced apoptosis but not to necroptosis. Bclaf1 exerts its anti-apoptotic function by promoting the transcription of CFLAR, a caspase 8 antagonist, downstream of NF-κB activation. Bclaf1 binds to the p50 subunit of NF-κB, which is required for Bclaf1 to stimulate CFLAR transcription. Finally, in Bclaf1 siRNA administered mice, TNF-induced small intestine injury is much more severe than in control mice with aggravated signs of apoptosis and pyroptosis. These results suggest Bclaf1 is a key regulator in TNF-induced apoptosis, both in vitro and in vivo.
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Affiliation(s)
- Rui Zhang
- College of Veterinary MedicineChina Agricultural UniversityBeijingChina
| | - Teng Xue
- College of Veterinary MedicineChina Agricultural UniversityBeijingChina
| | - Anwen Shao
- College of Veterinary MedicineChina Agricultural UniversityBeijingChina
| | - Yue Lang
- College of Veterinary MedicineChina Agricultural UniversityBeijingChina
| | - Chao Qin
- College of Veterinary MedicineChina Agricultural UniversityBeijingChina
| | - Mingliang Zhao
- College of Veterinary MedicineChina Agricultural UniversityBeijingChina
| | - Yu Kuang
- College of Veterinary MedicineChina Agricultural UniversityBeijingChina
| | - Zhengquan Yu
- State Key Laboratories for Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health and, College of Biological SciencesChina Agricultural UniversityBeijingChina
| | - Yunyun Geng
- Hebei Key Laboratory of Chinese Medicine Research on Cardiocerebrovascular DiseaseHebei University of Chinese MedicineShijiazhuangHebeiChina
| | - Chenyang Zhao
- School of Medicine and PharmacyOcean University of ChinaQingdaoChina
| | - Jun Tang
- College of Veterinary MedicineChina Agricultural UniversityBeijingChina
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9
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Afshari A, Yaghobi R, Rezaei G. Inter-regulatory role of microRNAs in interaction between viruses and stem cells. World J Stem Cells 2021; 13:985-1004. [PMID: 34567421 PMCID: PMC8422934 DOI: 10.4252/wjsc.v13.i8.985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/11/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are well known for post-transcriptional regulatory ability over specific mRNA targets. miRNAs exhibit temporal or tissue-specific expression patterns and regulate the cell and tissue developmental pathways. They also have determinative roles in production and differentiation of multiple lineages of stem cells and might have therapeutic advantages. miRNAs are a part of some viruses' regulatory machinery, not a byproduct. The trace of miRNAs was detected in the genomes of viruses and regulation of cell reprograming and viral pathogenesis. Combination of inter-regulatory systems has been detected for miRNAs during viral infections in stem cells. Contraction between viruses and stem cells may be helpful in therapeutic tactics, pathogenesis, controlling viral infections and defining stem cell developmental strategies that is programmed by miRNAs as a tool. Therefore, in this review we intended to study the inter-regulatory role of miRNAs in the interaction between viruses and stem cells and tried to explain the advantages of miRNA regulatory potentials, which make a new landscape for future studies.
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Affiliation(s)
- Afsoon Afshari
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran
| | - Ramin Yaghobi
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran.
| | - Ghazal Rezaei
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran
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10
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Kook I, Ziegelbauer JM. Monocyte chemoattractant protein-induced protein 1 directly degrades viral miRNAs with a specific motif and inhibits KSHV infection. Nucleic Acids Res 2021; 49:4456-4471. [PMID: 33823555 DOI: 10.1093/nar/gkab215] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 03/11/2021] [Accepted: 04/02/2021] [Indexed: 12/13/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) expresses miRNAs during latency. However, regulation of viral miRNAs remains largely unknown. Our prior studies demonstrated that MCPIP1 regulates KSHV miRNA biogenesis by degrading most KSHV pre-miRNAs through its RNase activity. Some viral pre-miRNAs are partially resistant to degradation by MCPIP1. Here, we further characterized MCPIP1 substrate specificity and its antiviral potential against KSHV infection. In vitro cleavage assays and binding assays showed that MCPIP1 cleavage efficiency is related to binding affinity. Motif-based sequence analysis identified that KSHV pre-miRNAs that are well degraded by MCPIP1 have a 5-base motif (M5 base motif) within their terminal loops and this motif region consists of multiple pyrimidine-purine-pyrimidine (YRY) motifs. We further demonstrated that mutation of this M5 base motif within terminal loop of pre-miRNAs inhibited MCPIP1-mediated RNA degradation. We also revealed that MCPIP1 has an antiviral effect against KSHV infection. MCPIP1 can reduce the expression of Dicer, which in turn restricts KSHV infection. Conclusively, our findings demonstrated that MCPIP1 inhibited KSHV infection and suppressed viral miRNA biogenesis by directly degrading KSHV pre-miRNAs and altering the expression of miRNA biogenesis factors.
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Affiliation(s)
- Insun Kook
- HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Joseph M Ziegelbauer
- HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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11
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Bamunuarachchi G, Pushparaj S, Liu L. Interplay between host non-coding RNAs and influenza viruses. RNA Biol 2021; 18:767-784. [PMID: 33404285 PMCID: PMC8078518 DOI: 10.1080/15476286.2021.1872170] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/28/2020] [Accepted: 01/01/2021] [Indexed: 01/20/2023] Open
Abstract
Influenza virus infection through seasonal epidemics and occasional pandemics has been a major public health concern for decades. Incomplete protection from vaccination and increased antiviral resistance due to frequent mutations of influenza viruses have led to a continuous need for new therapeutic options. The functional significance of host protein and influenza virus interactions has been established, but relatively less is known about the interaction of host noncoding RNAs, including microRNAs and long noncoding RNAs, with influenza viruses. In this review, we summarize host noncoding RNA profiles during influenza virus infection and the regulation of influenza virus infection by host noncoding RNAs. Influenza viral non-coding RNAs are briefly discussed. Increased understanding of the molecular regulation of influenza viral replication will be beneficial in identifying potential therapeutic targets against the influenza virus.
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Affiliation(s)
- Gayan Bamunuarachchi
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, USA
- Department of Physiological Sciences, Oklahoma State University, Stillwater, USA
| | - Samuel Pushparaj
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, USA
- Department of Physiological Sciences, Oklahoma State University, Stillwater, USA
| | - Lin Liu
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA
- Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, USA
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12
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Choi YB, Cousins E, Nicholas J. Novel Functions and Virus-Host Interactions Implicated in Pathogenesis and Replication of Human Herpesvirus 8. Recent Results Cancer Res 2021; 217:245-301. [PMID: 33200369 DOI: 10.1007/978-3-030-57362-1_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Human herpesvirus 8 (HHV-8) is classified as a γ2-herpesvirus and is related to Epstein-Barr virus (EBV), a γ1-herpesvirus. One important aspect of the γ-herpesviruses is their association with neoplasia, either naturally or in animal model systems. HHV-8 is associated with B-cell-derived primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD), endothelial-derived Kaposi's sarcoma (KS), and KSHV inflammatory cytokine syndrome (KICS). EBV is also associated with a number of B-cell malignancies, such as Burkitt's lymphoma, Hodgkin's lymphoma, and posttransplant lymphoproliferative disease, in addition to epithelial nasopharyngeal and gastric carcinomas. Despite the similarities between these viruses and their associated malignancies, the particular protein functions and activities involved in key aspects of virus biology and neoplastic transformation appear to be quite distinct. Indeed, HHV-8 specifies a number of proteins for which counterparts had not previously been identified in EBV, other herpesviruses, or even viruses in general, and these proteins are believed to play vital functions in virus biology and to be involved centrally in viral pathogenesis. Additionally, a set of microRNAs encoded by HHV-8 appears to modulate the expression of multiple host proteins to provide conditions conductive to virus persistence within the host and possibly contributing to HHV-8-induced neoplasia. Here, we review the molecular biology underlying these novel virus-host interactions and their potential roles in both virus biology and virus-associated disease.
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Affiliation(s)
- Young Bong Choi
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USA.
| | - Emily Cousins
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USA
| | - John Nicholas
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USA
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13
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Liao Y, Zhuang G, Sun A, Khan OA, Lupiani B, Reddy SM. Marek's Disease Virus Cluster 3 miRNAs Restrict Virus' Early Cytolytic Replication and Pathogenesis. Viruses 2020; 12:v12111317. [PMID: 33212952 PMCID: PMC7698348 DOI: 10.3390/v12111317] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 12/21/2022] Open
Abstract
Herpesvirus-encoded microRNAs (miRNAs) have been discovered in infected cells; however, lack of a suitable animal model has hampered functional analyses of viral miRNAs in vivo. Marek’s disease virus (MDV) (Gallid alphaherpesvirus 2, GaHV-2) genome contains 14 miRNA precursors, which encode 26 mature miRNAs, grouped into three clusters. In this study, the role of MDV-encoded cluster 3 miRNAs, also known as mdv1-miR-M8-M10, in pathogenesis was evaluated in chickens, the natural host of MDV. Our results show that deletion of cluster 3 miRNAs did not affect virus replication and plaque size in cell culture, but increased early cytolytic replication of MDV in chickens. We also observed that deletion of cluster 3 miRNAs resulted in significantly higher virus reactivation from peripheral blood lymphocytes. In addition, pathogenesis studies showed that deletion of cluster 3 miRNAs resulted in more severe atrophy of lymphoid organs and reduced mean death time, but did not affect the incidence of MDV-associated visceral tumors. We confirmed these results by generating a cluster 3 miRNA revertant virus in which the parental MDV phenotype was restored. To the best of our knowledge, our study provides the first evidence that MDV cluster 3 miRNAs play an important role in modulating MDV pathogenesis.
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The Oncogenic Kaposi's Sarcoma-Associated Herpesvirus Encodes a Mimic of the Tumor-Suppressive miR-15/16 miRNA Family. Cell Rep 2020; 29:2961-2969.e6. [PMID: 31801064 PMCID: PMC6939447 DOI: 10.1016/j.celrep.2019.11.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 10/07/2019] [Accepted: 11/01/2019] [Indexed: 12/16/2022] Open
Abstract
Many tumor viruses encode oncogenes of cellular origin. Here, we report an oncoviral mimic of a cellular tumor suppressor. The Kaposi’s sarcoma-associated herpesvirus (KSHV) microRNA (miRNA) miR-K6-5p shares sequence similarity to the tumor-suppressive cellular miR-15/16 miRNA family. We show that miR-K6-5p inhibits cell cycle progression, a hallmark function of miR-16. miR-K6-5p regulates conserved miR-15/16 family miRNA targets, including many cell cycle regulators. Inhibition of miR-K6-5p in KSHV-transformed B cells confers a significant growth advantage. Altogether, our data show that KSHV encodes a functional mimic of miR-15/16 family miRNAs. While it is exceedingly well established that oncogenic viruses encode oncogenes of cellular origin, this is an unusual example of an oncogenic virus that encodes a viral mimic of a cellular tumor suppressor. Encoding a tumor-suppressive miRNA could help KSHV balance viral oncogene expression and thereby avoid severe pathogenesis in the healthy host. Morrison et al. report that the tumor virus KSHV encodes a mimic of a cellular tumor suppressor. KSHV miR-K6-5p phenocopies miR-16-induced cell cycle inhibition, shares mRNA targets and binding sites with miR-16, and negatively regulates proliferation in KSHV-infected cells.
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15
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Macveigh-Fierro D, Rodriguez W, Miles J, Muller M. Stealing the Show: KSHV Hijacks Host RNA Regulatory Pathways to Promote Infection. Viruses 2020; 12:E1024. [PMID: 32937781 PMCID: PMC7551087 DOI: 10.3390/v12091024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/09/2020] [Accepted: 09/11/2020] [Indexed: 12/20/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) induces life-long infections and has evolved many ways to exert extensive control over its host's transcriptional and post-transcriptional machinery to gain better access to resources and dampened immune sensing. The hallmark of this takeover is how KSHV reshapes RNA fate both to control expression of its own gene but also that of its host. From the nucleus to the cytoplasm, control of RNA expression, localization, and decay is a process that is carefully tuned by a multitude of factors and that can adapt or react to rapid changes in the environment. Intriguingly, it appears that KSHV has found ways to co-opt each of these pathways for its own benefit. Here we provide a comprehensive review of recent work in this area and in particular recent advances on the post-transcriptional modifications front. Overall, this review highlights the myriad of ways KSHV uses to control RNA fate and gathers novel insights gained from the past decade of research at the interface of RNA biology and the field of KSHV research.
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Affiliation(s)
| | | | | | - Mandy Muller
- Department of Microbiology, University of Massachusetts, Amherst, MA 01003, USA; (D.M.-F.); (W.R.); (J.M.)
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16
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Gallo A, Bulati M, Miceli V, Amodio N, Conaldi PG. Non-Coding RNAs: Strategy for Viruses' Offensive. Noncoding RNA 2020; 6:38. [PMID: 32927786 PMCID: PMC7549346 DOI: 10.3390/ncrna6030038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/01/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023] Open
Abstract
The awareness of viruses as a constant threat for human public health is a matter of fact and in this resides the need of understanding the mechanisms they use to trick the host. Viral non-coding RNAs are gaining much value and interest for the potential impact played in host gene regulation, acting as fine tuners of host cellular defense mechanisms. The implicit importance of v-ncRNAs resides first in the limited genomes size of viruses carrying only strictly necessary genomic sequences. The other crucial and appealing characteristic of v-ncRNAs is the non-immunogenicity, making them the perfect expedient to be used in the never-ending virus-host war. In this review, we wish to examine how DNA and RNA viruses have evolved a common strategy and which the crucial host pathways are targeted through v-ncRNAs in order to grant and facilitate their life cycle.
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Affiliation(s)
- Alessia Gallo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Via E.Tricomi 5, 90127 Palermo, Italy; (M.B.); (V.M.); (P.G.C.)
| | - Matteo Bulati
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Via E.Tricomi 5, 90127 Palermo, Italy; (M.B.); (V.M.); (P.G.C.)
| | - Vitale Miceli
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Via E.Tricomi 5, 90127 Palermo, Italy; (M.B.); (V.M.); (P.G.C.)
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy;
| | - Pier Giulio Conaldi
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Via E.Tricomi 5, 90127 Palermo, Italy; (M.B.); (V.M.); (P.G.C.)
- UPMC Italy (University of Pittsburgh Medical Center Italy), Discesa dei Giudici 4, 90133 Palermo, Italy
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17
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Daba TM, Zhao Y, Pan Z. Advancement of Mechanisms of Coxsackie Virus B3-Induced Myocarditis Pathogenesis and the Potential Therapeutic Targets. Curr Drug Targets 2020; 20:1461-1473. [PMID: 31215390 DOI: 10.2174/1389450120666190618124722] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/21/2019] [Accepted: 05/29/2019] [Indexed: 02/06/2023]
Abstract
Viral myocarditis is a cardiac disease caused by Group B Coxsackie virus of Enterovirus genus in the Picorna viridae family. It causes heart failure in children, young and adults. Ten Percent (10%) of acute heart failure and 12% of sudden deaths in young and adults who are less than 40 years is due to this viral myocarditis. If treatment action is not taken earlier, the viral disease can develop into chronic myocarditis and Dilated Cardiomyopathy which lead to congestive heart failure. And these eventually result in a reduced cardiac function which finally brings the victim to death. The only treatment option of the disease is heart transplantation once the acute stage of disease develops to chronic and Dilated Cardiomyopathy. Currently, there is a limitation in daily clinical treatments and even some available treatment options are ineffective. Therefore, focusing on search for treatment options through investigation is imperative. Recent studies have reported that biological molecules show a promising role. But their mechanism of pathogenesis is still unclear. A detailed study on identifying the role of biological molecules involved in Coxsackie B3 virus induced myocarditis and their mechanisms of pathogenesis; compiling and disseminating the findings of the investigation to the scientific communities contribute one step forward to the solution. Therefore, this review is aimed at compiling information from findings of current studies on the potential therapeutic role of micro RNA, cytokines and chemokines on the mechanism of pathogenesis of Coxsackie virus B3- induced myocarditis to give brief information for scholars to conduct a detailed study in the area.
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Affiliation(s)
- Tolessa Muleta Daba
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China.,Department of Biology, College of Natural and Computational Sciences, Bule Hora University, Bule Hora, Ethiopia
| | - Yue Zhao
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Zhenwei Pan
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China
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18
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Campbell M, Yang WS, Yeh WW, Kao CH, Chang PC. Epigenetic Regulation of Kaposi's Sarcoma-Associated Herpesvirus Latency. Front Microbiol 2020; 11:850. [PMID: 32508765 PMCID: PMC7248258 DOI: 10.3389/fmicb.2020.00850] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 04/08/2020] [Indexed: 12/17/2022] Open
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic γ-herpesvirus that infects humans and exhibits a biphasic life cycle consisting of latent and lytic phases. Following entry into host cells, the KSHV genome undergoes circularization and chromatinization into an extrachromosomal episome ultimately leading to the establishment of latency. The KSHV episome is organized into distinct chromatin domains marked by variations in repressive or activating epigenetic modifications, including DNA methylation, histone methylation, and histone acetylation. Thus, the development of KSHV latency is believed to be governed by epigenetic regulation. In the past decade, interrogation of the KSHV epitome by genome-wide approaches has revealed a complex epigenetic mark landscape across KSHV genome and has uncovered the important regulatory roles of epigenetic modifications in governing the development of KSHV latency. Here, we highlight many of the findings regarding the role of DNA methylation, histone modification, post-translational modification (PTM) of chromatin remodeling proteins, the contribution of long non-coding RNAs (lncRNAs) in regulating KSHV latency development, and the role of higher-order episomal chromatin architecture in the maintenance of latency and the latent-to-lytic switch.
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Affiliation(s)
- Mel Campbell
- UC Davis Cancer Center, University of California, Davis, Davis, CA, United States
| | - Wan-Shan Yang
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Wayne W Yeh
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Chen-Hsuan Kao
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Pei-Ching Chang
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
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19
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Bclaf1 is a direct target of HIF-1 and critically regulates the stability of HIF-1α under hypoxia. Oncogene 2020; 39:2807-2818. [PMID: 32029898 DOI: 10.1038/s41388-020-1185-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 12/10/2019] [Accepted: 01/23/2020] [Indexed: 01/04/2023]
Abstract
Hypoxic stress is intimately connected with tumor progression, with hypoxia-inducible factor-1α (HIF-1α) being a critical regulator in this process. HIF-1α is stabilized in response to hypoxia, which is required for the induction of gene transcriptions important for hypoxic adaptation. Bclaf1 is a multifunctional protein involved in tumorigenesis, however, its role in this process is not well characterized. Here we report Bclaf1 is a direct transcriptional target of HIF-1 and upregulated in multiple cell lines during hypoxia. Importantly, we found Bclaf1 is involved in the stabilization of HIF-1α during long-term hypoxic treatments. Compared with the control cells, the protein level and stability of HIF-1α in Bclaf1 knockdown or knockout cells is greatly compromised after long-term hypoxic treatments, concomitant with the impaired inductions of HIF-1 target gene transcription. Bclaf1 knockout HeLa cells exhibit a reduced tumor growth in mice xenografts, in which the expressions of HIF-1α and its target genes are also decreased. Bclaf1 binds to HIF-1α in the nucleus, and this interaction is required for Bclaf1 to stabilize HIF-1α in hypoxic condition. These results uncover a positive feedback loop, HIF-1-Bclaf1, that sustains HIF-1 activity during long-term hypoxic conditions by binding to and protecting HIF-1α from degradation, and suggest that Bclaf1 may promote tumor progression by enhancing HIF-1α stability.
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20
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Mishra R, Kumar A, Ingle H, Kumar H. The Interplay Between Viral-Derived miRNAs and Host Immunity During Infection. Front Immunol 2020; 10:3079. [PMID: 32038626 PMCID: PMC6989438 DOI: 10.3389/fimmu.2019.03079] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 12/17/2019] [Indexed: 01/01/2023] Open
Abstract
MicroRNAs are short non-coding RNAs that play a crucial role in the regulation of gene expression during cellular processes. The host-encoded miRNAs are known to modulate the antiviral defense during viral infection. In the last decade, multiple DNA and RNA viruses have been shown to produce miRNAs known as viral miRNAs (v-miRNAs) so as to evade the host immune response. In this review, we highlight the origin and biogenesis of viral miRNAs during the viral lifecycle. We also explore the role of viral miRNAs in immune evasion and hence in maintaining chronic infection and disease. Finally, we offer insights into the underexplored role of viral miRNAs as potential targets for developing therapeutics for treating complex viral diseases.
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Affiliation(s)
- Richa Mishra
- Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India
| | - Ashish Kumar
- Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA, United States
| | - Harshad Ingle
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States
| | - Himanshu Kumar
- Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India
- Laboratory of Host Defense, WPI Immunology, Frontier Research Centre, Osaka University, Osaka, Japan
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21
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Fani M, Zandi M, Rezayi M, Khodadad N, Langari H, Amiri I. The Role of microRNAs in the Viral Infections. Curr Pharm Des 2019; 24:4659-4667. [PMID: 30636585 DOI: 10.2174/1381612825666190110161034] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/24/2018] [Accepted: 12/31/2018] [Indexed: 12/15/2022]
Abstract
MicroRNAs (miRNAs) are non-coding RNAs with 19 to 24 nucleotides which are evolutionally conserved. MicroRNAs play a regulatory role in many cellular functions such as immune mechanisms, apoptosis, and tumorigenesis. The main function of miRNAs is the post-transcriptional regulation of gene expression via mRNA degradation or inhibition of translation. In fact, many of them act as an oncogene or tumor suppressor. These molecular structures participate in many physiological and pathological processes of the cell. The virus can also produce them for developing its pathogenic processes. It was initially thought that viruses without nuclear replication cycle such as Poxviridae and RNA viruses can not code miRNA, but recently, it has been proven that RNA viruses can also produce miRNA. The aim of this articles is to describe viral miRNAs biogenesis and their effects on cellular and viral genes.
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Affiliation(s)
- Mona Fani
- Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Milad Zandi
- Department of Virology, School of Public Health, Tehran University of Medical Science, Tehran, Iran
| | - Majid Rezayi
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nastaran Khodadad
- Virology Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hadis Langari
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iraj Amiri
- Computational Optics Research Group, Advanced Institute of Materials Science, Ton Duc Thang University, Ho Chi Minh City, Vietnam.,Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
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22
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Sethuraman S, Thomas M, Gay LA, Renne R. Computational analysis of ribonomics datasets identifies long non-coding RNA targets of γ-herpesviral miRNAs. Nucleic Acids Res 2019; 46:8574-8589. [PMID: 29846699 PMCID: PMC6144796 DOI: 10.1093/nar/gky459] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 05/14/2018] [Indexed: 12/16/2022] Open
Abstract
Ribonomics experiments involving crosslinking and immuno-precipitation (CLIP) of Ago proteins have expanded the understanding of the miRNA targetome of several organisms. These techniques, collectively referred to as CLIP-seq, have been applied to identifying the mRNA targets of miRNAs expressed by Kaposi’s Sarcoma-associated herpes virus (KSHV) and Epstein–Barr virus (EBV). However, these studies focused on identifying only those RNA targets of KSHV and EBV miRNAs that are known to encode proteins. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are also targeted by miRNAs. In this study, we performed a systematic re-analysis of published datasets from KSHV- and EBV-driven cancers. We used CLIP-seq data from lymphoma cells or EBV-transformed B cells, and a crosslinking, ligation and sequencing of hybrids dataset from KSHV-infected endothelial cells, to identify novel lncRNA targets of viral miRNAs. Here, we catalog the lncRNA targetome of KSHV and EBV miRNAs, and provide a detailed in silico analysis of lncRNA–miRNA binding interactions. Viral miRNAs target several hundred lncRNAs, including a subset previously shown to be aberrantly expressed in human malignancies. In addition, we identified thousands of lncRNAs to be putative targets of human miRNAs, suggesting that miRNA–lncRNA interactions broadly contribute to the regulation of gene expression.
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Affiliation(s)
- Sunantha Sethuraman
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA
| | - Merin Thomas
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA
| | - Lauren A Gay
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA
| | - Rolf Renne
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.,UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA.,UF Genetics Institute, University of Florida, Gainesville, FL 32610, USA
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23
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Yan L, Majerciak V, Zheng ZM, Lan K. Towards Better Understanding of KSHV Life Cycle: from Transcription and Posttranscriptional Regulations to Pathogenesis. Virol Sin 2019; 34:135-161. [PMID: 31025296 PMCID: PMC6513836 DOI: 10.1007/s12250-019-00114-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 03/14/2019] [Indexed: 02/08/2023] Open
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), is etiologically linked to the development of Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. These malignancies often occur in immunosuppressed individuals, making KSHV infection-associated diseases an increasing global health concern with persistence of the AIDS epidemic. KSHV exhibits biphasic life cycles between latent and lytic infection and extensive transcriptional and posttranscriptional regulation of gene expression. As a member of the herpesvirus family, KSHV has evolved many strategies to evade the host immune response, which help the virus establish a successful lifelong infection. In this review, we summarize the current research status on the biology of latent and lytic viral infection, the regulation of viral life cycles and the related pathogenesis.
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Affiliation(s)
- Lijun Yan
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Vladimir Majerciak
- National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA
| | - Zhi-Ming Zheng
- National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
| | - Ke Lan
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
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24
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Zhou X, Wen Y, Tian Y, He M, Ke X, Huang Z, He Y, Liu L, Scharf A, Lu M, Zhang G, Deng Y, Yan Y, Mayer MP, Chen X, Zou F. Heat Shock Protein 90α-Dependent B-Cell-2-Associated Transcription Factor 1 Promotes Hepatocellular Carcinoma Proliferation by Regulating MYC Proto-Oncogene c-MYC mRNA Stability. Hepatology 2019; 69:1564-1581. [PMID: 30015413 PMCID: PMC6586158 DOI: 10.1002/hep.30172] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/20/2018] [Indexed: 12/14/2022]
Abstract
B-cell lymphoma 2 (Bcl-2)-associated transcription factor 1 (Bclaf1) is known to be involved in diverse biological processes, but, to date, there has been no evidence for any functional role of Bclaf1 in hepatocellular carcinoma (HCC) progression. Here, we demonstrate that Bclaf1 is frequently up-regulated in HCC and that Bclaf1 up-regulation is associated with Edmondson grade, lower overall survival rates, and poor prognosis. Overexpression of Bclaf1 in HCC cell lines HepG2 and Huh7 promoted proliferation considerably, whereas Bclaf1 knockdown had the opposite effect. Xenograft tumors grown from Bclaf1 knockdown Huh7 cells had smaller tumor volumes than tumors grown from control cells. Furthermore, our study describes MYC proto-oncogene (c-Myc) as a downstream target of Bclaf1, given that Bclaf1 regulates c-MYC expression posttranscriptionally by its RS domain. To exert this function, Bclaf1 must interact with the molecular chaperone, heat shock protein 90 alpha (Hsp90α). In HCC tissue samples, Hsp90α levels were also increased significantly and Hsp90α-Bclaf1 interaction was enhanced. Bclaf1 interacts with the C-terminal domain of Hsp90α, and this interaction is disrupted by the C-terminal domain inhibitor, novobiocin (NB), resulting in proteasome-dependent degradation of Bclaf1. Moreover, NB-induced disruption of Hsp90α-Bclaf1 interaction dampened the production of mature c-MYC mRNA and attenuated tumor cell growth in vitro and in vivo. Conclusion: Our findings suggest that Bclaf1 affects HCC progression by manipulating c-MYC mRNA stability and that the Hsp90α/Bclaf1/c-Myc axis might be a potential target for therapeutic intervention in HCC.
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Affiliation(s)
- Xueqiong Zhou
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Ying Wen
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Ye Tian
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Meiling He
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Xiangyu Ke
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Zhizhou Huang
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Yangfan He
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Lixia Liu
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Annette Scharf
- Center for Molecular Biology of Heidelberg University (ZMBH)DKFZ‐ZMBH‐AllianceHeidelbergGermany
| | - Meiting Lu
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Guowei Zhang
- Department of Hepatobiliary SurgeryNanfang Hospital, Southern Medical UniversityGuangzhouChina
| | - Yaotang Deng
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Yuxia Yan
- Department of Biostatistics, School of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Matthias P. Mayer
- Center for Molecular Biology of Heidelberg University (ZMBH)DKFZ‐ZMBH‐AllianceHeidelbergGermany
| | - Xuemei Chen
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina,Center for Molecular Biology of Heidelberg University (ZMBH)DKFZ‐ZMBH‐AllianceHeidelbergGermany
| | - Fei Zou
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
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25
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Qin C, Zhang R, Lang Y, Shao A, Xu A, Feng W, Han J, Wang M, He W, Yu C, Tang J. Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3. PLoS Pathog 2019; 15:e1007559. [PMID: 30682178 PMCID: PMC6364948 DOI: 10.1371/journal.ppat.1007559] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 02/06/2019] [Accepted: 01/03/2019] [Indexed: 01/12/2023] Open
Abstract
Type I interferon response plays a prominent role against viral infection, which is frequently disrupted by viruses. Here, we report Bcl-2 associated transcription factor 1 (Bclaf1) is degraded during the alphaherpesvirus Pseudorabies virus (PRV) and Herpes simplex virus type 1 (HSV-1) infections through the viral protein US3. We further reveal that Bclaf1 functions critically in type I interferon signaling. Knockdown or knockout of Bclaf1 in cells significantly impairs interferon-α (IFNα) -mediated gene transcription and viral inhibition against US3 deficient PRV and HSV-1. Mechanistically, Bclaf1 maintains a mechanism allowing STAT1 and STAT2 to be efficiently phosphorylated in response to IFNα, and more importantly, facilitates IFN-stimulated gene factor 3 (ISGF3) binding with IFN-stimulated response elements (ISRE) for efficient gene transcription by directly interacting with ISRE and STAT2. Our studies establish the importance of Bclaf1 in IFNα-induced antiviral immunity and in the control of viral infections.
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Affiliation(s)
- Chao Qin
- State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Rui Zhang
- State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yue Lang
- State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Anwen Shao
- Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Aotian Xu
- State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Wenhai Feng
- Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Jun Han
- State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Mengdong Wang
- State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Wanwei He
- State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Cuilian Yu
- State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Jun Tang
- State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, China
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26
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Katano H. Expression and Function of Kaposi’s Sarcoma-Associated Herpesvirus Non-coding RNAs. CURRENT CLINICAL MICROBIOLOGY REPORTS 2018. [DOI: 10.1007/s40588-018-0101-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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27
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Pathological Features of Kaposi's Sarcoma-Associated Herpesvirus Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1045:357-376. [PMID: 29896675 DOI: 10.1007/978-981-10-7230-7_16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus 8, or HHV-8) was firstly discovered in Kaposi's sarcoma tissue derived from patients with acquired immune deficiency syndrome. KSHV infection is associated with malignancies and certain inflammatory conditions. In addition to Kaposi's sarcoma, KSHV has been detected in primary effusion lymphoma, KSHV-associated lymphoma, and some cases of multicentric Castleman disease (MCD). Recently, KSHV inflammatory cytokine syndrome (KICS) was also defined as a KSHV-associated disease. In KSHV-associated malignancies, such as Kaposi's sarcoma and lymphoma, KSHV latently infects almost all tumor cells, and lytic proteins are rarely expressed. A high titer of KSHV is detected in the sera of patients with MCD and KICS, and the expression of lytic proteins such as ORF50, vIL-6, and vMIP-I and vMIP-II is frequently observed in the lesions of patients with these diseases. Immunohistochemistry of LANA-1 is an important diagnostic tool for KSHV infection. However, much of the pathogenesis of KSHV remains to be elucidated, especially regarding oncogenesis. Some viral proteins have been shown to have transforming activity in mammalian cells; however, these proteins are not expressed in latently KSHV-infected cells. KSHV encodes homologs of cellular proteins in its genome such as cyclin D, G-protein coupled protein, interleukin-6, and macrophage inflammatory protein-1 and -2. Molecular mimicry by these viral proteins may contribute to the establishment of microenvironments suitable for tumor growth. In this review, the virus pathogenesis is discussed based on pathological and experimental findings and clinical aspects.
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Li X, He Z, Cheng B, Fang Q, Ma D, Lu T, Wei D, Kuang X, Tang S, Xiong J, Wang J. Effect of BCLAF1 on HDAC inhibitor LMK-235-mediated apoptosis of diffuse large B cell lymphoma cells and its mechanism. Cancer Biol Ther 2018; 19:825-834. [PMID: 29969367 DOI: 10.1080/15384047.2018.1472188] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common type of adult lymphoma. It is a group of malignant tumors with a large number of clinical manifestations and prognoses. Therefore, it is necessary to explore its unknown potential therapeutic targets. Histone deacetylase inhibitor (HDACi) is a novel drug for the treatment of DLBCL, however pan-HDACis cannot be ignored because of their clinical efficacy. By contrast, specific HDACi is well-tolerated, and LMK-235 is a novel HDACi that is a specific inhibitor of HDAC4 and HDAC5. In this study, we investigated the up-regulation of BCLAF1 through NF-κB signaling pathways in LMK-235, mediating the apoptosis of two diffuse large B-cell lymphoma cell lines, OCI-LY10 and OCI-LY3. Further studies showed that BCLAF1 expression was increased in DLBCL cells after treatment with the NF-κB inhibitor Bay11-7082. The combination of Bay11-7082 and siRNA si-HDAC4 significantly increased BCLAF1 expression and further increased apoptosis. These results indicate that BCLAF1 plays an important role in LMK-235-mediated apoptosis and may be a potential target for the treatment of diffuse large B-cell lymphoma.
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Affiliation(s)
- Xinyao Li
- a Guizhou Medical University , Guiyang , Guizhou , China.,d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.,e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China
| | - Zhengchang He
- a Guizhou Medical University , Guiyang , Guizhou , China.,d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.,e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China
| | - Bingqing Cheng
- b Department of Pharmacy , Guizhou Medical University , Guiyang , Guizhou , China.,d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.,e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China
| | - Qin Fang
- b Department of Pharmacy , Guizhou Medical University , Guiyang , Guizhou , China.,c Department of Pharmacy , Affiliated BaiYun Hospital of Guizhou Medical University , Guiyang , Guizhou , China
| | - Dan Ma
- a Guizhou Medical University , Guiyang , Guizhou , China.,d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.,e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China
| | - Tingting Lu
- a Guizhou Medical University , Guiyang , Guizhou , China.,d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.,e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China
| | - Danna Wei
- a Guizhou Medical University , Guiyang , Guizhou , China.,d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.,e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China
| | - Xingyi Kuang
- a Guizhou Medical University , Guiyang , Guizhou , China.,d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.,e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China
| | - Sishi Tang
- a Guizhou Medical University , Guiyang , Guizhou , China.,d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.,e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China
| | - Jie Xiong
- a Guizhou Medical University , Guiyang , Guizhou , China.,d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.,e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China
| | - Jishi Wang
- a Guizhou Medical University , Guiyang , Guizhou , China.,d Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center , Guiyang , Guizhou , China.,e Department of Hematology , Affiliated Hospital of Guizhou Medical University , Guiyang , Guizhou , China
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Modified Cross-Linking, Ligation, and Sequencing of Hybrids (qCLASH) Identifies Kaposi's Sarcoma-Associated Herpesvirus MicroRNA Targets in Endothelial Cells. J Virol 2018; 92:JVI.02138-17. [PMID: 29386283 DOI: 10.1128/jvi.02138-17] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 01/24/2018] [Indexed: 12/12/2022] Open
Abstract
Kaposi's sarcoma (KS) tumors are derived from endothelial cells and express Kaposi's sarcoma-associated herpesvirus (KSHV) microRNAs (miRNAs). Although miRNA targets have been identified in B cell lymphoma-derived cells and epithelial cells, little has been done to characterize the KSHV miRNA targetome in endothelial cells. A recent innovation in the identification of miRNA targetomes, cross-linking, ligation, and sequencing of hybrids (CLASH), unambiguously identifies miRNAs and their targets by ligating the two species while both species are still bound within the RNA-induced silencing complex (RISC). We developed a streamlined quick CLASH (qCLASH) protocol that requires a lower cell input than the original method and therefore has the potential to be used on patient biopsy samples. Additionally, we developed a fast-growing, KSHV-negative endothelial cell line derived from telomerase-immortalized vein endothelial long-term culture (TIVE-LTC) cells. qCLASH was performed on uninfected cells and cells infected with either wild-type KSHV or a mutant virus lacking miR-K12-11/11*. More than 1,400 cellular targets of KSHV miRNAs were identified. Many of the targets identified by qCLASH lacked a canonical seed sequence match. Additionally, most target regions in mRNAs originated from the coding DNA sequence (CDS) rather than the 3' untranslated region (UTR). This set of genes includes some that were previously identified in B cells and some new genes that warrant further study. Pathway analysis of endothelial cell targets showed enrichment in cell cycle control, apoptosis, and glycolysis pathways, among others. Characterization of these new targets and the functional consequences of their repression will be important in furthering our understanding of the role of KSHV miRNAs in oncogenesis.IMPORTANCE KS lesions consist of endothelial cells latently infected with KSHV. Cells that make up these lesions express KSHV miRNAs. Identification of the targets of KSHV miRNAs will help us understand their role in viral oncogenesis. The cross-linking and sequencing of hybrids (CLASH) protocol is a method for unambiguously identifying miRNA targetomes. We developed a streamlined version of CLASH, called quick CLASH (qCLASH). qCLASH requires a lower initial input of cells than for its parent protocol. Additionally, a new fast-growing KSHV-negative endothelial cell line, named TIVE-EX-LTC cells, was established. qCLASH was performed on TIVE-EX-LTC cells latently infected with wild-type (WT) KSHV or a mutant virus lacking miR-K12-11/11*. A number of novel targets of KSHV miRNAs were identified, including targets of miR-K12-11, the ortholog of the cellular oncogenic miRNA (oncomiR) miR-155. Many of the miRNA targets were involved in processes related to oncogenesis, such as glycolysis, apoptosis, and cell cycle control.
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Liu X, Wei H, Liao S, Ye J, Zhu L, Xu Z. MicroRNA transcriptome analysis of porcine vital organ responses to immunosuppressive porcine cytomegalovirus infection. Virol J 2018; 15:16. [PMID: 29347945 PMCID: PMC5774105 DOI: 10.1186/s12985-018-0922-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 01/03/2018] [Indexed: 02/07/2023] Open
Abstract
Background Porcine cytomegalovirus (PCMV) is an immunosuppressive virus that mainly inhibits T-lymphocyte and macrophage immune functions; it has significantly damaged the farming industry. Although recent studies have shown that miRNAs play important roles in immune responses, the regulatory mechanisms of miRNAs during immunosuppressive virus infection remain unclear. Methods In this study, porcine small-RNA transcriptomes of PCMV-infected and uninfected vital organs were first characterised by high-throughput sequencing. miRDeep2 software was used to predict novel pig-encoded miRNAs. To verify the accuracy of the high-throughput sequencing results, stem-loop qRT-PCR was performed on 12 significantly DE miRNAs. The physical and functional interactions between the immune-related target genes of the DE miRNAs in PCMV-infected organs were analysed using the STRING database. Results In total, 306 annotated and 295 novel miRNAs were identified from PCMV-infected and uninfected porcine organs, respectively, through alignment with known Sus scrofa pre-miRNAs. Overall, 92, 107, 95, 77 and 111 miRNAs were significantly differentially expressed in lung, liver, spleen, kidney and thymus after PCMV infection, respectively. According to Gene Ontology enrichment analysis, target genes of the differentially expressed miRNAs associated with immune system processes, regulation of biological processes and metabolic processes were enriched in every sample. Integrated expression analysis of the differentially expressed miRNAs and their target mRNAs in PCMV-infected thymus showed that the significant differential expression of specific miRNAs under the pressure of PCMV infection in central immune organs interfered with the expression of genes involved in important immune-related signalling pathways, thus promoting the viral infection. Conclusions This is the first comprehensive analysis of the responses of host small-RNA transcriptomes to PCMV infection in vital porcine organs. It provides new insights into the regulatory mechanisms of miRNAs during infection by immunosuppressive viruses. Electronic supplementary material The online version of this article (10.1186/s12985-018-0922-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiao Liu
- Southwest University, College of Animal Science and technology, Chongqing, 400715, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province and Animal Biotechnology Center, College of Veterinary Medicine of Sichuan Agricultural University, 211#Huimin Road, Wenjiang District, Chengdu, Sichuan Province, 610000, China
| | - Haoche Wei
- College of Life Sciences, Sichuan University, Chengdu, 610000, China
| | - Shan Liao
- Southwest University, College of Animal Science and technology, Chongqing, 400715, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province and Animal Biotechnology Center, College of Veterinary Medicine of Sichuan Agricultural University, 211#Huimin Road, Wenjiang District, Chengdu, Sichuan Province, 610000, China
| | - Jianheng Ye
- Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China
| | - Ling Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province and Animal Biotechnology Center, College of Veterinary Medicine of Sichuan Agricultural University, 211#Huimin Road, Wenjiang District, Chengdu, Sichuan Province, 610000, China
| | - Zhiwen Xu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province and Animal Biotechnology Center, College of Veterinary Medicine of Sichuan Agricultural University, 211#Huimin Road, Wenjiang District, Chengdu, Sichuan Province, 610000, China.
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31
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Dai L, Bai L, Lin Z, Qiao J, Yang L, Flemington EK, Zabaleta J, Qin Z. Transcriptomic analysis of KSHV-infected primary oral fibroblasts: The role of interferon-induced genes in the latency of oncogenic virus. Oncotarget 2018; 7:47052-47060. [PMID: 27363016 PMCID: PMC5216923 DOI: 10.18632/oncotarget.9720] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Accepted: 05/20/2016] [Indexed: 11/25/2022] Open
Abstract
The Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), the most common HIV/AIDS-associated tumor worldwide. Involvement of the oral cavity portends a poor prognosis for patients with KS, but the mechanisms for KSHV regulation of the oral tumor microenvironment are largely unknown. Infiltrating fibroblasts are found within KS lesions, and KSHV can establish latent infection within human primary fibroblasts in vitro and in vivo, but contributions for KSHV-infected fibroblasts to the KS microenvironment have not been previously characterized. In the present study, we used Illumina microarray to determine global gene expression changes in KSHV-infected primary human oral fibroblasts (PDLF and HGF). Among significantly altered candidates, we found that a series of interferon-induced genes were strongly up-regulated in these KSHV-infected oral cells. Interestingly, some of these genes in particular ISG15 and ISG20 are required for maintenance of virus latency through regulation of specific KSHV microRNAs. Our data indicate that oral fibroblasts may represent one important host cellular defense component against viral infection, as well as acting as a reservoir for herpesvirus lifelong infection in the oral cavity.
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Affiliation(s)
- Lu Dai
- Department of Oncology, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.,Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.,Department of Medicine, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, 70112, USA
| | - Lihua Bai
- Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Zhen Lin
- Department of Pathology, Tulane University Health Sciences Center, Tulane Cancer Center, New Orleans, LA, 70112, USA
| | - Jing Qiao
- Department of Pediatrics, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Liang Yang
- Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, Singapore, 637551, Singapore
| | - Erik K Flemington
- Department of Pathology, Tulane University Health Sciences Center, Tulane Cancer Center, New Orleans, LA, 70112, USA
| | - Jovanny Zabaleta
- Department of Pediatrics, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, 70112, USA
| | - Zhiqiang Qin
- Department of Oncology, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.,Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.,Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, 70112, USA
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32
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Watanabe T, Sugimoto A, Hosokawa K, Fujimuro M. Signal Transduction Pathways Associated with KSHV-Related Tumors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1045:321-355. [PMID: 29896674 DOI: 10.1007/978-981-10-7230-7_15] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Signal transduction pathways play a key role in the regulation of cell growth, cell differentiation, cell survival, apoptosis, and immune responses. Bacterial and viral pathogens utilize the cell signal pathways by encoding their own proteins or noncoding RNAs to serve their survival and replication in infected cells. Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is classified as a rhadinovirus in the γ-herpesvirus subfamily and was the eighth human herpesvirus to be discovered from Kaposi's sarcoma specimens. KSHV is closely associated with an endothelial cell malignancy, Kaposi's sarcoma, and B-cell malignancies, primary effusion lymphoma, and multicentric Castleman's disease. Recent studies have revealed that KSHV manipulates the cellular signaling pathways to achieve persistent infection, viral replication, cell proliferation, anti-apoptosis, and evasion of immune surveillance in infected cells. This chapter summarizes recent developments in our understanding of the molecular mechanisms used by KSHV to interact with the cell signaling machinery.
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Affiliation(s)
- Tadashi Watanabe
- Department of Cell Biology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Atsuko Sugimoto
- Department of Cell Biology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Kohei Hosokawa
- Department of Cell Biology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Masahiro Fujimuro
- Department of Cell Biology, Kyoto Pharmaceutical University, Kyoto, Japan.
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33
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Li W, Jia X, Shen C, Zhang M, Xu J, Shang Y, Zhu K, Hu M, Yan Q, Qin D, Lee MS, Zhu J, Lu H, Krueger BJ, Renne R, Gao SJ, Lu C. A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway. Oncotarget 2017; 7:32286-305. [PMID: 27058419 PMCID: PMC5078013 DOI: 10.18632/oncotarget.8591] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 03/28/2016] [Indexed: 12/24/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). Most tumor cells in these malignancies are latently infected by KSHV. Thus, viral latency is critical for the development of tumor and induction of tumor-associated angiogenesis. KSHV encodes more than two dozens of miRNAs but their roles in KSHV-induced angiogenesis remains unknown. We have recently shown that miR-K12-3 (miR-K3) promoted cell migration and invasion by targeting GRK2/CXCR2/AKT signaling (PLoS Pathog, 2015;11(9):e1005171). Here, we further demonstrated a role of miR-K3 and its induced signal pathway in KSHV latency and KSHV-induced angiogenesis. We found that overexpression of miR-K3 not only promoted viral latency by inhibiting viral lytic replication, but also induced angiogenesis. Further, knockdown of GRK2 inhibited KSHV replication and enhanced KSHV-induced angiogenesis by enhancing the CXCR2/AKT signals. As a result, blockage of CXCR2 or AKT increased KSHV replication and decreased angiogenesis induced by PEL cells in vivo. Finally, deletion of miR-K3 from viral genome reduced KSHV-induced angiogenesis and increased KSHV replication. These findings indicate that the miR-K3/GRK2/CXCR2/AKT axis plays an essential role in KSHV-induced angiogenesis and promotes KSHV latency, and thus may be a potential therapeutic target of KSHV-associated malignancies.
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Affiliation(s)
- Wan Li
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P. R. China.,Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, P. R. China.,Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China
| | - Xuemei Jia
- Department of Gynecology and Obstetrics, Nanjing Maternity and Child Health Hospital Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China
| | - Chenyou Shen
- Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China
| | - Mi Zhang
- Department of Gynecology and Obstetrics, Nanjing Maternity and Child Health Hospital Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China.,The Fourth Clinical Medical College of Nanjing Medical University, Nanjing, P. R. China
| | - Jingyun Xu
- Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China
| | - Yuancui Shang
- Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China
| | - Kaixiang Zhu
- Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China
| | - Minmin Hu
- Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China
| | - Qin Yan
- Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China
| | - Di Qin
- Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China
| | - Myung-Shin Lee
- Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, Republic of Korea
| | - Jianzhong Zhu
- Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Hongmei Lu
- Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
| | - Brian J Krueger
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA
| | - Rolf Renne
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA
| | - Shou-Jiang Gao
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Chun Lu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P. R. China.,Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, P. R. China.,Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China
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Viral MicroRNAs Repress the Cholesterol Pathway, and 25-Hydroxycholesterol Inhibits Infection. mBio 2017; 8:mBio.00576-17. [PMID: 28698273 PMCID: PMC5513709 DOI: 10.1128/mbio.00576-17] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
From various screens, we found that Kaposi's sarcoma-associated herpesvirus (KSHV) viral microRNAs (miRNAs) target several enzymes in the mevalonate/cholesterol pathway. 3-Hydroxy-3-methylglutaryl-coenzyme A (CoA) synthase 1 (HMGCS1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR [a rate-limiting step in the mevalonate pathway]), and farnesyl-diphosphate farnesyltransferase 1 (FDFT1 [a committed step in the cholesterol branch]) are repressed by multiple KSHV miRNAs. Transfection of viral miRNA mimics in primary endothelial cells (human umbilical vein endothelial cells [HUVECs]) is sufficient to reduce intracellular cholesterol levels; however, small interfering RNAs (siRNAs) targeting only HMGCS1 did not reduce cholesterol levels. This suggests that multiple targets are needed to perturb this tightly regulated pathway. We also report here that cholesterol levels were decreased in de novo-infected HUVECs after 7 days. This reduction is at least partially due to viral miRNAs, since the mutant form of KSHV lacking 10 of the 12 miRNA genes had increased cholesterol compared to wild-type infections. We hypothesized that KSHV is downregulating cholesterol to suppress the antiviral response by a modified form of cholesterol, 25-hydroxycholesterol (25HC). We found that the cholesterol 25-hydroxylase (CH25H) gene, which is responsible for generating 25HC, had increased expression in de novo-infected HUVECs but was strongly suppressed in long-term latently infected cell lines. We found that 25HC inhibits KSHV infection when added exogenously prior to de novo infection. In conclusion, we found that multiple KSHV viral miRNAs target enzymes in the mevalonate pathway to modulate cholesterol in infected cells during latency. This repression of cholesterol levels could potentially be beneficial to viral infection by decreasing the levels of 25HC.IMPORTANCE A subset of viruses express unique microRNAs (miRNAs), which act like cellular miRNAs to generally repress host gene expression. A cancer virus, Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus 8 [HHV-8]), encodes multiple miRNAs that repress gene expression of multiple enzymes that are important for cholesterol synthesis. In cells with these viral miRNAs or with natural infection, cholesterol levels are reduced, indicating these viral miRNAs decrease cholesterol levels. A modified form of cholesterol, 25-hydroxycholesterol, is generated directly from cholesterol. Addition of 25-hydroxycholesterol to primary cells inhibited KSHV infection of cells, suggesting that viral miRNAs may decrease cholesterol levels to decrease the concentration of 25-hydroxycholesterol and to promote infection. These results suggest a new virus-host relationship and indicate a previously unidentified viral strategy to lower cholesterol levels.
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35
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Functional dissection of human targets for KSHV-encoded miRNAs using network analysis. Sci Rep 2017; 7:3159. [PMID: 28600495 PMCID: PMC5466626 DOI: 10.1038/s41598-017-03462-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 04/27/2017] [Indexed: 12/17/2022] Open
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman’s disease, etc. In this study, we firstly systematically constructed the KSHV-encoded miRNA-regulated co-expressed protein-protein interaction network (CePPIN), which display the biological knowledge regarding the mechanism of miRNA-regulated KSHV pathogenesis. Then, we investigated the topological parameters for the proteins in CePPIN, especially for those miRNA targets and we found that cellular target genes of KSHV-encoded miRNAs tend to be hubs and bottlenecks in the network. Then the GO and KEGG pathway analysis suggests that miRNA targets are involved in various cellular processes mostly related to immune regulate and cell cycle. Enrichment analysis was also performed to identify the six important functional modules which are proven to be highly related to KSHV pathogenesis. Finally, difference analysis of common targets and specific targets shows that two kinds of targets are different in terms of both topological properties and enriched functions, thus we can extrapolate that the functions of KSHV-encoded miRNAs can be also classified into two generic groups, one can act as functional mimics of some oncogenic human miRNAs which contribute to tumorigenesis and the other can contribute to maintaining viral survival.
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36
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Li W, Hu M, Wang C, Lu H, Chen F, Xu J, Shang Y, Wang F, Qin J, Yan Q, Krueger BJ, Renne R, Gao SJ, Lu C. A viral microRNA downregulates metastasis suppressor CD82 and induces cell invasion and angiogenesis by activating the c-Met signaling. Oncogene 2017; 36:5407-5420. [PMID: 28534512 PMCID: PMC5608636 DOI: 10.1038/onc.2017.139] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Revised: 03/21/2017] [Accepted: 03/24/2017] [Indexed: 02/06/2023]
Abstract
Kaposi’s sarcoma (KS) is the most common AIDS-associated malignancy etiologically caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). KS is a highly disseminated and vascularized tumor comprised of poorly differentiated spindle-shaped endothelial cells. KSHV encodes 12 pre-microRNAs (pre-miRNAs) that yield 25 mature miRNAs, but their roles in KSHV-induced tumor dissemination and angiogenesis remain largely unknown. KSHV-encoded miR-K12-6 (miR-K6) can produce two mature miRNAs, miR-K6-3p and miR-K6-5p. Recently, we have shown that miR-K6-3p promoted cell migration and angiogenesis by directly targeting SH3 domain binding glutamate-rich protein (SH3BGR) (PLoS Pathog. 2016;12(4):e1005605). Here, by using mass spectrometry, bioinformatics analysis and luciferase reporter assay, we showed that miR-K6-5p directly targeted the coding sequence (CDS) of CD82 molecule (CD82), a metastasis suppressor. Ectopic expression of miR-K6-5p specifically inhibited the expression of endogenous CD82 and strongly promoted endothelial cells invasion in vitro and angiogenesis in vivo. Overexpression of CD82 significantly inhibited cell invasion and angiogenesis induced by miR-K6-5p. Mechanistically, CD82 directly interacted with c-Met to inhibit its activation. MiR-K6-5p directly repressed CD82, relieving its inhibition on c-Met activation and inducing cell invasion and angiogenesis. Deletion of miR-K6 from KSHV genome abrogated KSHV suppression of CD82 resulting in compromised KSHV activation of c-Met pathway, and KSHV-induced invasion and angiogenesis. In conclusion, these results show that by inhibiting CD82, KSHV miR-K6-5p promotes cell invasion and angiogenesis by activating the c-Met pathway. Our findings illustrate that KSHV miRNAs may play an essential role in the dissemination and angiogenesis of KSHV-induced malignancies.
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Affiliation(s)
- W Li
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.,Department of Microbiology, Nanjing Medical University, Nanjing, China
| | - M Hu
- Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - C Wang
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - H Lu
- Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - F Chen
- Department of Microbiology, Nanjing Medical University, Nanjing, China
| | - J Xu
- Department of Microbiology, Nanjing Medical University, Nanjing, China
| | - Y Shang
- Department of Microbiology, Nanjing Medical University, Nanjing, China
| | - F Wang
- Department of Microbiology, Nanjing Medical University, Nanjing, China
| | - J Qin
- Department of Microbiology, Nanjing Medical University, Nanjing, China
| | - Q Yan
- Department of Microbiology, Nanjing Medical University, Nanjing, China
| | - B J Krueger
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA
| | - R Renne
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA
| | - S-J Gao
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - C Lu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.,Department of Microbiology, Nanjing Medical University, Nanjing, China
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Primary lymphocyte infection models for KSHV and its putative tumorigenesis mechanisms in B cell lymphomas. J Microbiol 2017; 55:319-329. [PMID: 28455586 DOI: 10.1007/s12275-017-7075-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 03/03/2017] [Accepted: 03/03/2017] [Indexed: 12/12/2022]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the latest addition to the human herpesvirus family. Unlike alpha- and beta-herpesvirus subfamily members, gamma-herpesviruses, including Epstein-Barr virus (EBV) and KSHV, cause various tumors in humans. KSHV primarily infects endothelial and B cells in vivo, and is associated with at least three malignancies: Kaposi's sarcoma and two B cell lymphomas, respectively. Although KSHV readily infects endothelial cells in vitro and thus its pathogenic mechanisms have been extensively studied, B cells had been refractory to KSHV infection. As such, functions of KSHV genes have mostly been elucidated in endothelial cells in the context of viral infection but not in B cells. Whether KSHV oncogenes, defined in endothelial cells, play the same roles in the tumorigenesis of B cells remains an open question. Only recently, through a few ground-breaking studies, B cell infection models have been established. In this review, those models will be compared and contrasted and putative mechanisms of KSHV-induced B cell transformation will be discussed.
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Qin J, Li W, Gao SJ, Lu C. KSHV microRNAs: Tricks of the Devil. Trends Microbiol 2017; 25:648-661. [PMID: 28259385 DOI: 10.1016/j.tim.2017.02.002] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Revised: 01/23/2017] [Accepted: 02/06/2017] [Indexed: 01/02/2023]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), a vascular tumor frequently found in immunodeficient individuals. KSHV encodes 12 pre-microRNAs (pre-miRNAs), which are processed into 25 mature microRNAs (miRNAs). KSHV miRNAs maintain KSHV latency, enhance angiogenesis and dissemination of the infected cells, and interfere with the host immune system by regulating viral and cellular gene expression, ultimately contributing to KS development. In this review, we briefly introduce the biogenesis of miRNAs and then describe the recent advances in defining the roles and mechanisms of action of KSHV miRNAs in KS development.
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Affiliation(s)
- Jie Qin
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P.R. China; Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, P.R. China; Department of Microbiology, Nanjing Medical University, Nanjing 211166, P.R. China
| | - Wan Li
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P.R. China; Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, P.R. China; Department of Microbiology, Nanjing Medical University, Nanjing 211166, P.R. China
| | - Shou-Jiang Gao
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Chun Lu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P.R. China.
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39
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Sorel O, Dewals BG. MicroRNAs in large herpesvirus DNA genomes: recent advances. Biomol Concepts 2017; 7:229-39. [PMID: 27544723 DOI: 10.1515/bmc-2016-0017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 07/18/2016] [Indexed: 12/26/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that regulate gene expression. They alter mRNA translation through base-pair complementarity, leading to regulation of genes during both physiological and pathological processes. Viruses have evolved mechanisms to take advantage of the host cells to multiply and/or persist over the lifetime of the host. Herpesviridae are a large family of double-stranded DNA viruses that are associated with a number of important diseases, including lymphoproliferative diseases. Herpesviruses establish lifelong latent infections through modulation of the interface between the virus and its host. A number of reports have identified miRNAs in a very large number of human and animal herpesviruses suggesting that these short non-coding transcripts could play essential roles in herpesvirus biology. This review will specifically focus on the recent advances on the functions of herpesvirus miRNAs in infection and pathogenesis.
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Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses. Sci Rep 2017; 7:40813. [PMID: 28102325 PMCID: PMC5244407 DOI: 10.1038/srep40813] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 12/12/2016] [Indexed: 12/13/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs during latency that are processed to yield ~25 mature microRNAs (miRNAs). We were interested in identifying cellular networks that were targeted by KSHV-miRNAs and employed network building strategies using validated KSHV miRNA targets. Here, we report the identification of a gene network centering on the transcription factor- signal transducer and activator of transcription 3 (STAT3) that is targeted by KSHV miRNAs. KSHV miRNAs suppressed STAT3 and STAT5 activation and inhibited STAT3-dependent reporter activation upon IL6-treatment. KSHV miRNAs also repressed the induction of antiviral interferon-stimulated genes upon IFNα- treatment. Finally, we observed increased lytic reactivation of KSHV from latently infected cells upon STAT3 repression with siRNAs or a small molecule inhibitor. Our data suggest that treatment of infected cells with a STAT3 inhibitor and a viral replication inhibitor, ganciclovir, represents a possible strategy to eliminate latently infected cells without increasing virion production. Together, we show that KSHV miRNAs suppress a network of targets associated with STAT3, deregulate cytokine-mediated gene activation, suppress an interferon response, and influence the transition into the lytic phase of viral replication.
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Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Target GADD45B To Protect Infected Cells from Cell Cycle Arrest and Apoptosis. J Virol 2017; 91:JVI.02045-16. [PMID: 27852859 DOI: 10.1128/jvi.02045-16] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Accepted: 11/15/2016] [Indexed: 12/25/2022] Open
Abstract
Kaposi's sarcoma is one of the most common malignancies in HIV-infected individuals. The responsible agent, Kaposi's sarcoma-associated herpesvirus (KSHV; HHV8), expresses multiple microRNAs (miRNAs), but the targets and functions of these miRNAs are not completely understood. After infection in primary endothelial cells with KSHV, growth arrest DNA damage-inducible gene 45 beta (GADD45B) is one of the most repressed genes using genomic expression profiling. GADD45B was also repressed in mRNA expression profiling experiments when KSHV miRNAs were introduced to uninfected cells. We hypothesized that KSHV miRNAs target human GADD45B to protect cells from consequences of DNA damage, which can be triggered by viral infection. Expression of GADD45B protein is induced by the p53 activator, Nutlin-3, and KSHV miRNA-K9 inhibits this induction. In addition, Nutlin-3 increased apoptosis and cell cycle arrest based on flow cytometry assays. KSHV miR-K9 protected primary endothelial cells from apoptosis and cell cycle arrest following Nutlin-3 treatment. Similar protective phenotypes were seen for targeting GADD45B with short interfering RNAs (siRNAs), as with miR-K9. KSHV miR-K9 also decreased the protein levels of cleaved caspase-3, cleaved caspase-7, and cleaved poly(ADP-ribose) polymerase (PARP). In B lymphocytes latently infected with KSHV, specific inhibitors of KSHV miR-K9 led to increased GADD45B expression and apoptosis, indicating that miR-K9 is important for reducing apoptosis in infected cells. Furthermore, ectopic expression of GADD45B in KSHV-infected cells promoted apoptosis. Together, these results identify a new miRNA target and demonstrate that KSHV miRNAs are important for protecting infected cells from DNA damage responses. IMPORTANCE Kaposi's sarcoma-associated herpesvirus is a leading cause of cancers in individuals with AIDS. Promoting survival of infected cells is essential for maintaining viral infections. A virus needs to combat various cellular defense mechanisms designed to eradicate the viral infection. One such response can include DNA damage response factors, which can promote an arrest in cell growth and trigger cell death. We used a new approach to search for human genes repressed by small nucleic acids (microRNAs) expressed by a gammaherpesvirus (KSHV), which identified a gene called GADD45B as a target of microRNAs. Repression of GADD45B, which is expressed in response to DNA damage, benefited survival of infected cells in response to a DNA damage response. This information could be used to design new treatments for herpesvirus infections.
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Viollet C, Davis DA, Tekeste SS, Reczko M, Ziegelbauer JM, Pezzella F, Ragoussis J, Yarchoan R. RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature. PLoS Pathog 2017; 13:e1006143. [PMID: 28046107 PMCID: PMC5234848 DOI: 10.1371/journal.ppat.1006143] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 01/13/2017] [Accepted: 12/19/2016] [Indexed: 01/09/2023] Open
Abstract
Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases.
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Affiliation(s)
- Coralie Viollet
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - David A. Davis
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Shewit S. Tekeste
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Martin Reczko
- Institute of Molecular Oncology, Alexander Fleming Biomedical Sciences Research Center, Vari, Greece
| | - Joseph M. Ziegelbauer
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Francesco Pezzella
- Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, United Kingdom
| | - Jiannis Ragoussis
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
- Institute of Molecular Oncology, Alexander Fleming Biomedical Sciences Research Center, Vari, Greece
- McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada
- Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
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Happel C, Ramalingam D, Ziegelbauer JM. Virus-Mediated Alterations in miRNA Factors and Degradation of Viral miRNAs by MCPIP1. PLoS Biol 2016; 14:e2000998. [PMID: 27893764 PMCID: PMC5125562 DOI: 10.1371/journal.pbio.2000998] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 10/26/2016] [Indexed: 12/20/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi's sarcoma, encodes 25 mature viral miRNAs. MCP-1-induced protein-1 (MCPIP1), a critical regulator of immune homeostasis, has been shown to suppress miRNA biosynthesis via cleavage of precursor miRNAs through its RNase domain. We demonstrate that MCPIP1 can directly cleave KSHV and EBV precursor miRNAs and that MCPIP1 expression is repressed following de novo KSHV infection. In addition, repression with siRNAs to MCPIP1 in KSHV-infected cells increased IL-6 and KSHV miRNA expression, supporting a role for MCPIP1 in IL-6 and KSHV miRNA regulation. We also provide evidence that KSHV miRNAs repress MCPIP1 expression by targeting the 3'UTR of MCPIP1. Conversely, expression of essential miRNA biogenesis components Dicer and TRBP is increased following latent KSHV infection. We propose that KSHV infection inhibits a negative regulator of miRNA biogenesis (MCPIP1) and up-regulates critical miRNA processing components to evade host mechanisms that inhibit expression of viral miRNAs. KSHV-mediated alterations in miRNA biogenesis represent a novel mechanism by which KSHV interacts with its host and a new mechanism for the regulation of viral miRNA expression.
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Affiliation(s)
- Christine Happel
- HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Dhivya Ramalingam
- HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Joseph M. Ziegelbauer
- HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
- * E-mail:
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Pan C, Zhu D, Wang Y, Li L, Li D, Liu F, Zhang CY, Zen K. Human Cytomegalovirus miR-UL148D Facilitates Latent Viral Infection by Targeting Host Cell Immediate Early Response Gene 5. PLoS Pathog 2016; 12:e1006007. [PMID: 27824944 PMCID: PMC5100954 DOI: 10.1371/journal.ppat.1006007] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 10/17/2016] [Indexed: 12/21/2022] Open
Abstract
The mechanisms underlying human cytomegalovirus (HCMV) latency remain incompletely understood. Here, we showed that a HCMV-encoded miRNA, miR-UL148D, robustly accumulates during late stages of experimental latent HCMV infection in host cells and promotes HCMV latency by modulating the immediate early response gene 5 (IER5)-cell division cycle 25B (CDC25B) axis in host cells. miR-UL148D inhibited IER5 expression by directly targeting the three-prime untranslated region(3'UTR) of IER5 mRNA and thus rescued CDC25B expression during the establishment of viral latency. Infection with NR-1ΔmiR-UL148D, a derivative of the HCMV clinical strain NR-1 with a miR-UL148D knockout mutation, resulted in sustained induction of IER5 expression but decreased CDC25B expression in host cells. Mechanistically, we further showed that CDC25B plays an important role in suppressing HCMV IE1 and lytic gene transcription by activating cyclin-dependent kinase 1 (CDK-1). Both gain-of-function and lose-of-function assays demonstrated that miR-UL148D promotes HCMV latency by helping maintain CDC25B activity in host cells. These results provide a novel mechanism through which a HCMV miRNA regulates viral latency.
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Affiliation(s)
- Chaoyun Pan
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Dihan Zhu
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Yan Wang
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Limin Li
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Donghai Li
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Fenyong Liu
- School of Public Health, University of California at Berkeley, Berkeley, California, Unites States of America
- * E-mail: (KZ); (CYZ); (FL)
| | - Chen-Yu Zhang
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
- * E-mail: (KZ); (CYZ); (FL)
| | - Ke Zen
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
- * E-mail: (KZ); (CYZ); (FL)
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HIV-1 Vpr Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by Inducing MicroRNA miR-942-5p and Activating NF-κB Signaling. J Virol 2016; 90:8739-53. [PMID: 27440900 DOI: 10.1128/jvi.00797-16] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 07/15/2016] [Indexed: 12/18/2022] Open
Abstract
UNLABELLED 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-κB signaling following internalization into PEL cells. By analyzing the expression profiles of microRNAs combined with target search by bioinformatics and luciferase reporter analyses, we identified a Vpr-upregulated cellular microRNA (miRNA), miR-942-5p, that directly targeted IκBα. Suppression of miR-942-5p relieved the expression of IκBα and reduced Vpr inhibition of KSHV lytic replication, while overexpression of miR-942-5p enhanced Vpr inhibition of KSHV lytic replication. Our findings collectively illustrate that, by activating NF-κB signaling through upregulating a cellular miRNA to target IκBα, internalized HIV-1 Vpr inhibits KSHV lytic replication. These results have demonstrated an essential role of Vpr in the life cycle of KSHV. IMPORTANCE Coinfection by HIV-1 promotes the aggressive growth of Kaposi's sarcoma-associated herpesvirus (KSHV)-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). In this study, we have shown that soluble HIV-1 Vpr inhibits KSHV lytic replication by activating NF-κB signaling following internalization into PEL cells. Mechanistic studies revealed that a cellular microRNA upregulated by Vpr, miR-942-5p, directly targeted IκBα. Suppression of miR-942-5p relieved IκBα expression and reduced Vpr inhibition of KSHV replication, while overexpression of miR-942-5p enhanced Vpr inhibition of KSHV replication. These results indicate that by activating NF-κB signaling through upregulating a cellular miRNA to target IκBα, internalized Vpr inhibits KSHV lytic replication. This work illustrates a molecular mechanism by which HIV-1-secreted regulatory protein Vpr regulates KSHV latency and the pathogenesis of AIDS-related malignancies.
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46
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Dittmer DP, Damania B. Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest 2016; 126:3165-75. [PMID: 27584730 DOI: 10.1172/jci84418] [Citation(s) in RCA: 152] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, is the etiologic agent underlying Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. This human gammaherpesvirus was discovered in 1994 by Drs. Yuan Chang and Patrick Moore. Today, there are over five thousand publications on KSHV and its associated malignancies. In this article, we review recent and ongoing developments in the KSHV field, including molecular mechanisms of KSHV pathogenesis, clinical aspects of KSHV-associated diseases, and current treatments for cancers associated with this virus.
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47
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Piedade D, Azevedo-Pereira JM. The Role of microRNAs in the Pathogenesis of Herpesvirus Infection. Viruses 2016; 8:v8060156. [PMID: 27271654 PMCID: PMC4926176 DOI: 10.3390/v8060156] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 05/25/2016] [Accepted: 05/30/2016] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs important in gene regulation. They are able to regulate mRNA translation through base-pair complementarity. Cellular miRNAs have been involved in the regulation of nearly all cellular pathways, and their deregulation has been associated with several diseases such as cancer. Given the importance of microRNAs to cell homeostasis, it is no surprise that viruses have evolved to take advantage of this cellular pathway. Viruses have been reported to be able to encode and express functional viral microRNAs that target both viral and cellular transcripts. Moreover, viral inhibition of key proteins from the microRNA pathway and important changes in cellular microRNA pool have been reported upon viral infection. In addition, viruses have developed multiple mechanisms to avoid being targeted by cellular microRNAs. This complex interaction between host and viruses to control the microRNA pathway usually favors viral infection and persistence by either reducing immune detection, avoiding apoptosis, promoting cell growth, or promoting lytic or latent infection. One of the best examples of this virus-host-microRNA interplay emanates from members of the Herperviridae family, namely the herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2), human cytomegalovirus (HCMV), human herpesvirus 8 (HHV-8), and the Epstein–Barr virus (EBV). In this review, we will focus on the general functions of microRNAs and the interactions between herpesviruses, human hosts, and microRNAs and will delve into the related mechanisms that contribute to infection and pathogenesis.
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Affiliation(s)
- Diogo Piedade
- Host-Pathogen Interaction Unit, iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
| | - José Miguel Azevedo-Pereira
- Host-Pathogen Interaction Unit, iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
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48
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Li W, Yan Q, Ding X, Shen C, Hu M, Zhu Y, Qin D, Lu H, Krueger BJ, Renne R, Gao SJ, Lu C. The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA. PLoS Pathog 2016; 12:e1005605. [PMID: 27128969 PMCID: PMC4851422 DOI: 10.1371/journal.ppat.1005605] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 04/08/2016] [Indexed: 12/27/2022] Open
Abstract
Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is a gammaherpesvirus etiologically associated with KS, a highly disseminated angiogenic tumor of hyperproliferative spindle endothelial cells. KSHV encodes 25 mature microRNAs but their roles in KSHV-induced tumor dissemination and angiogenesis remain unknown. Here, we investigated KSHV-encoded miR-K12-6-3p (miR-K6-3p) promotion of endothelial cell migration and angiogenesis, which are the underlying mechanisms of tumor dissemination and angiogenesis. We found that ectopic expression of miR-K6-3p promoted endothelial cell migration and angiogenesis. Mass spectrometry, bioinformatics and luciferase reporter analyses revealed that miR-K6-3p directly targeted sequence in the 3’ untranslated region (UTR) of SH3 domain binding glutamate-rich protein (SH3BGR). Overexpression of SH3BGR reversed miR-K6-3p induction of cell migration and angiogenesis. Mechanistically, miR-K6-3p downregulated SH3BGR, hence relieved STAT3 from SH3BGR direct binding and inhibition, which was required for miR-K6-3p maximum activation of STAT3 and induction of cell migration and angiogenesis. Finally, deletion of miR-K6 from the KSHV genome abrogated its effect on the SH3BGR/STAT3 pathway, and KSHV-induced migration and angiogenesis. Our results illustrated that, by inhibiting SH3BGR, miR-K6-3p enhances cell migration and angiogenesis by activating the STAT3 pathway, and thus contributes to the dissemination and angiogenesis of KSHV-induced malignancies. Kaposi’s Sarcoma (KS), caused by infection of Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV), is a tumor of endothelial cells characterized by angiogenesis and invasiveness. In vitro, KSHV-infected endothelial cells display an increased invasiveness and angiogenicity. KSHV encodes twelve precursor miRNAs (pre-miRNAs), which are processed into at least 25 mature miRNAs. However, the roles of these miRNAs in KSHV-induced tumor dissemination and angiogenesis remain unknown. Here, we investigated KSHV-encoded miR-K12-6-3p (miR-K6-3p) promotion of endothelial cell migration and angiogenesis, which are the underlying mechanisms of tumor dissemination and angiogenesis. We demonstrated that miR-K6-3p promoted cell migration and angiogenesis by directly targeting SH3 domain binding glutamate-rich protein (SH3BGR). Furthermore, we found that STAT3, which was negatively regulated by SH3BGR mediated miR-K6-3p-induced cell migration and angiogenesis. MiR-K6-3p downregulation of SH3BGR, hence relieved SH3BGR direct inhibition of STAT3 resulting in the activation of STAT3 and induction of cell migration and angiogenesis. These results identify miR-K6-3p and its the downstream pathway as potential therapeutic targets for the treatment of KSHV-associated malignancies.
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Affiliation(s)
- Wan Li
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, People's Republic of China.,Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, People's Republic of China.,Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Qin Yan
- Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiangya Ding
- Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Chenyou Shen
- Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Minmin Hu
- Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Ying Zhu
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Di Qin
- Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hongmei Lu
- Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Brian J Krueger
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America
| | - Rolf Renne
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America
| | - Shou-Jiang Gao
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Chun Lu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, People's Republic of China.,Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, People's Republic of China.,Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China
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Liu F, Zheng H, Tong W, Li GX, Tian Q, Liang C, Li LW, Zheng XC, Tong GZ. Identification and Analysis of Novel Viral and Host Dysregulated MicroRNAs in Variant Pseudorabies Virus-Infected PK15 Cells. PLoS One 2016; 11:e0151546. [PMID: 26998839 PMCID: PMC4801506 DOI: 10.1371/journal.pone.0151546] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 02/29/2016] [Indexed: 12/16/2022] Open
Abstract
Pseudorabies (PR) is one of the most devastating diseases in the pig industry. To identify changes in microRNA (miRNA) expression and post-transcriptional regulatory responses to PRV infection in porcine kidney epithelial (PK15) cells, we sequenced a small RNA (sRNA) library prepared from infected PK15 cells and compared it to a library prepared from uninfected cells using Illumina deep sequencing. Here we found 25 novel viral miRNAs by high-throughput sequencing and 20 of these miRNAs were confirmed through stem-loop RT-qPCR. Intriguingly, unlike the usual miRNAs encoded by the α-herpesviruses, which are found clustered in the large latency transcript (LLT), these novel viral miRNAs are throughout the PRV genome like β-herpesviruses. Viral miRNAs are predicted to target multiple genes and form a complex regulatory network. GO analysis on host targets of viral miRNAs were involved in complex cellular processes, including the metabolic pathway, biological regulation, stimulus response, signaling process and immune response. Moreover, 13 host miRNAs were expressed with significant difference after infection with PRV: 8 miRNAs were up-regulated and 5 miRNAs were down-regulated, which may affect viral replication in host cell. Our results provided new insight into the characteristic of miRNAs in response to PRV infection, which is significant for further study of these miRNAs function.
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Affiliation(s)
- Fei Liu
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Hao Zheng
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, People’s Republic of China
| | - Wu Tong
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, People’s Republic of China
| | - Guo-Xin Li
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, People’s Republic of China
| | - Qing Tian
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Chao Liang
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Li-Wei Li
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Xu-Chen Zheng
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Guang-Zhi Tong
- Department of Swine Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, People’s Republic of China
- * E-mail:
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Abstract
Over 12 % of all human cancers are caused by oncoviruses, primarily including Epstein-Barr virus (EBV), high-risk human papillomaviruses (HPVs), hepatitis B and C viruses (HBV and HCV, respectively), and Kaposi's sarcoma herpesvirus (KSHV). In addition to viral oncoproteins, a variety of noncoding RNAs (ncRNAs) produced by oncoviruses have been recognized as important cofactors that contribute to the oncogenic events. In this chapter, we will focus on the recent understanding of the long and short noncoding RNAs, as well as microRNAs of the viruses, and discuss their roles in the biology of multistep oncogenesis mediated by established human oncoviruses.
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