Identification of Kaposin (Open Reading Frame K12) as a Human Herpesvirus 8 (Kaposi’s Sarcoma-Associated Herpesvirus) Transforming Gene

Muralidhar, Sumitra; Pumfery, Anne; Hassani, Morad; Sadaie, M. Reza; Kishishita, Masamichi; Brady, John; Doniger, Jay; Medveczky, Peter G.; Rosenthal, Leonard J.

doi:10.1128/jvi.73.3.2568-2568.1999

Cited by 42 publications

(56 citation statements)

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“…We have previously shown that kaposin A, which is one of the proteins expressed during KSHV latency, played crucial roles in KSHV-induced cell proliferation by activating metabotropic glutamate receptor 1 (mGluR1) during KSHV infection (41). Kaposin A has also been shown to mediate oncogenesis in vitro in Rat3 fibroblasts and in nude mice (45,46). Another study by Kliche et al demonstrated the mechanistic role of kaposin A in the oncogenic transformation of NIH 3T3 fibroblasts (47).…”

Section: Discussionmentioning

confidence: 99%

HACE1, an E3 Ubiquitin Protein Ligase, Mitigates Kaposi’s Sarcoma-Associated Herpesvirus Infection-Induced Oxidative Stress by Promoting Nrf2 Activity

Kumar

Roy

Asha

et al. 2019

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV)-induced activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is essential for both the expression of viral genes (latency) and modulation of the host antioxidant machinery. Reactive oxygen species (ROS) are also regulated by the ubiquitously expressed HACE1 protein (HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1), which targets the Rac1 protein for proteasomal degradation, and this blocks the generation of ROS by Rac1-dependent NADPH oxidases. In this study, we examined the role of HACE1 in KSHV infection. Elevated levels of HACE1 expression were observed in de novo KSHV-infected endothelial cells, KSHV latently infected TIVE-LTC and PEL cells, and Kaposi's sarcoma skin lesion cells. The increased HACE1 expression in the infected cells was mediated by KSHV latent protein kaposin A. HACE1 knockdown resulted in high Rac1 and Nox 1 (NADPH oxidase 1) activity, increased ROS (oxidative stress), increased cell death, and decreased KSHV gene expression. Loss of HACE1 impaired KSHV infection-induced phosphoinositide 3-kinase (PI3-K), protein kinase C-(PKC-), extracellular signal-regulated kinase 1/2 (ERK1/2), NF-B, and Nrf2 activation and nuclear translocation of Nrf2, and it reduced the expression of Nrf2 target genes responsible for balancing the oxidative stress. In the absence of HACE1, glutamine uptake increased in the cells to cope with the KSHV-induced oxidative stress. These findings reveal for the first time that HACE1 plays roles during viral infection-induced oxidative stress and demonstrate that HACE1 facilitates resistance to KSHV infectioninduced oxidative stress by promoting Nrf2 activity. Our studies suggest that HACE1 could be a potential target to induce cell death in KSHV-infected cells and to manage KSHV infections. IMPORTANCE ROS play important roles in several cellular processes, and increased ROS cause several adverse effects. KSHV infection of endothelial cells induces ROS, which facilitate virus entry by amplifying the infection-induced host cell signaling cascade, which, in turn, induces the nuclear translocation of phospho-Nrf2 protein to regulate the expression of antioxidative genes and viral genes. The present study demonstrates that KSHV infection induces the E3 ligase HACE1 protein to regulate KSHV-induced oxidative stress by promoting the activation of Nrf2 and nuclear translocation. Absence of HACE1 results in increased ROS and cellular death and reduced nuclear Nrf2, antioxidant, and viral gene expression. Together, these studies suggest that HACE1 can be a potential target to induce cell death in KSHV-infected cells.

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Section: Discussionmentioning

confidence: 99%

HACE1, an E3 Ubiquitin Protein Ligase, Mitigates Kaposi’s Sarcoma-Associated Herpesvirus Infection-Induced Oxidative Stress by Promoting Nrf2 Activity

Kumar

Roy

Asha

et al. 2019

J Virol

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“…Kaposi's sarcoma (KS) is a multicentric neoplasm of vascular origin and very probably of HHV-8 or KSassociated herpes virus etiology (Chang et al, 1994). The kaposin oncogene of the HHV-8 is able to induce tumorigenic transformation and has been found to be expressed in the spindle-shaped cells of this tumor (Ganem, 1997;Muralidhar et al, 1998;Staskus et al, 1997). Kaposi's sarcoma is subdivided into classical KS in older males of mainly Mediterranean or eastern European Jewish backgrounds; endemic KS, found in parts of equatorial Africa; iatrogenic KS, including immunosuppressive drug-associated KS; and AIDS-associated KS.…”

Section: Kaposi's Sarcomamentioning

confidence: 99%

Lymphatic versus blood vascular endothelial growth factors and receptors in humans

Partanen

Paavonen

2001

Microscopy Res & Technique

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Three different growth factor systems have been described acting via endothelial cell-specific receptor tyrosine kinases (RTKs). These are vascular endothelial growth factors (VEGFs), angiopoietins, and ephrins. Recent studies on gene targeting suggest that they play critical roles in embryonic development and contribute to the integrity and responses to environmental factors in the adult vasculature. Coagulation, inflammation, immune response regulation, vascular tone, stromal component synthesis, and angiogenesis are all dependent on the physiological and pathological events that affect endothelial cells in the heart, arteries, veins, and lymphatic vessels. Angiogenesis, the formation of new blood vessels from preexisting ones, takes place in adults only during hormonal control of female reproduction. All other activation of angiogenesis in adulthood occurs in response to injury or pathological processes such as tumorigenesis, diabetes, or inflammatory conditions. Insufficient growth of collateral vessels is a major problem in atherosclerotic cardiovascular disease. Controlled stimulation of angiogenesis would be of therapeutic value. Lymphangiogenesis, the mechanisms involved in the development of lymphatic vessels, was studied intensively nearly a century ago, although since then it has been neglected, perhaps because, unlike the disorders of blood vessels, those of the lymphatic vessels are seldom life-threatening. Interrupting this one-way system can cause severe disorders, including liver dysfunction, genetic disease (e.g., Milroys disease), and degenerative disease (e.g., primary lymphangiosclerosis). Recently, novel growth factors, receptors, cell surface proteins, and transcription factors have been found which play a role in the lymphatic endothelium. These are VEGF-C, VEGF-D, VEGFR-3, LYVE-1, podoplanin, and Prox-1. Until recently lymphatic vessels have been difficult to study due to a lack of appropriate tools. Monoclonal antibodies raised against VEGFR-3 and against its ligands, VEGF-C and VEGF-D, have offered an insight into expression studies in tissues. In this review, we summarize the recent data on VEGFs in the human vasculature.

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“…Growth stimulation of neoplastic cells may be accomplished in a paracrine manner, as suggested by recent studies of multiple myeloma [40]. Recently, Muralidhar et al [41] demonstrated oncogenicity of a small latency-associated protein named kaposin, which is also produced in HHV-8 cell lines. Alternatively, HHV-8 may sometimes act in conjunction with EBV in causing malignancy.…”

Section: Discussionmentioning

confidence: 99%

Human herpesvirus-8 (HHV-8) associated with small non-cleaved cell lymphoma in a child with AIDS

et al. 1999

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The association of human herpesvirus-8 (HHV-8) with a small non-cleaved cell lymphoma is described in a child with the acquired immunodeficiency syndrome (AIDS) who developed a malignant pleural effusion and radiologic evidence of multiple solid tumors. HHV-8 DNA and Epstein-Barr virus DNA were identified in pleural fluid cells by polymer-ase chain reaction (PCR) amplification. The serum antibody titer against lytic HHV-8 proteins was 1:640; antibodies to latent HHV-8 proteins were not detected. Cytogenetic analysis of malignant cells revealed three abnormal karyotypes sharing the common finding of a t(8;14) translocation. Rearrangement of c-myc was demonstrated by PCR analysis. Oligoclonal JH immunoglobulin bands were found. Insufficient pleural fluid cells were available to permit localization of HHV-8 to malignant cells by in situ hybrid-ization. This malignancy contrasts with HHV-8-associated lymphomas reported in adult patients with AIDS with respect to cell morphology, c-myc translocation, and oligoclonal immunoglobulin gene rearrangement. HHV-8 is associated with a wider spectrum of ma-lignancies than recognized previously. Am. J. Hematol. 60:215-221, 1999.

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Identification of Kaposin (Open Reading Frame K12) as a Human Herpesvirus 8 (Kaposi’s Sarcoma-Associated Herpesvirus) Transforming Gene

Abstract: The byline should read as shown above. In addition, permission to cite the unpublished data by Adduci et al. (reference 1) was not obtained.

Cited by 42 publications

References 0 publications

HACE1, an E3 Ubiquitin Protein Ligase, Mitigates Kaposi’s Sarcoma-Associated Herpesvirus Infection-Induced Oxidative Stress by Promoting Nrf2 Activity

HACE1, an E3 Ubiquitin Protein Ligase, Mitigates Kaposi’s Sarcoma-Associated Herpesvirus Infection-Induced Oxidative Stress by Promoting Nrf2 Activity

Lymphatic versus blood vascular endothelial growth factors and receptors in humans

Human herpesvirus-8 (HHV-8) associated with small non-cleaved cell lymphoma in a child with AIDS

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