Cell signaling pathways engaged by KSHV

Järviluoma, Annika; Ojala, Päivi M.

doi:10.1016/j.bbcan.2006.05.001

Cited by 45 publications

(54 citation statements)

References 226 publications

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“…In fact, KSHV targets NF-κB signaling to influence gene expression and apoptosis. KSHV-encoded v-FLIP, K15, v-GPCR, K1 and K7 activate NF-κB signaling to achieve antiapoptosis in KSHV-infected cells, including PEL cells (4,6). Therefore, DAT-mediated destabilization of TRAF6 induces stabilization of IκBα and the subsequent inhibition of NF-κB signaling, which in turn may result in apoptosis of PEL cells.…”

Section: Discussionmentioning

confidence: 99%

“…Several signaling pathways are activated in PEL cells to maintain malignant potential and enhance cell survival. Especially, the constitutive and/or transient activation of NF-κB signaling is necessary for PEL to achieve the establishment of KSHV infection, survival of infected cells, and viral replication (4,(7)(8)(9)(10)(11). To obtain insight into the machinery by which DAT induces apoptosis of KSHV-infected PEL cells, we analyzed the effect of DAT treatment on NF-κB signaling.…”

Section: Dat Induces Apoptosis Through the Activation Of Caspases In mentioning

confidence: 99%

“…LANA is required for the replication and maintenance of viral DNA, and contributes to KSHV-associated oncogenesis through interaction with cellular molecules, such as p53, Rb and GSK-3. These viral proteins and RNA manipulate cellular signaling pathways, including nuclear factor-κB (NF-κB), Akt, Wnt and Erk, to maintain the malignant phenotype and ensure PEL cell survival (4)(5)(6). Especially, NF-κB signaling is constitutively activated in KSHV-infected PEL cells to facilitate antiapoptosis and growth (7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Shigemi

Furukawa

Hosokawa

et al. 2015

International Journal of Oncology

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Abstract. The allyl sulfides, including diallyl sulfide (DAS), diallyl disulfide (DAD), and diallyl trisulfide (DAT), contained in garlic and members of the Allium family, have a variety of pharmacological activities. Therefore, allyl sulfides have been evaluated as potential novel chemotherapeutic agents. Here, we found that DAT inhibited nuclear factor-κB (NF-κB) signaling and induced apoptosis in primary effusion lymphoma (PEL), a subtype of non-Hodgkin's B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). We examined the cytotoxic effects of DAS, DAD and DAT on PEL cells. DAT significantly reduced the viability of PEL cells compared with uninfected B-lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9. DAT induced stabilization of IκBα, and suppressed NF-κB transcriptional activity in PEL cells. We examined the mechanism underlying DAT-mediated IκBα stabilization. The results indicated that DAT stabilized IκBα by inhibiting the phosphorylation of IκBα by the IκB kinase (IKK) complex. Furthermore, DAT induced proteasomal degradation of TRAF6, and DAT suppressed IKKβ-phosphorylation through downregulation of TRAF6. It is known that activation of NF-κB is essential for survival of PEL cells. In fact, the NF-κB inhibitor BAY11-7082 induced apoptosis in PEL cells. In addition, DAT suppressed the production of progeny virus from PEL cells. The administration of DAT suppressed the development of PEL cells and ascites in SCID mice xenografted with PEL cells. These findings provide evidence that DAT has antitumor activity against PEL cells in vitro and in vivo, suggesting it to be a novel therapeutic agent for the treatment of PEL. IntroductionPrimary effusion lymphoma (PEL, also termed body-cavitybased lymphoma) is a malignant B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV, also named HHV-8) in immunosuppressed individuals, such as AIDS patients or those that have undergone organ transplantation (1,2). PEL is a subtype of non-Hodgkin's lymphoma and is characterized by lymphomatous effusions of pleural and abdominal cavities. KSHV is a rhadinovirus of the γ-herpesvirus subfamily and is closely related to herpesvirus Saimiri and Epstein-Barr virus (EBV). KSHV is the causative agent of Kaposi's sarcoma and AIDS-related lymphoproliferative disorders, such as PEL and multicentric Castleman's disease (3). Similar to other herpesviruses, KSHV has two life cycles (latency and lytic replication). The KSHV genome circularizes and forms a double-stranded DNA, the episome, in the nucleus of PEL cells during latent infection. To establish a latent infection, KSHV expresses several viral genes, including latency-associated nuclear antigen (LANA), v-FLIP, v-cyclin, kaposin and microRNAs, in PEL cells. LANA is required for the replication and maintenance of viral DNA, and contributes to KSHV-associated oncogenesis through interaction with cellular molecules, such as p53, Rb and GSK-3. These viral proteins and RNA manipulate cellular signaling pathways, includ...

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Section: Discussionmentioning

confidence: 99%

Section: Dat Induces Apoptosis Through the Activation Of Caspases In mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Shigemi

Furukawa

Hosokawa

et al. 2015

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…During latent infections, the KSHV genome persists as a circular doublestranded DNA (episome) with most viral genes being silenced, except for a small number of latent genes, which include the viral cyclin (v-cyclin), the latency-associated nuclear antigen (LANA), and the viral FLICE inhibitory protein (vFLIP). These latent proteins are well known to be involved in the regulation of cell survival, cell cycle, and tumor suppressor pathways, such as P53, pRb, and VHL (9).…”

mentioning

confidence: 99%

Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis

Sun

Jha

Robertson

2015

J Virol

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Latent DNA replication of Kaposi's sarcoma-associated herpesvirus (KSHV) initiates at the terminal repeat (TR) element and requires trans-acting elements, both viral and cellular, such as ORCs, MCMs, and latency-associated nuclear antigen (LANA). However, how cellular proteins are recruited to the viral genome is not very clear. Here, we demonstrated that the host cellular protein, Bub1, is involved in KSHV latent DNA replication. We show that Bub1 constitutively interacts with proliferating cell nuclear antigen (PCNA) via a highly conserved PIP box motif within the kinase domain. Furthermore, we demonstrated that Bub1 can form a complex with LANA and PCNA in KSHV-positive cells. This strongly indicated that Bub1 serves as a scaffold or molecular bridge between LANA and PCNA. LANA recruited PCNA to the KSHV genome via Bub1 to initiate viral replication in S phase and interacted with PCNA to promote its monoubiquitination in response to UV-induced damage for translesion DNA synthesis. This resulted in increased survival of KSHV-infected cells. IMPORTANCEDuring latency in KSHV-infected cells, the viral episomal DNA replicates once each cell cycle. KSHV does not express DNA replication proteins during latency. Instead, KSHV LANA recruits the host cell DNA replication machinery to the replication origin. However, the mechanism by which LANA mediates replication is uncertain. Here, we show that LANA is able to form a complex with PCNA, a critical protein for viral DNA replication. Furthermore, our findings suggest that Bub1, a spindle checkpoint protein, serves as a scaffold or molecular bridge between LANA and PCNA. Our data further support a role for Bub1 and LANA in PCNA-mediated cellular DNA replication processes as well as monoubiquitination of PCNA in response to UV damage. These data reveal a therapeutic target for inhibition of KSHV persistence in malignant cells. K aposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8, an oncogenic member of the gammaherpesvirus subfamily, was first identified in 1994 from body cavity-based lymphoma (BCBL) and HIV-infected patients with Kaposi's sarcoma (KS) (1). KSHV is believed to be the etiological agent of several human cancers, including KS (1, 2), primary effusion lymphoma (PEL) or body cavity based lymphoma (3), and multicentric Castleman's disease (MCD) (4, 5). Additionally, there have been reports of KSHV-associated solid lymphomas in HIV-positive and -negative patients as well as KSHV-associated lymphomas in patients with primary immune deficiencies, such as common variable immune deficiency (6, 7). Similar to other members of the gammaherpesvirus family, KSHV establishes a predominantly latent infection in host cells after primary infection (8). During latent infections, the KSHV genome persists as a circular doublestranded DNA (episome) with most viral genes being silenced, except for a small number of latent genes, which include the viral cyclin (v-cyclin), the latency-associated nuclear antigen (LANA), and the viral FLICE inhibitory prote...

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“…During KSHV infection, host cells recognize viral proteins and nucleic acid and elicit innate immune responses to eliminate the invading viruses, while the viruses encode many immunomodulatory proteins to evade innate immune responses (8,10,27). The early events of the interaction of the virus and host cells during primary KSHV infection have not been fully demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Guanylate-Binding Protein 1 Inhibits Nuclear Delivery of Kaposi's Sarcoma-Associated Herpesvirus Virions by Disrupting Formation of Actin Filament

Zou

Meng

et al. 2017

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) is a typical gammaherpesvirus that establishes persistent lifelong infection in host cells. In order to establish successful infection, KSHV has evolved numerous immune evasion strategies to bypass or hijack the host immune system. However, host cells still produce immune cytokines abundantly during primary KSHV infection. Whether the immune effectors produced are able to inhibit viral infection and how KSHV successfully conquers these immune effectors remain largely unknown. The guanylate-binding protein 1 (GBP1) gene is an interferon-stimulated gene and exerts antiviral functions on several RNA viruses; however, its function in DNA virus infection is less well understood. In this study, we found that KSHV infection increases both the transcriptional and protein levels of GBP1 at the early stage of primary infection by activating the NF-B pathway. The overexpression of GBP1 significantly inhibited KSHV infection, while the knockdown of GBP1 promoted KSHV infection. The GTPase activity and dimerization of GBP1 were demonstrated to be responsible for its anti-KSHV activity. Furthermore, we found that GBP1 inhibited the nuclear delivery of KSHV virions by disrupting the formation of actin filaments. Finally, we demonstrated that replication and transcription activator (RTA) promotes the degradation of GBP1 through a proteasome pathway. Taken together, these results provide a new understanding of the antiviral mechanism of GBP1, which possesses potent anti-KSHV activity, and suggest the critical role of RTA in the evasion of the innate immune response during primary infection by KSHV. IMPORTANCE GBP1 can be induced by various cytokines and exerts antiviral activities against several RNA viruses. Our study demonstrated that GBP1 can exert anti-KSHV function by inhibiting the nuclear delivery of KSHV virions via the disruption of actin filaments. Moreover, we found that KSHV RTA can promote the degradation of GBP1 through a proteasome-mediated pathway. Taken together, our results elucidate a novel mechanism of GBP1 anti-KSHV activity and emphasize the critical role of RTA in KSHV evasion of the host immune system during primary infection.KEYWORDS KSHV, GBP1, GTPase activity, actin filaments, RTA, Kaposi's sarcomaassociated herpesvirus K aposi's sarcoma (KS)-associated herpesvirus (KSHV) belongs to the Gammaherpesviridae subfamily. It is a DNA tumor virus that causes several malignancies such as KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD) (1-3). KSHV displays two different phases in its life cycle: latent infection and lytic reactivation (4). To establish successful infection, KSHV needs to cross the plasma membrane and

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Cell signaling pathways engaged by KSHV

Cited by 45 publications

References 226 publications

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis

Guanylate-Binding Protein 1 Inhibits Nuclear Delivery of Kaposi's Sarcoma-Associated Herpesvirus Virions by Disrupting Formation of Actin Filament

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