Blockade of viral interleukin-6 expression of Kaposi's sarcoma–associated herpesvirus

Zhang, Yan‐Jin; Bonaparte, Rheba S.; Patel, Dil V.; Stein, David A.; Iversen, Patrick L.

doi:10.1158/1535-7163.mct-07-2036

Cited by 22 publications

(27 citation statements)

References 53 publications

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“…Increases in intracellular viral DNA levels 4 days post-induction in BCBL1 TReX-RTA cells were very modest (∼5–7 fold), in agreement with other reports [48], [49]; this level was further decreased when cells were electroporated prior to induction. The low levels of intracellular viral DNA make it difficult to conclude definitively whether the knockdown of PAN RNA specifically inhibits viral DNA replication.…”

Section: Resultssupporting

confidence: 92%

A Viral Nuclear Noncoding RNA Binds Re-localized Poly(A) Binding Protein and Is Required for Late KSHV Gene Expression

et al. 2011

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During the lytic phase of infection, the gamma herpesvirus Kaposi's Sarcoma-Associated Herpesvirus (KSHV) expresses a highly abundant, 1.1 kb nuclear noncoding RNA of unknown function. We observe that this polyadenylated nuclear (PAN) RNA avidly binds host poly(A)-binding protein C1 (PABPC1), which normally functions in the cytoplasm to bind the poly(A) tails of mRNAs, regulating mRNA stability and translation efficiency. During the lytic phase of KSHV infection, PABPC1 is re-localized to the nucleus as a consequence of expression of the viral shutoff exonuclease (SOX) protein; SOX also mediates the host shutoff effect in which host mRNAs are downregulated while viral mRNAs are selectively expressed. We show that whereas PAN RNA is not required for the host shutoff effect or for PABPC1 re-localization, SOX strongly upregulates the levels of PAN RNA in transient transfection experiments. This upregulation is destroyed by the same SOX mutation that ablates the host shutoff effect and PABPC1 nuclear re-localization or by removal of the poly(A) tail of PAN. In cells induced into the KSHV lytic phase, depletion of PAN RNA using RNase H-targeting antisense oligonucleotides reveals that it is necessary for the production of late viral proteins from mRNAs that are themselves polyadenylated. Our results add to the repertoire of functions ascribed to long noncoding RNAs and suggest a mechanism of action for nuclear noncoding RNAs in gamma herpesvirus infection.

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Section: Resultssupporting

confidence: 92%

A Viral Nuclear Noncoding RNA Binds Re-localized Poly(A) Binding Protein and Is Required for Late KSHV Gene Expression

et al. 2011

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“…Depletion of vIL-6 in these cells induces apoptosis and slows the rate of cell growth (Chen et al 2009a). Similar growth effects were observed with intracellularly delivered single-chain antibody and peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) directed to vIL-6 and its transcript (Kovaleva et al 2006; Zhang et al 2008). Fully ER-retained vIL-6 (cloned to include an ER-targeting KDEL motif) is capable of rescuing the growth effects mediated by vIL-6 depletion (Chen et al 2009a).…”

Section: Hhv-8 Latency Products and Autocrine Dysregulationsupporting

confidence: 53%

Molecular Biology of Human Herpesvirus 8: Novel Functions and Virus–Host Interactions Implicated in Viral Pathogenesis and Replication

Cousins

Nicholas

2013

Recent Results in Cancer Research

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Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), is the second identified human gammaherpesvirus. Like its relative Epstein-Barr virus, HHV-8 is linked to B-cell tumors, specifically primary effusion lymphoma and multicentric Castleman’s disease, in addition to endothelial-derived KS. HHV-8 is unusual in its possession of a plethora of “accessory” genes and encoded proteins in addition to the core, conserved herpesvirus and gammaherpesvirus genes that are necessary for basic biological functions of these viruses. The HHV-8 accessory proteins specify not only activities deducible from their cellular protein homologies but also novel, unsuspected activities that have revealed new mechanisms of virus–host interaction that serve virus replication or latency and may contribute to the development and progression of virus-associated neoplasia. These proteins include viral interleukin-6 (vIL-6), viral chemokines (vCCLs), viral G protein–coupled receptor (vGPCR), viral interferon regulatory factors (vIRFs), and viral antiapoptotic proteins homologous to FLICE (FADD-like IL-1β converting enzyme)-inhibitory protein (FLIP) and survivin. Other HHV-8 proteins, such as signaling membrane receptors encoded by open reading frames K1 and K15, also interact with host mechanisms in unique ways and have been implicated in viral pathogenesis. Additionally, a set of micro-RNAs encoded by HHV-8 appear to modulate expression of multiple host proteins to provide conditions conducive to virus persistence within the host and could also contribute 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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“…This was the primary goal of the present study. Previously, investigations touching on this issue have demonstrated that vIL-6 is capable of signaling in the ER when directed to this compartment by virtue of "KDEL" tagging (19), that ER-targeted single-chain antibodies specific for vIL-6 are able to inhibit vIL-6 signaling in HepG2 cells (16), and that vIL-6 depletion in PEL cells negatively affects cell growth (30). However, these results do not demonstrate that vIL-6 is naturally located predominantly in the ER, nor do they address the nature of the vIL-6-induced signaling complexes in this compartment or the biological activities specifically associated with ER signaling by vIL-6.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Signaling Mechanisms and Activities of Human Herpesvirus 8 Interleukin-6

Chen

Sandford

Nicholas

2009

J Virol

122

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Human herpesvirus 8 (HHV-8)-encoded viral interleukin-6 (vIL-6) has been implicated as a key factor in virus-associated neoplasia because of its proproliferative and survival effects and also in view of its angiogenic properties. A major difference between vIL-6 and human IL-6 (hIL-6) is that vIL-6, uniquely, is largely retained and can signal intracellularly. While vIL-6 is generally considered to be a lytic gene, several reports have noted its low-level expression in latently infected primary effusion lymphoma (PEL) cultures, in the absence of other lytic gene expression. Thus, intracellular autocrine signal transduction by the viral cytokine may be of particular relevance to the growth and survival of latently infected cells and to pathogenesis. Here we report that most intracellular vIL-6 is located in the endoplasmic reticulum (ER), signals via the gp130 signal transducer in this compartment, and does so independently of the gp80 ␣-subunit of the IL-6 receptor, required for hIL-6 signal transduction. Signaling and biological assays incorporating ER-retained vIL-6 and hIL-6 confirmed vIL-6 activity, specifically, in this compartment. Knockdown of vIL-6 expression in PEL cells led to markedly reduced cell growth in normal culture, independently of extracellular cytokines. This could be reversed by reintroduction via virus vector of exclusively ER-retained vIL-6. These data indicate that in virus biology vIL-6 may act to support the growth and survival of cells latently infected with HHV-8 in an autocrine manner via intracrine signaling and that these activities may contribute to the maintenance of latently infected cells and to virus-induced neoplasia.

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Blockade of viral interleukin-6 expression of Kaposi's sarcoma–associated herpesvirus

Abstract: Kaposi's sarcoma -associated herpesvirus

Cited by 22 publications

References 53 publications

A Viral Nuclear Noncoding RNA Binds Re-localized Poly(A) Binding Protein and Is Required for Late KSHV Gene Expression

A Viral Nuclear Noncoding RNA Binds Re-localized Poly(A) Binding Protein and Is Required for Late KSHV Gene Expression

Molecular Biology of Human Herpesvirus 8: Novel Functions and Virus–Host Interactions Implicated in Viral Pathogenesis and Replication

Intracellular Signaling Mechanisms and Activities of Human Herpesvirus 8 Interleukin-6

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