Leucine Zipper Domain Is Required for Kaposi Sarcoma-associated Herpesvirus (KSHV) K-bZIP Protein to Interact with Histone Deacetylase and Is Important for KSHV Replication

Martinez, Francisco W. Puerta; Tang, Qiyi

doi:10.1074/jbc.m111.315861

Cited by 21 publications

(18 citation statements)

References 69 publications

(61 reference statements)

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“…HCMV encodes IE1, IE2, and pUL29/28, which target HDACs to promote viral gene expression during lytic infection (13)(14)(15). Paradoxically, Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded K-bZIP has recently been shown to recruit HDAC1 and -2 to KSHV RTA promoters during reactivation (16). While treatment with HDAC inhibitors enhances immediate early mouse gammaherpesvirus-68 (MHV68) gene expression during de novo lytic infection and induces reactivation of Epstein-Barr virus (EBV), KSHV, and MHV68 (17)(18)(19), the mechanisms by which gammaherpesviruses counteract HDACs during lytic replication remain poorly understood.…”

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confidence: 99%

A Conserved Gammaherpesvirus Protein Kinase Targets Histone Deacetylases 1 and 2 To Facilitate Viral Replication in Primary Macrophages

Mounce

Mboko

Bigley

et al. 2013

J Virol

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Gammaherpesviruses are ubiquitious pathogens that establish lifelong infection and are associated with several malignancies. All gammaherpesviruses encode a conserved protein kinase that facilitates viral replication and chronic infection and thus represents an attractive therapeutic target. In this study, we identify a novel function of gammaherpesvirus protein kinase as a regulator of class I histone deacetylases (HDAC). Mouse gammaherpesvirus 68 (MHV68)-encoded protein kinase orf36 interacted with HDAC1 and 2 and prevented association of these HDACs with the viral promoter driving expression of RTA, a critical immediate early transcriptional activator. Furthermore, the ability to interact with HDAC1 and 2 was not limited to the MHV68 orf36, as BGLF4, a related viral protein kinase encoded by Epstein-Barr virus, interacted with HDAC1 in vitro. Importantly, targeting of HDAC1 and 2 by orf36 was independent of the kinase's enzymatic activity. Additionally, orf36 expression, but not its enzymatic activity, induced changes in the global deacetylase activity observed in infected primary macrophages. Combined deficiency of HDAC1 and 2 rescued attenuated replication and viral DNA synthesis of the orf36 null MHV68 mutant, indicating that the regulation of HDAC1 and 2 by orf36 was relevant for viral replication. Understanding the mechanism by which orf36 facilitates viral replication, including through HDAC targeting, will facilitate the development of improved therapeutics against gammaherpesvirus kinases.

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confidence: 99%

A Conserved Gammaherpesvirus Protein Kinase Targets Histone Deacetylases 1 and 2 To Facilitate Viral Replication in Primary Macrophages

Mounce

Mboko

Bigley

et al. 2013

J Virol

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“…Induction of KSHV lytic gene expression, governed by the lytic “switch” gene ORF50, typically results in PEL cell death 42–44), and this concept has been explored as a therapeutic strategy given that standard cytotoxic agents, as well as bortezomib and valproic acid (the latter a histone deacetylase inhibitor used for a variety of clinical applications), induce lytic gene expression and reduce PEL cell viability (36, 37, 42, 45). KSHV lytic gene expression is inhibited through histone deacetylase (HDAC) binding to ORF50, (46), and viral genes expressed predominantly during lytic replication suppress HDAC activity (47). A role for SphK in epigenetic regulation was revealed through its direct association with core histone H3 and generation of intranuclear S1P which binds active sites on HDACs to inhibit their enzymatic activity (48).…”

Section: Discussionmentioning

confidence: 99%

Targeting Sphingosine Kinase Induces Apoptosis and Tumor Regression for KSHV-Associated Primary Effusion Lymphoma

Qin

Dai

Trillo-Tinoco

et al. 2014

Molecular Cancer Therapeutics

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Sphingosine kinase (SphK) is overexpressed by a variety of cancers, and its phosphorylation of sphingosine results in accumulation of sphingosine-1-phosphate (S1P) and activation of anti-apoptotic signal transduction. Existing data indicate a role for S1P in viral pathogenesis, but roles for SphK and S1P in virus-associated cancer progression have not been defined. Rare pathologic variants of diffuse large B-cell lymphoma arise preferentially in the setting of HIV infection, including primary effusion lymphoma (PEL), a highly mortal tumor etiologically linked to the Kaposi’s sarcoma-associated herpesvirus (KSHV). We have found that ABC294640, a novel clinical-grade small molecule selectively targeting SphK (SphK2 >> SphK1), induces dose-dependent caspase cleavage and apoptosis for KSHV+ patient-derived PEL cells, in part though inhibition of constitutive signal transduction associated with PEL cell proliferation and survival. These results were validated with induction of PEL cell apoptosis using SphK2-specific siRNA, as well as confirmation of drug-induced SphK inhibition in PEL cells with dose-dependent accumulation of pro-apoptotic ceramides and reduction of intracellular S1P. Furthermore, we demonstrate that systemic administration of ABC294640 induces tumor regression in an established human PEL xenograft model. Complimentary ex vivo analyses revealed suppression of signal transduction and increased KSHV lytic gene expression within drug-treated tumors, with the latter validated in vitro through demonstration of dose-dependent viral lytic gene expression within PEL cells exposed to ABC294640. Collectively, these results implicate interrelated mechanisms and SphK2 inhibition in the induction of PEL cell death by ABC294640 and rationalize evaluation of ABC294640 in clinical trials for the treatment of KSHV-associated lymphoma.

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“…The involvement of HDAC1 and -2 in the induction of the type I IFN response illuminates a novel aspect of the interaction between herpesviruses and class I HDACs. Multiple reports identified viral proteins encoded by all three families of herpesviruses that target class I HDACs, including HDAC1 and -2, presumably to relieve HDAC-mediated repression of viral genes (51)(52)(53)(54)(55)(56)(57)(58). Furthermore, global HDAC inhibition induces reactivation of EBV, KSHV, and MHV68 (59-61); however, it is not known whether HDACs directly affect viral gene expression during reactivation.…”

Section: Discussionmentioning

confidence: 99%

Primary Macrophages Rely on Histone Deacetylase 1 and 2 Expression To Induce Type I Interferon in Response to Gammaherpesvirus Infection

Mounce

Mboko

Kanack

et al. 2014

J Virol

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Type I interferon is induced shortly following viral infection and represents a first line of host defense against a majority of viral pathogens. Not surprisingly, both replication and latency of gammaherpesviruses, ubiquitous cancer-associated pathogens, are attenuated by type I interferon, although the mechanism of attenuation remains poorly characterized. Gammaherpesviruses also target histone deacetylases (HDACs), a family of pleiotropic enzymes that modify gene expression and several cell signaling pathways. Specifically, we have previously shown that a conserved gammaherpesvirus protein kinase interacts with HDAC1 and -2 to promote gammaherpesvirus replication in primary macrophages. In the current study, we have used genetic approaches to show that expression of HDAC1 and -2 is critical for induction of a type I interferon response following gammaherpesvirus infection of primary macrophages. Specifically, expression of HDAC1 and -2 was required for phosphorylation of interferon regulatory factor 3 (IRF3) and accumulation of IRF3 at the beta interferon promoter in gammaherpesvirus-infected primary macrophages. To our knowledge, this is the first demonstration of a specific role for HDAC1 and -2 in the induction of type I interferon responses in primary immune cells following virus infection. Furthermore, because HDAC1 and -2 are overexpressed in several types of cancer, our findings illuminate potential side effects of HDAC1-and -2-specific inhibitors that are currently under development as cancer therapy agents. IMPORTANCEGammaherpesviruses establish chronic infection in a majority of the adult population and are associated with several malignancies. Infected cells counteract gammaherpesvirus infection via innate immune signaling mediated primarily through type I interferon. The induction of type I interferon expression proceeds through several stages using molecular mechanisms that are still incompletely characterized. In this study, we show that expression of HDAC1 and -2 by macrophages is required to mount a type I interferon response to incoming gammaherpesvirus. The involvement of HDAC1 and -2 in the type I interferon response highlights the pleiotropic roles of these enzymes in cellular signaling. Interestingly, HDAC1 and -2 are deregulated in cancer and are attractive targets of new cancer therapies. Due to the ubiquitous and chronic nature of gammaherpesvirus infection, the role of HDAC1 and -2 in the induction of type I interferon responses should be considered during the clinical development of HDAC1-and -2-specific inhibitors.

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Leucine Zipper Domain Is Required for Kaposi Sarcoma-associated Herpesvirus (KSHV) K-bZIP Protein to Interact with Histone Deacetylase and Is Important for KSHV Replication

Cited by 21 publications

References 69 publications

A Conserved Gammaherpesvirus Protein Kinase Targets Histone Deacetylases 1 and 2 To Facilitate Viral Replication in Primary Macrophages

A Conserved Gammaherpesvirus Protein Kinase Targets Histone Deacetylases 1 and 2 To Facilitate Viral Replication in Primary Macrophages

Targeting Sphingosine Kinase Induces Apoptosis and Tumor Regression for KSHV-Associated Primary Effusion Lymphoma

Primary Macrophages Rely on Histone Deacetylase 1 and 2 Expression To Induce Type I Interferon in Response to Gammaherpesvirus Infection

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