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

Mounce, Bryan C.; Mboko, Wadzanai P.; Bigley, Tarin M.; Terhune, Scott S.; Tarakanova, Vera L.

doi:10.1128/jvi.02713-12

Cited by 14 publications

(28 citation statements)

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“…In the absence of orf36, attenuated viral DNA synthesis and replication were rescued in HDAC1 and -2-depleted primary macrophages (25). Thus, we hypothesized that a cellular pathway (or pathways) dependent on HDAC1 and -2 may restrict viral replication and that the antiviral impact of this pathway is neutralized by orf36.…”

Section: Expression Of Interferon-stimulated Genes Is Attenuated In Hmentioning

confidence: 97%

“…C57BL/6J (BL6) mice were obtained from Jackson Laboratories (Bar Harbor, ME). HDAC1/2 flox/flox (HDAC1/2 F/F) mice (28) were crossed to mice expressing modified estrogen receptor-Cre fusion protein under the control of the Rosa promoter (29) (obtained from Jackson Laboratories) to generate HDAC1/2 F/F ϫ ER-Cre mice as previously described (25).…”

Section: Methodsmentioning

confidence: 99%

“…Bone marrow was harvested from mice between 3 and 10 weeks of age. Primary bone marrow-derived macrophages were generated and treated with 4-hydroxytamoxifen (OHT) as previously described (25). HDAC1/2 protein depletion was confirmed at 13 days posttreatment, before the initiation of the experiment.…”

Section: Irf3mentioning

confidence: 99%

“…To determine the extent to which HDAC1 and -2 regulated the type I IFN response during MHV68 infection of primary macrophages, we utilized a mouse model of inducible HDAC1 and -2 depletion (25). Primary bone marrow-derived macrophages generated from these mice were treated with 4-hydroxytamoxifen (OHT) during in vitro culture to induce depletion of HDAC1 and -2 ( Fig.…”

Section: Expression Of Interferon-stimulated Genes Is Attenuated In Hmentioning

confidence: 99%

“…Murine gammaherpesvirus 68 (MHV68) is genetically and biologically related to the human gammaherpesviruses and offers an experimental system that overcomes the challenges associated with the exquisite species specificity of EBV and KSHV (23,24). We have previously shown that orf36, a conserved gammaherpesvirus protein kinase encoded by MHV68, targets HDAC1 and -2 to facilitate viral DNA synthesis and replication in primary macrophages (25). Because herpesvirus protein kinases encoded by EBV, MHV68, KSHV (26), and herpes simplex virus 1 (HSV-1) (27) also attenuate antiviral effects of type I IFN, we used the phenotypes revealed by orf36 to probe the potential cross talk between HDAC1 and -2 and type I IFN responses.…”

mentioning

confidence: 99%

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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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Section: Expression Of Interferon-stimulated Genes Is Attenuated In Hmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Irf3mentioning

confidence: 99%

Section: Expression Of Interferon-stimulated Genes Is Attenuated In Hmentioning

confidence: 99%

mentioning

confidence: 99%

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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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Direct Substrate Identification with an Analog Sensitive (AS) Viral Cyclin-Dependent Kinase (v-Cdk)

2017

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Viral cyclin-dependent kinases (v-Cdks) functionally emulate their cellular Cdk counterparts. Such viral mimicry is an established phenomenon that we extend here through chemical genetics. Kinases contain gatekeeper residues that limit the size of molecules that can be accommodated within the enzyme active site. Mutating gatekeeper residues to smaller amino acids allows larger molecules access to the active site. Such mutants can utilize bio-orthoganol ATPs for phosphate transfer and are inhibited by compounds ineffective against the wild type protein, and thus are referred to as analog-sensitive (AS) kinases. We identified the gatekeeper residues of the v-Cdks encoded by Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) and mutated them to generate AS kinases. The AS-v-Cdks are functional and utilize different ATP derivatives with a specificity closely matching their cellular ortholog, AS-Cdk2. The AS derivative of the EBV v-Cdk was used to transfer a thiolated phosphate group to targeted proteins which were then purified through covalent capture and identified by mass spectrometry. Pathway analysis of these newly identified direct substrates of the EBV v-Cdk extends the potential influence of this kinase into all stages of gene expression (transcription, splicing, mRNA export, and translation). Our work demonstrates the biochemical similarity of the cellular and viral Cdks, as well as the utility of AS v-Cdks for substrate identification to increase our understanding of both viral infections and Cdk biology.

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Patho-epigenetics: histone deacetylases as targets of pathogens and therapeutics

et al. 2021

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In recent years the interplay of epigenetics and infection moved into the limelight. Epigenetic regulation describes modifications in gene expression without alterations of the DNA sequence. In eukaryotes, this mechanism is central for fundamental cellular processes such as cell development and differentiation, but it is also involved in more specific tasks such as the response to infection by a pathogen. One of the most common types of epigenetic changes is the modification of histones. Histones, the small protein building blocks that are wrapped with DNA are the fundamental packaging unit of chromatin. Histones can be modified by linking different moieties to them—one of the most abundant ones is acetylation. Histone acetylation is regulated by two main classes of enzymes, histone acetyl transferases (HAT) and their counterparts, histone deacetylases (HDAC). Given the high abundance and importance in regulating gene expression, histone acetylation is an excellent target for pathogens to manipulate the host cell to their advantage. Targeting HDACs gained particular interest in recent years, due to the increased use of HDAC inhibitors in clinical practice. Recently, the possibility to fight an infection with HDAC inhibitors was suggested as an alternative to overcome the ever-growing problem of antibiotic resistance. In this review we focus on the regulation of HDACs and their involvement in immune cell function. We then highlight different mechanisms employed by pathogens to manipulate histone deacetylases and we discuss the possibility of HDAC inhibitors as therapeutics to fight infections.

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

Cited by 14 publications

References 54 publications

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

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

Direct Substrate Identification with an Analog Sensitive (AS) Viral Cyclin-Dependent Kinase (v-Cdk)

Patho-epigenetics: histone deacetylases as targets of pathogens and therapeutics

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