Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Targets Expression of Cellular IRF4 and the Myc Gene To Facilitate Lytic Replication

Lee, Hye‐Ra; Doğanay, Sultan; Chung, Brian; Tóth, Zsolt; Brulois, Kevin; Lee, Stacy; Kanketayeva, Zhansaya; Feng, Pinghui; Ha, Taekjip; Jung, Jae U.

doi:10.1128/jvi.02106-13

Cited by 33 publications

(29 citation statements)

References 44 publications

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“…vIRFs were believed to be unable to directly bind DNA as a result of the absence of the tryptophan residues that are essential for DNA binding (9). However, some evidence suggested that vIRFs might play unexpected roles in transcription regulation, and recent studies showed vIRF4 may compete with c-IRF4 for binding to the specific promoter region of the c-Myc gene (21,38). A consensus sequence interacting with vIRF1 from a pool of random oligonucleotides in the KSHV genome was identified recently (21).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Mapping of the Binding Sites and Structural Analysis of Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 2 Reveal that It Is a DNA-Binding Transcription Factor

Dong

Liang

et al. 2016

J Virol

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The oncogenic herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is known to encode four viral interferon regulatory factors (vIRF1 to -4) to subvert the host antiviral immune response, but their detailed DNA-binding profiles as transcription factors in the host remain uncharacterized. Here, we first performed genome-wide vIRF2-binding site mapping in the human genome using chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq). vIRF2 was capable of binding to the promoter regions of 100 putative target genes. Importantly, we confirmed that vIRF2 can specifically interact with the promoters of the genes encoding PIK3C3, HMGCR, and HMGCL, which are associated with autophagosome formation or tumor progression and metastasis, and regulate their transcription in vivo. The crystal structure of the vIRF2 DNA-binding domain (DBD) (referred to here as vIRF2 DBD ) showed variable loop conformations and positive-charge distributions different from those of vIRF1 and cellular IRFs that are associated with DNA-binding specificities. Structure-based mutagenesis revealed that Arg82 and Arg85 are required for the in vitro DNA-binding activity of vIRF2 DBD and can abolish the transcription regulation function of vIRF2 on the promoter reporter activity of PIK3C3, HMGCR, and HMGCL. Collectively, our study provided unique insights into the DNA-binding potency of vIRF2 and suggested that vIRF2 could act as a transcription factor of its target genes in the host antiviral immune response. IMPORTANCEThe oncogenic herpesvirus KSHV is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. KSHV has developed a unique mechanism to subvert the host antiviral immune responses by encoding four homologues of cellular interferon regulatory factors (vIRF1 to -4). However, none of their DNA-binding profiles in the human genome have been characterized until now, and the structural basis for their diverse DNA-binding properties remain poorly understood. In this study, we performed the first genome-wide vIRF2-binding site mapping in the human genome and found vIRF2 can bind to the promoter regions of 100 target cellular genes. X-ray structure analysis and functional studies provided unique insights into its DNA-binding potency and regulation of target gene expression. Our study suggested that vIRF2 could act as a transcription factor of its target genes and contribute to KSHV infection and pathogenesis through versatile functions. K aposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD) (1-3). Moreover, KS is the first tumor to be associated with HIV infection and the most common AIDS-associated malignancy in sub-Saharan Africa and the second most common cancer in HIV-infected patients (2-5). KSHV has developed a unique mechanism to subvert host antiviral immune responses by encoding four homologu...

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Mapping of the Binding Sites and Structural Analysis of Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 2 Reveal that It Is a DNA-Binding Transcription Factor

Dong

Liang

et al. 2016

J Virol

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“…The late-acting aspect of protein is beyond the scope of this review, and we refer the reader to (Pflanz et al, 2002). KSHV has many mimics, which include three cysteine-cysteine (CC)-chemokines, an IL-6 mimic, and viral versions of IRF proteins (Burýšek and Pitha, 2001; Burýšek et al, 1999; Joo et al, 2007; Lee et al, 2014; Molden et al, 1997; Yamin et al, 2013). …”

Section: Viral Mimicry Of Host Factors To Inhibit Immune Responsesmentioning

confidence: 99%

Diverse mechanisms evolved by DNA viruses to inhibit early host defenses

Crow

Lum

Sheng

et al. 2016

Critical Reviews in Biochemistry and Molecular Biology

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In mammalian cells, early defenses against infection by pathogens are mounted through a complex network of signaling pathways shepherded by immune-modulatory pattern-recognition receptors. As obligate parasites, the survival of viruses is dependent upon the evolutionary acquisition of mechanisms that tactfully dismantle and subvert the cellular intrinsic and innate immune responses. Here, we review the diverse mechanisms by which viruses that accommodate DNA genomes are able to circumvent activation of cellular immunity. We start by discussing viral manipulation of host defense protein levels by either transcriptional regulation or protein degradation. We next review viral strategies used to repurpose or inhibit these cellular immune factors by molecular hijacking or by regulating their post-translational modification status. Additionally, we explore the infection-induced temporal modulation of apoptosis to facilitate viral replication and spread. Lastly, the co-evolution of viruses with their hosts is highlighted by the acquisition of elegant mechanisms for suppressing host defenses via viral mimicry of host factors. In closing, we present a perspective on how characterizing these viral evasion tactics both broadens the understanding of virus-host interactions and reveals essential functions of the immune system at the molecular level. This knowledge is critical in understanding the sources of viral pathogenesis, as well as for the design of antiviral therapeutics and autoimmunity treatments.

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“…For example, the KSHV encoded viral FLICE inhibitory protein (vFLIP) induces IRF4 expression by activation of NF-κB signaling (Forero et al, 2013). During KSHV replication, the cellular form of IRF4 (cIRF4) is inhibited by viral IRF4 (vIRF4) which subsequently suppresses c-myc expression to induce viral lytic cycle (Lee et al, 2014). Furthermore, IRF4 is expressed in PEL however; the functional significance of IRF4 expression in KSHV associated PEL is still ambiguous (Arguello et al, 2003).…”

Section: Viral Infections and Associated Malignanciesmentioning

confidence: 99%

IRF4 and IRF8: governing the virtues of B lymphocytes

Shukla

2014

Front. Biol.

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Interferon Regulatory Factor 4 (IRF4) and IRF8 are critical regulators of immune system development and function. In B lymphocytes, IRF4 and IRF8 have been shown to control important events during their development and maturation including pre-B cell differentiation, induction of B cell tolerance pathways, marginal zone B cell development, germinal center reaction and plasma cell differentiation. Mechanistically, IRF4 and IRF8 are found to function redundantly to control certain stages of B cell development, but in other stages, they function nonredundantly to play distinct roles in B cell biology. In line with their essential roles in B cell development, deregulated expressions of IRF4 and IRF8 have been associated to the pathogenesis of several B cell malignancies and diseases. Recent studies have elucidated diverse transcriptional networks regulated by IRF4 and IRF8 at distinct B cell developmental stages and related malignancies. In this review we will discuss the recent advances for the roles of IRF4 and IRF8 during B cell development and associated diseases.

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Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Targets Expression of Cellular IRF4 and the Myc Gene To Facilitate Lytic Replication

Cited by 33 publications

References 44 publications

Genome-Wide Mapping of the Binding Sites and Structural Analysis of Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 2 Reveal that It Is a DNA-Binding Transcription Factor

Genome-Wide Mapping of the Binding Sites and Structural Analysis of Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 2 Reveal that It Is a DNA-Binding Transcription Factor

Diverse mechanisms evolved by DNA viruses to inhibit early host defenses

IRF4 and IRF8: governing the virtues of B lymphocytes

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