Highly Selective Escape from KSHV-mediated Host mRNA Shutoff and Its Implications for Viral Pathogenesis

Glaunsinger, Britt A.; Ganem, Don

doi:10.1084/jem.20031881

Cited by 101 publications

(125 citation statements)

References 25 publications

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“…A KSHV lytic gene, ORF74, which encodes a viral G-protein-coupled receptor (vGPCR), can lead to the activation of HIF1␣ when ectopically expressed, though this is not at the transcriptional level (51). Interestingly, HIF1␣ mRNA escapes lytic KSHV-induced host shutoff in endothelial cells and this was shown to be separable from the activity of the vGPCR (21). Also, work in a PEL cell line demonstrated an increase in lytic reactivation mediated by hypoxia (13) and the same group identified functional HREs within the KSHV genome (23).…”

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confidence: 85%

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Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells Activates Hypoxia-Induced Factors

Carroll¹,

Kenerson

Yeung

et al. 2006

J Virol

102

113

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Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is the etiological agent of Kaposi's sarcoma, a highly vascularized, endothelial-derived tumor. A direct role for KSHV-mediated induction of angiogenesis has been proposed based upon the nature of the neoplasia and various KSHV gene overexpression and infection model systems. We have found that KSHV infection of endothelial cells induces mRNA of hypoxia-induced factor 1␣ (HIF1␣) and HIF2␣, two homologous alpha subunits of the heterodimeric transcription factor HIF. HIF is a master regulator of both developmental and pathological angiogenesis, composed of an oxygensensitive alpha subunit and a constitutively expressed beta subunit. HIF is classically activated posttranscriptionally with hypoxia, leading to increased protein stability of HIF1␣ and/or HIF2␣. However, we demonstrate that both alpha subunits are up-regulated at the transcript level by KSHV infection. The transcriptional activation of HIF leads to a functional increase in HIF activity under normoxic conditions, as demonstrated by both luciferase reporter assay and the increased expression of vascular endothelial growth factor receptor 1 (VEGFR1), an HIF-responsive gene. KSHV infection synergizes with hypoxia mimics and induces higher expression levels of HIF1␣ and HIF2␣ protein, and HIF1␣ is increased in a significant proportion of the latently infected endothelial cells. Src family kinases are required for the activation of HIF and the downstream gene VEGFR1 by KSHV. We also show that KS lesions, in vivo, express elevated levels of HIF1␣ and HIF2␣ proteins. Thus, KSHV stimulates the HIF pathway via transcriptional up-regulation of both HIF alphas, and this activation may play a role in KS formation, localization, and progression.

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confidence: 85%

“…VEGFR1 is not induced by KSHV lytic gene expression. HIF1␣ mRNA can survive host shutoff during lytic KSHV infection (21). The effects of lytic reactivation on TIME cell VEGFR1 expression was monitored by Western blot analysis of cells induced to go lytic.…”

Section: Kshv Induces Hif Alpha Transcripts Upon Infection Of Endothementioning

confidence: 99%

Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells Activates Hypoxia-Induced Factors

Carroll¹,

Kenerson

Yeung

et al. 2006

J Virol

102

113

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“…The IL-6 mRNA is directly refractory to SOX cleavage and thus remains robustly induced during host shutoff due to the presence of a specific 'SOX resistance element' (SRE) [26,29]. Even in the absence of infection, reporter mRNAs bearing the IL-6 SRE remain stable in SOX-expressing cells, an observation that has helped delineate features of this novel RNA element required for the protective phenotype [26,27].…”

Section: Introductionmentioning

confidence: 95%

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

Muller

Glaunsinger

2017

Preprint

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During lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection, the viral endonuclease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs, including the transcript encoding interleukin-6 (IL-6), escape SOX-induced cleavage. IL-6 escape is mediated through a 3' UTR RNA regulatory element that overrides the SOX targeting mechanism. Here, we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases. However, it does not impede cleavage by cellular endonucleases. The IL-6 protective sequence may be representative of a larger class of nuclease escape elements, as we identified a similar protective element in the GADD45B mRNA. The IL-6 and GADD45B-derived elements display similarities in their sequence, putative structure, and several associated RNA binding proteins. However, the overall composition of their ribonucleoprotein complexes appears distinct, leading to differences in the breadth of nucleases restricted. These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus-induced mRNA degradation.

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“…The fact that vGPCR expression triggers an angiogenic gene program has led to the hypothesis that vGPCR contributes to angioproliferation and tumorigenesis via paracrine mechanisms (9,10,(15)(16)(17). The relevance of this mechanism in cells undergoing lysis has been questioned because expression of most vGPCR target genes is drastically curtailed during the lytic cycle (18). Others, however, have speculated that dysregulation of the viral gene program may lead to nonlytic expression of vGPCR and favor development of KS (5,10).…”

Section: Introductionmentioning

confidence: 99%

The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells

Grisotto

Garin²,

Martín³

et al. 2006

Journal of Clinical Investigation

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We have used a novel conditional transgenic system to study the mechanisms of angioproliferation induced by viral G protein-coupled receptor (vGPCR), the constitutively active chemokine receptor encoded by human herpesvirus 8 (HHV8, also known as Kaposi sarcoma herpesvirus). Using this system, we were able to control temporal expression of vGPCR and to monitor its expression in situ via the use of the surrogate marker LacZ. Our lab and others have shown that transgenic expression of viral G protein-coupled receptor (vGPCR), the chemokine receptor encoded by HHV8 ORF74, induces development of angioproliferative lesions that resemble those seen in KS (9-11). In our model, the lesions are observed in ears, limbs, and tail and progress from erythematous lesions to nodules and tumors within 6 months (9). The lesions are composed of large numbers of spindleshaped CD34 + cells, vascular channels, and inflammatory cells. Conditional expression of vGPCR triggers expression of several angiogenic factors in lesional areas, and its inactivation results in regression of the angioproliferative lesions (12).

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Highly Selective Escape from KSHV-mediated Host mRNA Shutoff and Its Implications for Viral Pathogenesis

Cited by 101 publications

References 25 publications

Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells Activates Hypoxia-Induced Factors

Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells Activates Hypoxia-Induced Factors

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells

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