Role of ORF74-Encoded Viral G Protein-Coupled Receptor in Human Herpesvirus 8 Lytic Replication

Sandford, Gordon R.; Choi, Young Bong; Nicholas, John

doi:10.1128/jvi.01399-09

Cited by 25 publications

(14 citation statements)

References 26 publications

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“…It seems counterintuitive that vGPCR is implicated in KSHV-induced tumorigenesis, because vGPCR is an early lytic gene and cells supporting lytic viral replication are destined to die [31, 32]. It is only expressed in a small subset of cells (∼5%) in human KS or KS-like lesions in model animals [25, 29, 30, 33].…”

Section: Kshv Vgpcrmentioning

confidence: 99%

Hijacking GPCRs by viral pathogens and tumor

Zhang

Feng

et al. 2016

Biochemical Pharmacology

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G protein-coupled receptors (GPCRs) constitute the largest family of molecules that transduce signal across the plasma membrane. Herpesviruses are successful pathogens that evolved diverse mechanisms to benefit their infection. Several human herpesviruses express GPCRs to exploit cellular signaling cascades during infection. These viral GPCRs demonstrate distinct biochemical and biophysical properties that result in the activation of a broad spectrum of signaling pathways. In immune-deficient individuals, human herpesvirus infection and the expression of their GPCRs are implicated in virus-associated diseases and pathologies. Emerging studies also uncover diverse mutations in components, particularly GPCRs and small G proteins, of GPCR signaling pathways that render the constitutive activation of proliferative and survival signal, which contributes to the oncogenesis of various human cancers. Hijacking GPCR-mediated signaling is a signature shared by diseases associated with constitutively active viral GPCRs and cellular mutations activating GPCR signaling, exposing key molecules that can be targeted for anti-viral and anti-tumor therapy.

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Section: Kshv Vgpcrmentioning

confidence: 99%

Hijacking GPCRs by viral pathogens and tumor

Zhang

Feng

et al. 2016

Biochemical Pharmacology

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“…For instance, Pim1 and Pim3, proto-oncoproteins involved in cell cycle and apoptotic pathways, upregulate Rta autoactivation by binding to and repressing LANA’s inhibition of the Rta promoter [ 86 ]. Viral G protein coupled receptor (vGPCR) may also negate LANA inhibition by reducing HDAC activity to allow for Sp1- and Sp3-dependent Rta promoter activity [ 87 , 88 ]. Hypoxia inducible factor (HIF)-1α can directly activate the Rta promoter, due to the presence of several putative hypoxic response elements (HREs) [ 69 , 89 , 90 ].…”

Section: Function and Regulation Of Rta Lytic Switch Proteinmentioning

confidence: 99%

KSHV Reactivation and Novel Implications of Protein Isomerization on Lytic Switch Control

Guito

Lukac

2015

Viruses

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In Kaposi’s sarcoma-associated herpesvirus (KSHV) oncogenesis, both latency and reactivation are hypothesized to potentiate tumor growth. The KSHV Rta protein is the lytic switch for reactivation. Rta transactivates essential genes via interactions with cofactors such as the cellular RBP-Jk and Oct-1 proteins, and the viral Mta protein. Given that robust viral reactivation would facilitate antiviral responses and culminate in host cell lysis, regulation of Rta’s expression and function is a major determinant of the latent-lytic balance and the fate of infected cells. Our lab recently showed that Rta transactivation requires the cellular peptidyl-prolyl cis/trans isomerase Pin1. Our data suggest that proline‑directed phosphorylation regulates Rta by licensing binding to Pin1. Despite Pin1’s ability to stimulate Rta transactivation, unchecked Pin1 activity inhibited virus production. Dysregulation of Pin1 is implicated in human cancers, and KSHV is the latest virus known to co-opt Pin1 function. We propose that Pin1 is a molecular timer that can regulate the balance between viral lytic gene expression and host cell lysis. Intriguing scenarios for Pin1’s underlying activities, and the potential broader significance for isomerization of Rta and reactivation, are highlighted.

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“…These include a viral IL-6 (vIL-6), viral macrophage inflammatory proteins 1, 2, and 3 (vMIP-1, 2, and 3), and viral G-protein coupled receptor (vGPCR) [10][11][12][13][14]. The vMIP proteins have been reported to serve as chemoattractants of immune cells [12,13,15] and vGPCR has been reported to increase angiogenesis [16]. Taken together, HHV-8 may be responsible for inducing a chronic, pro-inflammatory immune response in the microenvironment of the prostate, leading to the development of prostatitis and increased levels of serum PSA.…”

Section: Introductionmentioning

confidence: 99%

Elevated Serum PSA is Associated With Human Herpesvirus 8 Infection and Increased Circulating Cytokine Levels in Men From Tobago

et al. 2017

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Background Serum prostate specific antigen (PSA) levels have been used for many years as a biomarker for prostate cancer. This usage is under scrutiny due to the fact that elevated PSA levels can be caused by other conditions such as benign prostatic hyperplasia and infections of or injury to the prostate. As a result, the identification of specific pathogens capable of increasing serum levels of PSA is important. A potential candidate responsible for elevated PSA is human herpesvirus 8 (HHV-8). We have reported previously that HHV-8 is capable of infecting and establishing a latent infection in the prostate. In this current study we test the hypothesis that HHV-8 infection is associated with elevated PSA levels. Circulating cytokine levels between men with elevated PSA and controls are also compared. Methods HHV-8 serostatus was determined among men with elevated serum PSA (≥4ng/ml; n=168, no prostate cancer on biopsy) and age-matched controls (PSA<4ng/ml; n=234), Circulating cytokine levels were determined among a subset of each group (116 with elevated PSA and 85 controls). Results Men with an elevated serum PSA were significantly more likely to be HHV-8 seropositive (42.9%) than the age-matched cancer-free men (22.2%; OR 2.51; 95% CI 1.48 – 4.29, P=00001). Comparison of circulating cytokine levels between men with elevated serum PSA and controls indicated that elevated serum PSA is associated with a pro-inflammatory response with a mixed Th1/Th2 response while HHV-8 infection was associated with significantly higher levels of IL12p70, IL-10 and IL-13 indicating a Th2 immune response. Conclusions We found a significant association between HHV-8 infection and increased levels of serum PSA. In an age of patient-centered medicine, men with an elevated serum PSA should be considered for HHV-8 serology testing to determine if HHV-8 is responsible for the elevated PSA.

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Role of ORF74-Encoded Viral G Protein-Coupled Receptor in Human Herpesvirus 8 Lytic Replication

Cited by 25 publications

References 26 publications

Hijacking GPCRs by viral pathogens and tumor

Hijacking GPCRs by viral pathogens and tumor

KSHV Reactivation and Novel Implications of Protein Isomerization on Lytic Switch Control

Elevated Serum PSA is Associated With Human Herpesvirus 8 Infection and Increased Circulating Cytokine Levels in Men From Tobago

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