scholarly journals Kaposi's Sarcoma-Associated Herpesvirus G-Protein-Coupled Receptor Prevents AU-Rich-Element-Mediated mRNA Decay

2012 ◽  
Vol 86 (16) ◽  
pp. 8859-8871 ◽  
Author(s):  
Jennifer A. Corcoran ◽  
Denys A. Khaperskyy ◽  
Benjamin P. Johnston ◽  
Christine A. King ◽  
David P. Cyr ◽  
...  
Keyword(s):  
Gene Expression ◽  
G Protein ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Mrna Degradation ◽  
Lytic Replication ◽  
G Protein Coupled Receptor ◽  
Infected Cells ◽  
Host Shutoff ◽  
G Protein Coupled

During lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection, host gene expression is severely restricted by a process of global mRNA degradation known as host shutoff, which rededicates translational machinery to the expression of viral proteins. A subset of host mRNAs is spared from shutoff, and a number of these containcis-acting AU-rich elements (AREs) in their 3′ untranslated regions. AREs are found in labile mRNAs encoding cytokines, growth factors, and proto-oncogenes. Activation of the p38/MK2 signal transduction pathway reverses constitutive decay of ARE-mRNAs, resulting in increased protein production. The viral G-protein-coupled receptor (vGPCR) is thought to play an important role in promoting the secretion of angiogenic molecules from KSHV-infected cells during lytic replication, but to date it has not been clear how vGPCR circumvents host shutoff. Here, we demonstrate that vGPCR activates the p38/MK2 pathway and stabilizes ARE-mRNAs, augmenting the levels of their protein products. Using MK2-deficient cells, we demonstrate that MK2 is essential for maximal vGPCR-mediated ARE-mRNA stabilization. ARE-mRNAs are normally delivered to cytoplasmic ribonucleoprotein granules known as processing bodies (PBs) for translational silencing and decay. We demonstrate that PB formation is prevented during KSHV lytic replication or in response to vGPCR-mediated activation of RhoA subfamily GTPases. Together, these data show for the first time that vGPCR impacts gene expression at the posttranscriptional level, coordinating an attack on the host mRNA degradation machinery. By suppressing ARE-mRNA turnover, vGPCR may facilitate escape of certain target mRNAs from host shutoff and allow secretion of angiogenic factors from lytically infected cells.

scholarly journals Expression of the Open Reading Frame 74 (G-Protein-Coupled Receptor) Gene of Kaposi’s Sarcoma (KS)-Associated Herpesvirus: Implications for KS Pathogenesis

1999 ◽  
Vol 73 (7) ◽  
pp. 6006-6014 ◽  
Author(s):  
Jessica R. Kirshner ◽  
Katherine Staskus ◽  
Ashley Haase ◽  
Michael Lagunoff ◽  
Don Ganem
Keyword(s):  
G Protein ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Lytic Replication ◽  
Lymphoid Cells ◽  
Lytic Cycle ◽  
Viral Gene ◽  
G Protein Coupled Receptor ◽  
Nuclease Mapping ◽  
G Protein Coupled

ABSTRACT Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) encodes a G-protein-coupled receptor (GCR) homolog. This protein is a potent, constitutively active signalling molecule that can influence both proliferation and angiogenesis when ectopically expressed in fibroblasts in vitro. Here we have examined the expression of the KSHV GCR gene in virus-infected lymphoid cells and in KS tumors. Our results show that in both situations the gene is expressed primarily during lytic replication; its transcription is unaffected by inhibition of viral DNA synthesis, indicating that it is expressed in the early phases of the lytic program. The major transcript bearing GCR sequences is bicistronic, harboring coding sequences for another viral gene, K14, at its 5′ end. Extensive searches for monocistronic GCR mRNAs using nuclease mapping and reverse transcription-PCR failed to detect such species. The 5′ end of K14/GCR mRNA maps to nucleotide (nt) 127848, and its poly(A) addition site maps to nt 130546; a 149-nt intron is present in the K14/GCR intergenic region. These results suggest that the KSHV GCR is translated by unconventional mechanisms involving either translational reinitiation, internal ribosomal entry, or leaky ribosomal scanning. The restriction of GCR expression to the lytic cycle has important implications for the potential role(s) of the GCR in KS pathogenesis.

G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator

Nature ◽  
10.1038/32472 ◽  
1998 ◽  
Vol 392 (6672) ◽  
pp. 210-210 ◽  
Author(s):  
Carlos Bais ◽  
Bianca Santomasso ◽  
Omar Coso ◽  
Leandros Arvanitakis ◽  
Elizabeth Geras Raaka ◽  
...  
Keyword(s):  
G Protein ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
G Protein Coupled Receptor ◽  
Viral Oncogene ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
G Protein Coupled

scholarly journals The Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Has Broad Signaling Effects in Primary Effusion Lymphoma Cells

2003 ◽  
Vol 77 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Mark Cannon ◽  
Nicola J. Philpott ◽  
Ethel Cesarman
Keyword(s):  
G Protein ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Cell Cycle Control ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
G Protein Coupled Receptor ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
G Protein Coupled

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8 [HHV-8]) is a gamma-2-herpesvirus responsible for Kaposi's sarcoma as well as primary effusion lymphoma (PEL). KSHV is a lymphotropic virus that has pirated many mammalian genes involved in inflammation, cell cycle control, and angiogenesis. Among these is the early lytic viral G protein-coupled receptor (vGPCR), a homologue of the human interleukin-8 (IL-8) receptor. When expressed, vGPCR is constitutively active and can signal via mitogen- and stress-activated kinases. In certain models it activates the transcriptional potential of NF-κB and activator protein 1 (AP-1) and induces vascular endothelial growth factor (VEGF) production. Despite its importance to the pathogenesis of all KSHV-mediated disease, little is known about vGPCR activity in hematopoietic cells. To study the signaling potential and downstream effects of vGPCR in such cells, we have developed PEL cell lines that express vGPCR under the control of an inducible promoter. The sequences required for tetracycline-mediated induction were cloned into a plasmid containing adeno-associated virus type 2 elements to enhance integration efficiency. This novel plasmid permitted studies of vGPCR activity in naturally infected KSHV-positive lymphocytes. We show that vGPCR activates ERK-2 and p38 in PEL cells. In addition, it increases the transcription of reporter genes under the control of AP-1, NF-κB, CREB, and NFAT, a Ca2+-dependent transcription factor important to KSHV lytic gene expression. vGPCR also increases the transcription of KSHV open reading frames 50 and 57, thereby displaying broad potential to affect viral transcription patterns. Finally, vGPCR signaling results in increased PEL cell elaboration of KSHV vIL-6 and VEGF, two growth factors involved in KSHV-mediated disease pathogenesis.

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