Kaposi's sarcoma-associated herpesvirus G-protein-coupled receptor prevents AU-rich-element-mediated mRNA decay.
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 contain cis-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.
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Jennifer A
JA
Corcoran
Denys A
DA
Khaperskyy
Benjamin P
BP
Johnston
Christine A
CA
King
David P
DP
Cyr
Alisha V
AV
Olsthoorn
Craig
C
McCormick
D015870:Gene Expression; D006367:HeLa Cells; D019288:Herpesvirus 8, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D020935:MAP Kinase Signaling System; D020871:RNA Stability; D019707:Receptors, Chemokine / Q000378:metabolism*; D014779:Virus Replication
C115448:G protein-coupled receptor, Human herpesvirus 8; D019707:Receptors, Chemokine