Similar activation of signal transduction pathways by the herpesvirus-encoded chemokine receptors US28 and ORF74

Abstract

The virally encoded chemokine receptors US28 from human cytomegalovirus and ORF74 from human herpesvirus 8 are both constitutively active. We show that both receptors constitutively activate the transcription factors nuclear factor of activated T cells (NFAT) and cAMP response element binding protein (CREB) and that both pathways are modulated by their respective endogenous receptor ligands. By addition of specific pathway modulators against the G protein subunit Galphai, phospholipase C, protein kinase C, calcineurin, p38 MAP kinase, and MEK1, we find that the constitutive and ligand-dependent inductions are mediated by multiple yet similar pathways in both receptors. The NFAT and CREB transcription factors and their upstream activators are known inducers of host and virally encoded genes. We propose that the activity of these virally encoded chemokine receptors coordinates host and potentially viral gene expression similarly. As ORF74 is a known inducer of neoplasia, these findings may have important implications for cytomegalovirus-associated pathogenicity.

Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes

“…25,39 Changes in PEPCK gene transcription are controlled by many tissuespecific factors, including CCAAT/enhancer binding protein ␣ (C/EBPa), C/EBP␤ 40,41 , and hepatic nuclear factors 1, 3, and 4, 42 as well as multiple hormone-responsive factors such as CREB, 43,44 the glucocorticoid retinoic acid, retinoid X, and thyroid hormone receptors, and a poorly defined insulin-responsive system (for review see Chakravarty et al 45 ). Our result that MCP-1 activates CREB in Huh-7 cells, similar to that reported for HEK-cells, 46 allows us to propose a new mechanism of MCP-1-induced fat accumulation in hepatocytes via glyceroneogenesis.…”

Functional analysis of human cytomegalovirus pUS28 mutants in infected cells

“…More detailed analyses of the biological and signalling activities of pUS28 are required to gain a better understanding regarding how this protein contributes to viral pathogenesis. pUS28 exhibits significant signalling activity, including the ability to activate the phospholipase C-b (PLC-b), the tyrosine kinase c-Src and the small G protein RhoA (Billstrom et al, 1998;Casarosa et al, 2001;Gao & Murphy, 1994;McLean et al, 2004;Melnychuk et al, 2004;Minisini et al, 2003;Streblow et al, 2003;Waldhoer et al, 2002). pUS28 shares significant homology to C-C chemokine receptors and, accordingly, can bind C-C chemokines, including CCL5/RANTES, CCL2/MCP-1 and CCL4/MIP1b (Bodaghi et al, 1998;Kledal et al, 1998;Kuhn et al, 1995;Neote et al, 1993).…”

Cell transformation mediated by the Epstein–Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling

“…Furthermore, both US28 and ORF74 are constitutively active (Arvanitakis et al, 1997;Waldhoer et al, 2002). US28 signals through Ga q , Ga s and Ga 12/13 , further activating kinases and transcription factors, whereas ORF74 signals through Ga q , Ga s and Ga i , virtually activating the same downstream signal transduction pathways as US28 (Smit et al, 2002;Waldhoer et al, 2002;Streblow et al, 2003;McLean et al, 2004). Furthermore, ORF74 and US28 stimulate the secretion of cytokines and growth factors, including vascular endothelial growth factor (VEGF) (Bais et al, 1998;Sodhi et al, 2000;Pati et al, 2001;Maussang et al, 2006).…”