CMV and MAPK Pathways
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CMV and MAPK Pathways
Signal transduction is a common process used by an extensive array of biological ligands to modulate various host cell processes such as growth, differentiation, and proliferation. Cells respond to CMV (Cytomegalovirus) by invoking a cascade of biological and physiological responses resulting in signal transduction and regulation of cellular gene expression, including induction of genes in the IFN (Interferons)-responsive family (Ref.1). CMV is a herpes virus that infects most cell types and establishes latency in leukocytes. A CMV infection is normally subclinical but can be fatal in immunocompromised individuals or if the infection is acquired in utero.

One of the major components of the CMV virion is the Glycoprotein GB, and a significant proportion of the virus-host interactions are mediated through GB. CMV stimulates a large number of typical proinflammatory signaling events, including nuclear translocation of NF-KappaB (Ref.2). The first step in CMV infection is attachment to its cellular target; however, the receptors for CMV have not yet been delineated. Heparin sulfate and CD13 have been suggested to be involved in CMV attachment (Ref.3). One of the early cellular responses to HCMV (Human CMV) infection is production of IP3 (Inositol 1,4,5-triphosphate) and DAG (1,2-Diacylglycerol) from PI3K (Phosphatidylinositol 3-Kinases) by phosphorylation at the D-3 position. Once phosphorylated at the D-3 position, these lipids serve as second messengers and are able to regulate phosphorylation of a number of kinases, including Akt/PKB (Protein Kinase-B), cAMP (cyclic Adenosine 3, 5’-Monophosphate)-dependent PKA (Protein Kinase-A), some isoforms of PKC (Protein Kinase-C), p70S6K and p85S6K (Ribosomal S6 Kinases), respectively (Ref.4). In addition, the HCMV particle in the host cell carry phosphatase activity and activate the membrane-proximal PLC (Phospholipases-C) and A2 as well as the prototypical MAPK (Mitogen-Activated Protein Kinase) pathway. The MAPK signal transduction cascade consists of a three-component module consisting of MAPK , MEK (MAP/ERK Kinase), and MEKK (MAP/ERK Kinase Kinase), which are conserved from yeasts to humans (Ref.5). MAPK activation by CMV leads to activation of transcription of viral genes, increasing the production of viral gene products. The MEKK1 regulates the immediate early promoter indirectly through downstream kinase signaling and directly through activation of NF-KappaB (Nuclear Factor-kappaB). The mechanism of activation of NF-KappaB involves the liberation of transcription factor from the inhibitory subunit I-KappaB-Alpha (Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells-Alpha) and is mediated by a GB-dependent mechanism through IKKs (I-KappaB Kinases). The early activation of NF-KappaB is amplified by other mechanisms later during infection. This second wave of NF-KappaB activation relies on NF-KappaB-dependent activation of the CMV major immediate-early promoter. MAPK pathways activated by CMV converge on increased transcription of viral genes and increased replication of the viral genome. ERK1/2 (Extracellular Signal-Regulated Kinases) and p38 immediately follow infection that regulates the activity of viral genes by cellular transcription factors acting through the basal transcription elements and viral UL4 promoter located upstream. Another target of prolonged p38 activation during infection is Rb (Retinoblastoma), contributing to viral replication (Ref.6). The classical binding partner for Rb is the E2F family of transcription factors, and hyperphosphorylation of pRb is necessary for relieving pRb-mediated suppression of E2F, which results in cell cycle progression past the G1/S-phase transition point. However, the HCMV IE2-86 protein binds to pRb and alleviates pRb-mediated suppression of E2F transactivation function.

Cellular proto-oncogenes such as c-Fos, c-Jun, and c-Myc, which are upregulated in response to mitogenic stimuli, are also stimulated by HCMV infection. Furthermore, TPA (12-O Tetradecanoylphorbol-13-Acetate), which stimulates the ERK pathway activate the HCMV MIEP (Ref.7). The MAPKs also activate viral transactivators, which are important in the activation of early viral promoters. For example, ERK phosphorylates both IE72 and IE86 proteins in vitro and in vivo. In addition, MEK1/2 inhibitors UO126 and PD98059 repress phosphorylation of IE72 and IE86 proteins in infected cells without decreasing the level of IE proteins (Ref.5). Cooperation of IE1-72, IE2-55, and IE2-86 proteins with the cellular transcription factor Sp1 (Selective promoter factor-1) up-regulates the promoters for the NF-KappaB subunits p65 and p105/p50. HCMV has also been reported to activate IRF3 (Interferon Regulatory Factor-3) through a rapid de novo protein synthesis-independent mechanism.

HCMV is a widespread human pathogen that does not cause significant clinical manifestations in healthy individuals. Following primary infection HCMV persists for life as a latent infection with periodic asymptomatic excretion of virus in saliva, breast milk, urine, semen and cervical secretions. The major neutralization epitopes of HCMV are located on its glycoprotein, GB. CMV in immunocompetent individuals is etiologically associated with infectious mononucleosis as well as other disease presentations and malignancies (Ref.8) and if left untreated, can be fatal. In addition, it is a leading cause of certain types of birth defects. Individuals suffering from diseases caused by HCMV are currently treated with chemical compounds, such as ganciclovir and phosphocarnet, which block the viral lytic life cycle by inhibiting viral DNA replication. However, the substantial toxicity of these drugs and the emergence of drug-resistant strains of HCMV indicate that better antiviral compounds are needed (Ref.9).