Inhibition of the extracellular signal-regulated kinase signaling pathway is correlated with proteasome inhibitor suppression of coxsackievirus replication

Department of Pathology and Laboratory Medicine, University of British Columbia - Vancouver, Vancouver, British Columbia, Canada
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 08/2007; 358(3):903-7. DOI: 10.1016/j.bbrc.2007.05.013
Source: PubMed


The ubiquitin/proteasome system (UPS), a major intracellular protein degradation pathway, plays a critical role in coxsackieviral replication. To elucidate the mechanisms by which the UPS regulates viral replication, we studied the influence of proteasome inhibition on signaling through the extracellular signal-regulated kinase (ERK) pathway, a pathway which has been previously demonstrated to be necessary for coxsackieviral replication and contribute to virus-mediated pathogenesis. We found that proteasome inhibition reduced coxsackievirus-induced ERK phosphorylation in a dose-dependent manner, which is correlated with an induction of the mitogen-activated protein kinase phosphatase-1 (MKP-1). Blockade of MKP induction by short-interfering RNA attenuated the loss of ERK phosphorylation, and subsequently restored viral replication. Our results suggest that inhibition of the ERK signaling pathway contributes, as least in part, to proteasome inhibitor-mediated reduction of coxsackievirus replication, demonstrating a converging function of major intracellular signaling and protein degradation pathways in the regulation of viral replication.

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    • "Inhibition of proteasome activity was shown to impair coxsackievirus B3 replication (Luo et al., 2003). A recent report indicated that coxsackievirus-induced activation of the extracellular signal-regulated kinase (ERK) pathway, which is required for its replication (Luo et al., 2002), is reduced following proteasome inhibition (Wong et al., 2007), suggesting a possible mechanism of proteasome action. The ubiquitin–proteasome pathway also appears to be a critical factor in the lifecycle of HIV, as well. "
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