Inhibition of the extracellular signal-regulated kinase signaling pathway is correlated with proteasome inhibitor suppression of coxsackievirus replication.
ABSTRACT 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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ABSTRACT: Like the other more well-characterized post-translational modifications (phosphorylation, methylation, acetylation, acylation, etc.), the attachment of the 76 amino acid ubiquitin (Ub) protein to substrates has been shown to govern countless cellular processes. As obligate intracellular parasites, viruses have evolved the capability to commandeer many host processes in order to maximize their own survival, whether it be to increase viral production or to ensure the long-term survival of latently infected host cells. The first evidence that viruses could usurp the Ub system came from the DNA tumor viruses and Adenoviruses, each of which use Ub to dysregulate the host cell cycle (Scheffner et al., 1990; Querido et al., 2001). Today, the list of viruses that utilize Ub includes members from almost every viral class, encompassing both RNA and DNA viruses. Among these, there are examples of Ub usage at every stage of the viral life cycle, involving both ubiquitination and de-ubiquitination. In addition to viruses that merely modify the host Ub system, many of the large DNA viruses encode their own Ub modifying machinery. In this review, we highlight the latest discoveries regarding the myriad ways that viruses utilize Ub to their advantage.Frontiers in Microbiology 01/2011; 2:161. · 3.90 Impact Factor
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ABSTRACT: The lifecycle of intracellular pathogens, especially viruses, is intimately tied to the macromolecular synthetic processes of their host cell. In the case of positive-stranded RNA viruses, the ability to translate and, thus, replicate their infecting genome is dependent upon hijacking host proteins. To identify proteins that participate in West Nile virus (WNV) replication, we tested the ability of siRNAs designed to knock-down the expression of a large subset of human genes to interfere with replication of WNV replicons. Here we report that multiple siRNAs for proteasome subunits interfered with WNV genome amplification. Specificity of the interference was shown by demonstrating that silencing proteasome subunits did not interfere with Venezuelan equine encephalitis virus replicons. Drugs that blocked proteasome activity were potent inhibitors of WNV genome amplification even if cells were treated 12 h after infection, indicating that the proteasome is required at a post-entry stage(s) of the WNV infection cycle.Virology 01/2009; · 3.35 Impact Factor
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ABSTRACT: The morphology of Al2O3 has been modified for use in the commerical SCR process as a support of V2O5/Al2O3 catalyst. A test program for accelerated deactivation at 400°C and continuous deactivation at 250°C has been developed for four kinds of V2O5/Al2O3 catalysts containing the distinctive pore size distributions of Al2O3. The program reveals that both the pore size and the surface area of the catalyst are important for the deactivation of V2O5/Al2O3 catalyst by SO2 to remove NO by NH3. This suggests that a high surface area catalyst with a large mean pore may be an ideal catalyst tolerable to catalyst deactivation by SO2 for SCR reaction. The deactivating agents formed on the catalyst surface confirmed by TGA, XPS and BET analysis of the deactivated catalysts may be Al2(SO4)3 and NH4Al(SO4)2 at 400°C, and NH4Al(SO4)2, NH4HSO4 and (NH4)2SO4 at 250°C.Studies in Surface Science and Catalysis - STUD SURF SCI CATAL. 01/1999; 126:389-396.