Inhibition of the extracellular signal-regulated kinase signaling pathway is correlated with proteasome inhibitor suppression of coxsackievirus replication.
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.
Wong
Jerry
J
The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Pathology and Laboratory Medicine, St. Paul's Hospital-University of British Columbia, Vancouver, BC, Canada V6Z 1Y6.
Zhang
Jingchun
J
Si
Xiaoning
X
Gao
Guang
G
Luo
Honglin
H
D018797:Cell Cycle Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1; D004770:Enterovirus / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D008954:Models, Biological; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D014779:Virus Replication
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D046988:Proteasome Endopeptidase Complex