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* Division of Respirology and
Multi-Organ Transplantation Programme, University Health Network, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and
Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
Human rhinovirus (HRV) causes the common cold. The most common acute infection in humans, HRV is a leading cause of exacerbations of asthma and chronic obstruction pulmonary disease because of its ability to exacerbate airway inflammation by altering epithelial cell biology upon binding to its receptor, ICAM-1. ICAM-1 regulates not only viral entry and replication but also signaling pathways that lead to inflammatory mediator production. We recently demonstrated the Syk tyrosine kinase to be an important mediator of HRV-ICAM-1 signaling: Syk regulates replication-independent p38 MAPK activation and IL-8 expression. In leukocytes, Syk regulates receptor-mediated internalization via PI3K. Although PI3K has been shown to regulate HRV-induced IL-8 expression and clathrin-mediated endocytosis of HRV, the role of airway epithelial Syk in this signaling pathway is not known. We postulated that Syk regulates PI3K activation and HRV endocytosis in the airway epithelium. Using confocal microscopy and immunoprecipitation, we demonstrated recruitment of the normally cytosolic Syk to the plasma membrane upon HRV16-ICAM-1 binding, along with Syk-clathrin coassociation. Subsequent incubation at 37°C to permit internalization revealed redistribution of Syk to punctate structures resembling endosomes and colocalization with HRV16. Internalized HRV was not detected in cells overexpressing the kinase inactive SykK396R mutant, indicating that kinase activity was necessary for endocytosis. HRV-induced PI3K activation was dependent on Syk; Syk knockdown by small interfering RNA significantly decreased phosphorylation of the PI3K substrate Akt. Together, these data reveal Syk to be an important mediator of HRV endocytosis and HRV-induced PI3K activation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work is supported by grants from the Canadian Institutes for Health Research (Grant MOP 83388), Ontario Thoracic Society, the J.P. Bickell Foundation, and the University of Toronto Multi-Organ Transplant Programme.
2 Address correspondence and reprint requests to Dr. Chung-Wai Chow, University of Toronto, 1 King’s College Circle, Room 6270, Toronto, Ontario, Canada M5S 1A8. E-mail address: cw.chow{at}utoronto.ca
3 Abbreviations used in this paper: HRV, human rhinovirus; BEBM, bronchial epithelial basal medium; BEGM, bronchial epithelial growth medium; NHBE, normal human bronchial epithelial (cell); siRNA, small interfering RNA; WT, wild type.
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