Virus-Induced Abl and Fyn Kinases Signals Permit Coxsackievirus Entry through Epithelial Tight Junctions

Carolyn B. Coyne et al., Cell 124, 119-131 (2006)

Speaker: 張家綸                                          Time: 15:10~16:00, Apr. 26, 2006

Commentator: 蕭璦莉 老師                    Place: Room 601

Abstract

Group B coxsackieviruses (CVBs) must cross the epithelium to initiate infection, but the mechanism remains uncertain. Previous studies revealed that the coxsackievirus and adenovirus receptor (CAR), a major receptor for all CVBs, is also a component of tight junction¹ and is absent from the apical surface of polarized epithelial cells thus inaccessible to virus approaching. Many CVB isolates also interact with a second receptor, decay-accelerating factor (DAF), which is abundant on the apical surface of polarized epithelial cells². In this study, the authors examined the process by which CVBs bind to DAF and enter the polarized epithelial cells. Confocal fluorescence microscopy was used to observe the localization of CAR, DAF, and other cellular proteins involved in viral entry, including actin and caveolin-1. They also investigated the interaction of above proteins with CVBs during the entry of CVBs into the polarized epithelial cells. Pharmaceutical inhibitors were utilized to confirm that the pathways of entry were indeed responsible for CVBs infection. Moreover, the authors used immunoblotting and kinase assay to detect Abl and Src family kinase related signals, which mediate actin remodeling and caveolin-1 phosphorylation, respectly. The authors found that the attachment of CVBs to DAF on the apical cell surface activates Abl kinases and triggers actin rearrangements, which are responsible for the delivery of the virus to the tight junction and the interaction of the virus with CAR. The interaction between the virus and CAR results in conformational changes of the virus capsid. Interaction of the virus with DAF also activates Fyn kinase, which is required for the phosphorylation of caveolin and transportation of the virus into the cell within caveolar vesicles. Thus understanding the process of CVBs cross the epithelium and molecules involved may give us new targets for viral therapy.

References

1.      Cohen, C.J., Shieh, J.T., Pickles, R.J., Okegawa, T., Hsieh, J.T., and Bergelson, J.M. (2001). The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc. Natl. Acad. Sci. USA 98, 15191–15196.

2. Bergelson, J.M. (2002). Receptors for Coxsackieviruses and Echoviruses. In Molecular Biology of Picornaviruses, B.L. Semler and E. Wimmer, eds. (Washington, DC: ASM Press), pp. 107–113.