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Journal of Virology, October 2008, p. 9615-9628, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.02633-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Remodeling of Endothelial Adherens Junctions by Kaposi's Sarcoma-Associated Herpesvirus{triangledown}

Mandana Mansouri, Patrick P. Rose, Ashlee V. Moses, and Klaus Früh*

Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon

Received 11 December 2007/ Accepted 22 July 2008

Vascular endothelial cadherin (VE-cadherin) connects neighboring endothelial cells (ECs) via interendothelial junctions and regulates EC proliferation and adhesion during vasculogenesis and angiogenesis. The cytoplasmic domain of VE-cadherin recruits {alpha}- and β-catenins and {gamma}-catenin, which interact with the actin cytoskeleton, thus modulating cell morphology. Dysregulation of the adherens junction/cytoskeletal axis is a hallmark of invasive tumors. We now demonstrate that the transmembrane ubiquitin ligase K5/MIR-2 of Kaposi's sarcoma-associated herpesvirus targets VE-cadherin for ubiquitin-mediated destruction, thus disturbing EC adhesion. In contrast, N-cadherin levels in K5-expressing cells were increased compared to those in control cells. Steady-state levels of {alpha}- and β-catenins and {gamma}-catenin in K5-expressing ECs were drastically reduced due to proteasomal destruction. Moreover, the actin cytoskeleton was rearranged, resulting in the dysregulation of EC barrier function as measured by electric cell-substrate impedance sensing. Our data represent the first example of a viral protein targeting adherens junction proteins and suggest that K5 contributes to EC proliferation, vascular leakage, and the reprogramming of the EC proteome during Kaposi's sarcoma tumorigenesis.

* Corresponding author. Mailing address: Vaccine and Gene Therapy Institute, Oregon Health & Science University, 505 NW 185th Ave., Beaverton, OR 97006. Phone: (503) 418-2735. Fax: (503) 418-2701. E-mail: fruehk{at}ohsu.edu

{triangledown} Published ahead of print on 30 July 2008.

Journal of Virology, October 2008, p. 9615-9628, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.02633-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Mansouri, M., Viswanathan, K., Douglas, J. L., Hines, J., Gustin, J., Moses, A. V., Fruh, K. (2009). Molecular Mechanism of BST2/Tetherin Downregulation by K5/MIR2 of Kaposi's Sarcoma-Associated Herpesvirus. J. Virol. 83: 9672-9681 [Abstract] [Full Text]  


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