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Blood, 15 September 2006, Vol. 108, No. 6, pp. 1932-1940.
Prepublished online as a Blood First Edition Paper on April 6, 2006; DOI 10.1182/blood-2005-11-4404.
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IMMUNOBIOLOGY
Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells
Mandana Mansouri,
Janet Douglas,
Patrick P. Rose,
Kristine Gouveia,
Gary Thomas,
Robert E. Means,
Ashlee V. Moses, and
Klaus Früh
From the Vaccine and Gene Therapy Institute and the Vollum Institute, Oregon Health and Science University, Portland; and the Department of Pathology, Yale University School of Medicine, New Haven, CT.
The transmembrane ubiquitin ligase K5/MIR2 of Kaposi sarcoma herpesvirus (KSHV) mediates internalization and lysosomal degradation of glycoproteins involved in antigen presentation and co-stimulation. In endothelial cells (ECs), K5 additionally reduced expression of CD31/platelet–endothelial cell adhesion molecule (PECAM), an adhesion molecule regulating cell-cell interactions of ECs, platelets, monocytes, and T cells. K5 also reduced EC migration, a CD31-dependent process. Unlike other K5 substrates, both newly synthesized and pre-existing CD31 molecules were targeted by K5. K5 was transported to the cell surface and ubiquitinated pre-existing CD31, resulting in endocytosis and lysosomal degradation. In the endoplasmic reticulum, newly synthesized CD31 was degraded by proteasomes, which required binding of phosphofurin acidic cluster sorting protein-2 (PACS-2) to acidic residues in the carboxyterminal tail of K5. Thus, CD31, a novel target of K5, is efficiently removed from ECs by a dual degradation mechanism that is regulated by the subcellular sorting of the ubiquitin ligase. K5-mediated degradation of CD31 is likely to affect EC function in KS tumors.
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