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Updated: Aug 9, 2026
An In Vitro Model for Studying Cellular Transformation by Kaposi Sarcoma Herpesvirus
Published on: August 25, 2017
Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells
Mandana Mansouri1, Janet Douglas, Patrick P Rose
1Vaccine and Gene Therapy Institute and Vollum Institute, Oregon Health and Science University, Portland, OR, USA.
Abstract:
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.
Insights
Kaposi sarcoma herpesvirus K5 ligase targets CD31 in endothelial cells, reducing cell migration. This novel dual degradation mechanism impacts Kaposi sarcoma tumor development.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Kaposi sarcoma herpesvirus (KSHV) utilizes transmembrane ubiquitin ligase K5 to degrade host glycoproteins.
- Endothelial cells (ECs) play crucial roles in immune cell interactions and vascular integrity.
- CD31 (platelet-endothelial cell adhesion molecule) is vital for cell-cell adhesion and migration in ECs.
Purpose of the Study:
- To investigate the role of KSHV K5 in regulating CD31 expression and function in endothelial cells.
- To elucidate the degradation mechanisms of CD31 targeted by K5.
- To understand the implications of K5-mediated CD31 downregulation in Kaposi sarcoma pathogenesis.
Main Methods:
- Cell culture of endothelial cells.
- Immunoblotting and immunofluorescence to detect CD31 expression and localization.
- Ubiquitination assays to assess K5 activity.
- Proteasome and lysosome inhibition assays.
- Analysis of K5-PACS-2 interaction.
Main Results:
- KSHV K5 ligase targets and reduces CD31 expression in endothelial cells.
- K5 mediates dual degradation of CD31: lysosomal degradation of existing CD31 and proteasomal degradation of newly synthesized CD31.
- K5-mediated CD31 downregulation impairs endothelial cell migration.
- Phosphofurin acidic cluster sorting protein-2 (PACS-2) is required for the proteasomal degradation of newly synthesized CD31.
Conclusions:
- CD31 is a novel substrate of KSHV K5, removed through a dual degradation pathway.
- K5-mediated CD31 degradation affects endothelial cell function and may contribute to Kaposi sarcoma development.
- Subcellular localization of K5 regulates the distinct degradation pathways for CD31.
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