Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells.
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.
Mansouri
Mandana
M
Vaccine and Gene Therapy Institute and Vollum Institute, Oregon Health and Science University, Portland, OR, USA.
Douglas
Janet
J
Rose
Patrick P
PP
Gouveia
Kristine
K
Thomas
Gary
G
Means
Robert E
RE
Moses
Ashlee V
AV
Früh
Klaus
K
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D019288:Herpesvirus 8, Human / Q000201:enzymology* / Q000472:pathogenicity*; D006801:Humans; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000201:enzymology / Q000276:immunology / Q000821:virology; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D033921:Vesicular Transport Proteins; D014764:Viral Proteins / Q000378:metabolism; D017874:Immediate-Early Proteins
D048868:Adaptor Proteins, Signal Transducing; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D046988:Proteasome Endopeptidase Complex; D044767:Ubiquitin-Protein Ligases; D033921:Vesicular Transport Proteins; D014764:Viral Proteins; C499638:PACS2 protein, human; C405867:K5 protein, Human herpesvirus 8; D017874:Immediate-Early Proteins