Remodeling of endothelial adherens junctions by Kaposi's sarcoma-associated herpesvirus.
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 beta-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 beta-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.
Mansouri
Mandana
M
Vaccine and Gene Therapy Institute, Oregon Health & Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA.
Rose
Patrick P
PP
Moses
Ashlee V
AV
Früh
Klaus
K
D000199:Actins / Q000378:metabolism; D022005:Adherens Junctions / Q000378:metabolism*; D019921:Biotinylation; D051177:Catenins / Q000378:metabolism; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D003599:Cytoskeleton / Q000378:metabolism; D017097:Electric Impedance; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D012867:Skin / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D000199:Actins; D051177:Catenins; D025801:Ubiquitin