Signaling by human herpesvirus 8 kaposin A through direct membrane recruitment of cytohesin-1

The induction of a transformed cellular phenotype by viruses requires the m odulation of signaling pathways through viral proteins. We show here that t he phenotypic changes induced by the kaposin A protein of human herpesvirus 8 are mediated through its direct interaction with cytohesin-1, a guanine nucleotide exchange factor for ARF GTPases and regulator of integrin-mediat ed cell adhesion. Focus formation, stress fiber dissolution, and activation of the ERK-1/2 MAP kinase signal cascade were reverted by the cytohesin-1 E157K mutant, which is deficient in catalyzing guanine nucleotide exchange. Furthermore, liposome-embedded kaposin A specifically stimulates cytohesin -1 dependent GTP binding of myristoylated ARF1 in vitro. These results sugg est a previously unknown involvement of ARF GTPases in the control of cellu lar functions by herpesviruses.