RESUMEN

During the late stages of the HIV-1 replication cycle, the viral polyprotein Pr55(Gag) is recruited to the plasma membrane (PM), where it binds phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and directs HIV-1 assembly. We show that Rab27a controls the trafficking of late endosomes carrying phosphatidylinositol 4-kinase type 2 α (PI4KIIα) toward the PM of CD4(+) T cells. Hence, Rab27a promotes high levels of PM phosphatidylinositol 4-phosphate and the localized production of PI(4,5)P2, therefore controlling Pr55(Gag) membrane association. Rab27a also controls PI(4,5)P2 levels at the virus-containing compartments of macrophages. By screening Rab27a effectors, we identified that Slp2a, Slp3, and Slac2b are required for the association of Pr55(Gag) with the PM and that Slp2a cooperates with Rab27a in the recruitment of PI4KIIα to the PM. We conclude that by directing the trafficking of PI4KIIα-positive endosomes toward the PM, Rab27a controls PI(4,5)P2 production and, consequently, HIV-1 replication.

Asunto(s)

Membrana Celular/metabolismo , VIH-1/fisiología , Fosfatidilinositol 4,5-Difosfato/metabolismo , Ensamble de Virus/fisiología , Replicación Viral/fisiología , Proteínas de Unión al GTP rab/metabolismo , Transporte Biológico Activo/genética , Membrana Celular/genética , Membrana Celular/virología , Endosomas/genética , Endosomas/metabolismo , Endosomas/virología , Humanos , Células Jurkat , Macrófagos/metabolismo , Macrófagos/virología , Proteínas de la Membrana/metabolismo , Antígenos de Histocompatibilidad Menor , Fosfatidilinositol 4,5-Difosfato/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismo , Proteínas de Unión al GTP rab/genética , Proteínas rab27 de Unión a GTP