RAB27A CONTROLS HIV-1 ASSEMBLY BY REGULATING PLASMA MEMBRANE LEVELS OF PHOSPHATIDYLINOSITOL 4,5-BISP

PEHUÉN PEREYRA GERBER; MERCEDES CABRINI; CAROLINA JANCIC; CLAUDIA BANCHIO; CATALINA VON BILDERLING; LORENA SIGAUT; LÍA ISABEL PIETRASANTA; MATÍAS OSTROWSKI

Mendoza

Congreso; 50th. Annual Meeting Argentine Society for Biochemistry and Molecular Biology; 2014

During the late stages of theHIV-1 replication cycle, the viral polyprotein Pr55Gag is recruited to theplasma membrane (PM), where it binds phosphatidylinositol 4,5-bisphosphate[PI(4,5)P2] and directs HIV-1 assembly. We demonstrate that the small GTPaseRab27a regulates Pr55Gag membrane association, both in primary macrophages andCD4+T lymphocytes, thus controlling viral assembly and replication. We showthat Rab27a controls the trafficking of multivesicular endosomes (MVEs)carrying phosphatidylinositol 4-kinase type 2 alpha (PI4KIIalpha) towards thePM of CD4+ T lymphocytes. Hence, Rab27a promotes high levels of PMphosphatidylinositol 4-phosphate and the localized production of PI(4,5)P2 , controllingthe formation of the HIV-1 assembly platform. Rab27a also controls PI(4,5)P2levels at the Virus-Containing Compartments of macrophages. By screening Rab27aeffectors, we identified that Slp2a, Slp3 and Slac2b are required for theassociation of Pr55Gag with the PM. We conclude that by directing thetrafficking of PI4KIIalpha-positive endosomes towards the PM, Rab27a controlsPI(4,5)P2 levels and HIV-1 replication.