Nai-Yun Hsu 1 , 7 , Olha Ilnytska 1 , 7 , Georgiy Belov 2 , Marianita Santiana 1 , Ying-Han Chen 1 , Peter M. Takvorian 1 , Cyrilla Pau 1 , Hilde van der Schaar 3 , Neerja Kaushik-Basu 4 , Tamas Balla 5 , Craig E. Cameron 6 , Ellie Ehrenfeld 2 , Frank J.M. van Kuppeveld 3 , Nihal Altan-Bonnet 1 , ∗
27 May 2010
Many RNA viruses remodel intracellular membranes to generate specialized sites for RNA replication. How membranes are remodeled and what properties make them conducive for replication are unknown. Here we show how RNA viruses can manipulate multiple components of the cellular secretory pathway to generate organelles specialized for replication that are distinct in protein and lipid composition from the host cell. Specific viral proteins modulate effector recruitment by Arf1 GTPase and its guanine nucleotide exchange factor GBF1, promoting preferential recruitment of phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) to membranes over coat proteins, yielding uncoated phosphatidylinositol-4-phosphate (PI4P) lipid-enriched organelles. The PI4P-rich lipid microenvironment is essential for both enteroviral and flaviviral RNA replication; PI4KIIIβ inhibition interferes with this process; and enteroviral RNA polymerases specifically bind PI4P. These findings reveal how RNA viruses can selectively exploit specific elements of the host to form specialized organelles where cellular phosphoinositide lipids are key to regulating viral RNA replication.
► RNA viruses generate specialized RNA replication organelles enriched in PI4P lipids ► Host PI4KIIIβ enzyme is co-opted by the virus to generate PI4P lipid-rich organelles ► Enteroviral RNA polymerases specifically and preferentially bind PI4P lipids ► PI4P microenvironment is essential for enteroviral and flaviviral RNA synthesis