Minor lipids with major roles: Viral exploitation of phosphoinositides during RNA replication

Positive-sense (+)RNA viruses are major pathogens of humans, animals and plants. This review summarizes the complex subversion of the host phosphoinositide cycles for virus replication. Phosphoinositides (PIPs) are generated by tightly regulated activity of dedicated PIP kinases from PI in different subcellular locations. Phosphoinositides frequently act as molecular switches and are master regulators of membrane dynamics. Phosphoinositides are exploited by (+)RNA viruses to build membrane-associated viral RNA replication machinery called viral replication organelles (VROs) inside the infected cells. Recent discoveries with +RNA viruses demonstrated the exploitation of two phosphoinositides, PI3P and PI4P, which will be the focus in this review. Selected + RNA viruses exploit PI4P to drive nonvesicular lipid transport via counter transport of sterols and phosphatidylserine from the ER to the VRO through membrane contact sites (MCSs) and lipid transport proteins. The co-opted PI4P and PI4K kinases regulate and maintain the lipid composition of VROs during virus replication. The common strategy of exploiting PI4P and PI4K and co-opted conserved host factors involved in PI4P cycle, such as OSBP-like proteins, opens up new avenues for broad-range antiviral approaches. Several + RNA viruses exploit PI3P cycle to hijack different set of effectors and organelles or pathways to support replication. Enrichment of either PI4P or PI3P in VRO membranes leads to protective environment for RNA replication. Overall, exploitation of PI3P and PI4P phosphoinositides, which are exclusively present in different membrane microdomains, allows viruses to gain access to different resources in the host cell membranes and to regulate spatiotemporally cellular pathways and antiviral responses.