title: The role of phosphatidylinositol 4-kinases and phosphatidylinositol 4-phosphate during viral replication.
abstract: Phosphoinositides (PI) are phospholipids that mediate signaling cascades in the cell by binding to effector proteins. Reversible phosphorylation of the inositol ring at positions 3, 4 and 5 results in the synthesis of seven different phosphoinositides. Each phosphoinositide has a unique subcellular distribution with a predominant localization in subsets of membranes. These lipids play a major role in recruiting and regulating the function of proteins at membrane interfaces [1]. Several bacteria and viruses modulate and exploit the host PI metabolism to ensure efficient replication and survival. Here, we focus on the roles of cellular phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 4-kinases (PI4Ks) during the replication cycle of various viruses. It has been well documented that phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ, EC 2.7.1.67) is indispensable for viral RNA replication of several picornaviruses. Two recruitment strategies were reported: (i) binding and modulation of GBF1/Arf1 to enhance recruitment of PI4KIIIβ and (ii) interaction with ACBD3 for recruitment of PI4KIIIβ. PI4KIII has also been demonstrated to be crucial for hepatitis C virus (HCV) replication. PI4KIII appears to be directly recruited and activated by HCV NS5A protein to the replication complexes. In contrast to picornaviruses, it is still debated whether the α or the β isoform is the most important. PI4KIII can be explored as a target for inhibition of viral replication. The challenge will be to develop highly selective inhibitors for PI4KIIIα and/or β and to avoid off-target toxicity.
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Delang
authors.forename: Jan
authors.initials: J
authors.lastname: Paeshuyse
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D018129:Phosphatidylinositol Phosphates; C037178:phosphatidylinositol 4-phosphate; D019870:1-Phosphatidylinositol 4-Kinase