Abstract
Eukaryotes possess seven different phosphoinositides (PIPs) that help form the unique signatures of various intracellular membranes. PIPs serve as docking sites for the recruitment of specific proteins to mediate membrane alterations and integrate various signaling cascades. The spatio-temporal regulation of PI kinases and phosphatases generates distinct intracellular hubs of PIP signaling. Hepatitis C virus (HCV), like other plus-strand RNA viruses, promotes the rearrangement of intracellular membranes to assemble viral replication complexes. HCV stimulates enrichment of phosphatidylinositol 4-phosphate (PI4P) pools near endoplasmic reticulum (ER) sites by activating PI4KIIIα, the kinase responsible for generation of ER-specific PI4P pools. Inhibition of PI4KIIIα abrogates HCV replication. PI4P, the most abundant phosphoinositide, predominantly localizes to the Golgi and plays central roles in Golgi secretory functions by recruiting effector proteins involved in transport vesicle generation. The PI4P effector proteins also include the lipid-transfer and structural proteins such as ceramide transfer protein (CERT), oxysterol binding protein (OSBP) and Golgi phosphoprotein 3 (GOLPH3) that help maintain Golgi-membrane composition and structure. Depletion of Golgi-specific PI4P pools by silencing PI4KIIIβ, expression of dominant negative CERT and OSBP mutants, or silencing GOLPH3 perturb HCV secretion. In this review we highlight the role of PIPs and specifically PI4P in the HCV life cycle.
Highlights
Hepatitis C virus (HCV) infection is a looming silent pandemic with an estimated 2%–3% of global population afflicted [1]
These studies indicate that NS5A recruits PI4KIIIα to the membranous replication compartment and stimulates PI4KIIIα activity resulting in robust induction of phosphatidylinositol 4-phosphate (PI4P) pools that are required to maintain the integrity of the membranous web structure (Figure 3)
It is known that the both bacteria and viruses exploit phosphoinositide metabolism in various fashions to facilitate their lifecycle
Summary
Hepatitis C virus (HCV) infection is a looming silent pandemic with an estimated 2%–3% of global population afflicted [1]. Direct-acting antivirals are very effective, the rapid emergence of resistant mutants can lead to recurrence of infection, underscoring the need for the development of treatment strategies that target host factors critical for viral lifecycle. A member of the Flaviviridae family of viruses, HCV contains a positive-stranded RNA genome that encodes a ~3,000 amino acid polyprotein. This polyprotein is cleaved co- and post-translationally by cellular and viral proteases to form the viral proteome of three structural and seven non-structural proteins [3]. HCV infection robustly stimulates ER-specific PI4P pools by activating phosphatidylinositol(4)phosphate kinase IIIα (PI4KIIIα), responsible for generating ER-specific.
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