FIG4 is a hepatitis C virus particle-bound protein implicated in virion morphogenesis and infectivity with cholesteryl ester modulation potential

Abstract

There is growing evidence that virus particles also contain host cell proteins, which provide viruses with certain properties required for entry and release. A proteomic analysis performed on double-gradient-purified hepatitis C virus (HCV) from two highly viraemic patients identified the phosphatidylinositol 3,5-bisphosphate 5-phosphatase FIG4 (KIAA0274) as part of the viral particles. We validated the association using immunoelectron microscopy, immunoprecipitation and neutralization assays in vitro as well as patient-derived virus particles. RNA interferencemediated reduction of FIG4 expression decreased cholesteryl ester (CE) levels along with intraand extracellular viral infectivity without affecting HCV RNA levels. Likewise, overexpressing FIG4 increased intracellular CE levels as well as intra-and extracellular viral infectivity without affecting viral RNA levels. Triglyceride levels and lipid droplet (LD) parameters remained unaffected. The 3,5-bisphosphate 5-phosphatase active site of FIG4 was found to strongly condition these results. Whilst FIG4 was found to localize to areas corresponding to viral assembly sites, at the immediate vicinity of LDs in calnexin-positive and HCV core-positive regions, no implication of FIG4 in the secretory pathway of the hepatocytes could be found using either FIG4-null mice, in vitro morphometry or functional assays of the ERGIC/Golgi compartments. This indicates that FIG4-dependent modulation of HCV infectivity is unrelated to alterations in the functionality of the secretory pathway. As a result of the documented implication of CE in the composition and infectivity of HCV particles, these results suggest that FIG4 binds to HCV and modulates particle formation in a CE-related manner.

Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism

“…The classical link between HCV lipo-viral particles and the association with VLDL assembly and release has been shown previously 21 . However, new pathways including the canonical endoplasmic reticulum-Golgi intermediate compartment, as well as the endosome-dependent pathway have been shown to be involved in HCV particle release 26, 27 . Hence, growing evidence supports the involvement of host proteins in viral entry, assembly, and release, and emphasizes the importance of targeting host proteins as a broad spectrum antiviral approach.…”

SNV discovery and functional candidate gene identification for milk composition based on whole genome resequencing of Holstein bulls with extremely high and low breeding values

“…The protein encoded by FIG4 belongs to the SAC domain-containing protein gene family. FIG4 binds to hepatitis C virus and modulates particle formation in a cholesteryl ester-related manner [63].…”

Whole Lotta Lipids—From HCV RNA Replication to the Mature Viral Particle

“…Other lipid-modulating host proteins that associate with viral particles have been identified. It was previously reported that the PI(3,5)P 2 5-phosphatase FIG4 is associated with viral particles [52]. Additionally, FIG4 deficiency impairs CE levels and HCV infectivity, whereas overexpression has the opposite effect, both without changing HCV RNA levels.…”