Phosphoinositides in the Hepatitis C Virus Life Cycle

Bishé, Bryan; Syed, Gulam Hussain; Siddiqui, Aleem

doi:10.3390/v4102340

Cited by 41 publications

(49 citation statements)

References 102 publications

(189 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This location would be in accordance with previous data obtained for the two proposed α-helical elements of the C-terminal region [16,33]. Interestingly, NS4B AH2 is capable of binding different phosphatidyl inositol phosphates with high affinity, implying that this NS4B segment could be implicated in either the recruitment of phosphatidyl inositol phosphates in the replication complex or specific domain formation or both [63]. Moreover, its interfacial properties suggest that this segment could behave similarly to a pre-transmembrane domain partitioning into and interacting with the membrane depending on the membrane composition and/or other proteins [36,64,65], being the responsible of the fluctuation of the protein between different topologies and therefore possible locations [8,9,66].…”

Section: Discussionsupporting

confidence: 87%

N-Terminal AH2 segment of protein NS4B from hepatitis C virus. Binding to and interaction with model biomembranes

Palomares

Nemésio

Franquelim

et al. 2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

View full text Add to dashboard Cite

HCV NS4B, a highly hydrophobic protein involved in the alteration of the intracellular host membranes forming the replication complex, plays a critical role in the HCV life cycle. NS4B is a multifunctional membrane protein that possesses different regions where diverse and significant functions are located. One of these important regions is the AH2 segment, which besides being highly conserved has been shown to play a significant role in NS4B functioning. We have carried out an in-depth biophysical study aimed at the elucidation of the capacity of this region to interact, modulate and disrupt membranes, as well as to study the structural and dynamic features relevant for that disruption. We show that a peptide derived from this region, NS4BAH2, is capable of specifically binding phosphatidyl inositol phosphates with high affinity, and its interfacial properties suggest that this segment could behave similarly to a pre-transmembrane domain partitioning into and interacting with the membrane depending on the membrane composition and/or other proteins. Moreover, NS4BAH2 is capable of rupturing membranes even at very low peptide-to-lipid ratios and its membrane-activity is modulated by lipid composition. NS4BAH2 is located in a shallow position in the membrane but it is able to affect the lipid environment from the membrane surface down to the hydrophobic core. The NS4B region where peptide NS4BAH2 resides might have an essential role in the membrane replication and/or assembly of the viral particle through the modulation of the membrane structure and hence the replication complex.

show abstract

Section: Discussionsupporting

confidence: 87%

N-Terminal AH2 segment of protein NS4B from hepatitis C virus. Binding to and interaction with model biomembranes

Palomares

Nemésio

Franquelim

et al. 2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

View full text Add to dashboard Cite

show abstract

“…HCV RNA replication is regulated by numerous cellular factors and environments (6,7,45). To identify the target molecules of NeoB, we performed a transcriptome analysis that compared cellular gene expression between NeoB-treated and untreated Huh-7.5.1 cells.…”

Section: Resultsmentioning

confidence: 99%

Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System

Nakajima

Watashi

Ohashi

et al. 2016

J Virol

View full text Add to dashboard Cite

Cell culture systems reproducing virus replication can serve as unique models for the discovery of novel bioactive molecules. Here, using a hepatitis C virus (HCV) cell culture system, we identified neoechinulin B (NeoB), a fungus-derived compound, as an inhibitor of the liver X receptor (LXR). NeoB was initially identified by chemical screening as a compound that impeded the production of infectious HCV. Genome-wide transcriptome analysis and reporter assays revealed that NeoB specifically inhibits LXR-mediated transcription. NeoB was also shown to interact directly with LXRs. Analysis of structural analogs suggested that the molecular interaction of NeoB with LXR correlated with the capacity to inactivate LXR-mediated transcription and to modulate lipid metabolism in hepatocytes. Our data strongly suggested that NeoB is a novel LXR antagonist. Analysis using NeoB as a bioprobe revealed that LXRs support HCV replication: LXR inactivation resulted in dispersion of double-membrane vesicles, putative viral replication sites. Indeed, cells treated with NeoB showed decreased replicative permissiveness for poliovirus, which also replicates in double-membrane vesicles, but not for dengue virus, which replicates via a distinct membrane compartment. Together, our data suggest that LXR-mediated transcription regulates the formation of virus-associated membrane compartments. Significantly, inhibition of LXRs by NeoB enhanced the activity of all known classes of anti-HCV agents, and NeoB showed especially strong synergy when combined with interferon or an HCV NS5A inhibitor. Thus, our chemical genetics analysis demonstrates the utility of the HCV cell culture system for identifying novel bioactive molecules and characterizing the virushost interaction machinery. IMPORTANCEHepatitis C virus (HCV) is highly dependent on host factors for efficient replication. In the present study, we used an HCV cell culture system to screen an uncharacterized chemical library. Our results identified neoechinulin B (NeoB) as a novel inhibitor of the liver X receptor (LXR). NeoB inhibited the induction of LXR-regulated genes and altered lipid metabolism. Intriguingly, our results indicated that LXRs are critical to the process of HCV replication: LXR inactivation by NeoB disrupted double-membrane vesicles, putative sites of viral replication. Moreover, NeoB augmented the antiviral activity of all known classes of currently approved anti-HCV agents without increasing cytotoxicity. Thus, our strategy directly links the identification of novel bioactive compounds to basic virology and the development of new antiviral agents.

show abstract

“…This relocation permits the interaction of LDs with viral proteins and genomes[7]. While much is known about the role of lipoproteins and LDs in the HCV life cycle, studies are only now emerging on the modulation of phosphoinositides (PI) by HCV infection[8]. …”

Section: Introductionmentioning

confidence: 99%

PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis

Awad

Gassama‐Diagne

2017

WJH

View full text Add to dashboard Cite

Hepatitis C virus (HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides (PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol (PtdIns) 4-kinases, and their lipid products PtdIns(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase (SHIP2), phosphoinositide 3-kinase (PI3K) and their lipid products PtdIns(3,4)P2 and PtdIns(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.

show abstract

Phosphoinositides in the Hepatitis C Virus Life Cycle

Cited by 41 publications

References 102 publications

N-Terminal AH2 segment of protein NS4B from hepatitis C virus. Binding to and interaction with model biomembranes

N-Terminal AH2 segment of protein NS4B from hepatitis C virus. Binding to and interaction with model biomembranes

Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System

PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis

Contact Info

Product

Resources

About