PTEN protein phosphatase activity regulates hepatitis C virus secretion through modulation of cholesterol metabolism

Peyrou, Marion; Clément, Sophie; Maier, Christiane; Bourgoin, Lucie; Branche, Emilie; Conzelmann, Stéphanie; Kaddai, Vincent; Foti, Michelangelo; Negro, Francesco

doi:10.1016/j.jhep.2013.04.012

Cited by 39 publications

(36 citation statements)

References 42 publications

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“…Therefore, an impairment of PI3K/PTEN signaling could be involved in some NASH/HCC cases in humans. These results are very compatible with the down-regulation of PTEN in HCV infection, which leads to an acceleration of lipid droplet formation and insulin resistance[67,68]. Taken together, these studies have suggested a role for PTEN in regulating lipogenesis in liver cells; however, less information is available on the effects of another lipid phosphatase, SHIP2, on lipid and lipoprotein metabolism in the liver.…”

Section: Pi3k/ship2/pten Pathway and Nafldsupporting

confidence: 61%

“…HCV infection leads to a down-regulation of PTEN, triggering an acceleration of lipid droplet formation and insulin resistance[67,68]. The down-regulation of PTEN causes a malformation of the apical domain in an MDCK 3D culture[60], suggesting that the multi-lumen phenotype in MCDK cells expressing HCV core protein may be caused not only by RhoA down-regulation[50] but also by modifying PTEN expression.…”

Section: Pten and Ptdins(45)p2 Cell Polarity And Hcv Infectionmentioning

confidence: 99%

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

Awad

Gassama‐Diagne

2017

WJH

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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.

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Section: Pi3k/ship2/pten Pathway and Nafldsupporting

confidence: 61%

Section: Pten and Ptdins(45)p2 Cell Polarity And Hcv Infectionmentioning

confidence: 99%

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

Awad

Gassama‐Diagne

2017

WJH

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“…Using a new bioassay to measure PTEN function in living tissue, it was recently shown that PTEN auto-dephosphorylates serine and/or threonine residues in its own C-terminal region; this event(s) appears to promote its lipid phosphatase activity [12, 13]. The protein phosphatase activity of PTEN also regulates secretion of hepatitis C virus particles in liver, possibly via regulation of cholesterol metabolism [14]. …”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of Cancers with Loss of PTEN Function

Dillon¹,

Miller²

2014

CDT

204

159

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Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is one of the most frequently disrupted tumor suppressors in cancer. The lipid phosphatase activity of PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway to repress tumor cell growth and survival. In the nucleus, PTEN promotes chromosome stability and DNA repair. Consequently, loss of PTEN function increases genomic instability. PTEN deficiency is caused by inherited germline mutations, somatic mutations, epigenetic and transcriptional silencing, post-translational modifications, and protein-protein interactions. Given the high frequency of PTEN deficiency across cancer subtypes, therapeutic approaches that exploit PTEN loss-of-function could provide effective treatment strategies. Herein, we discuss therapeutic strategies aimed at cancers with loss of PTEN function, and the challenges involved in treating patients afflicted with such cancers. We review preclinical and clinical findings, and highlight novel strategies under development to target PTEN-deficient cancers.

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“…Nevertheless, an increasing number of reports show that PI-mediated signalling events are at least in some cases cholesterol-dependent. Interestingly, the PTEN phosphatase influences CE levels through its protein phosphatase activity (Peyrou et al, 2013) and FIG4 may stimulate CE synthesis possibly by also acting as a protein phosphatase (Duex et al, 2006). Given the importance of CE biology in HCV pathophysiology and VLDL formation (Alvisi et al, 2011;Lambert et al, 2013), future studies aiming at identifying the molecular bases of this finding are certainly needed.…”

Section: Fig4 Ce Levels and The Secretory Pathwaymentioning

confidence: 99%

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

Jessica

Plissonnier

Kullolli

et al. 2016

Journal of General Virology

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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.

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PTEN protein phosphatase activity regulates hepatitis C virus secretion through modulation of cholesterol metabolism

Cited by 39 publications

References 42 publications

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

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

Therapeutic Targeting of Cancers with Loss of PTEN Function

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

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