The life cycle of human equilibrative nucleoside transporter 1: From ER export to degradation

Nivillac, Nicole M.I.; Bacani, Joseph; Coe, Imogen R.

doi:10.1016/j.yexcr.2011.03.008

Cited by 20 publications

(22 citation statements)

References 46 publications

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“…Inhibition of endocytosis with CPZ 30 caused an increase in adenosine transport in cells from pGWG, but not in cells from spGWG, suggesting that hENT1 protein recycles in HUVECs from pGWG. The latter agrees with findings for hENT1 reported in the MCF-7 cell line, 38 and with the possibility that recycling could be altered in cells from spGWG. Thus, spGWG is a pathological condition that could results in lower availability of hENT1 protein at the plasma membrane in HUVECs.…”

Section: Discussionsupporting

confidence: 92%

Human supraphysiological gestational weight gain and fetoplacental vascular dysfunction

et al. 2015

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Section: Discussionsupporting

confidence: 92%

Human supraphysiological gestational weight gain and fetoplacental vascular dysfunction

et al. 2015

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“…The ENT1 isoform, which is expressed primarily on the plasma membrane, is important in transporting nucleoside analogue drugs used in antiviral therapy. The ENT1 protein is translated and folded in the ER and is transported via the Golgi apparatus to the plasma membrane (23). In the plasma membrane, ENT1 is internalized by clathrin-dependent endocytosis and recycled following clathrinmediated internalization.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study demonstrated that human ENT1 is trafficked to the plasma membrane in association with microtubules and is then recycled by clathrinmediated endocytosis (23). A chimeric clone of ENT1 and a green fluorescent protein developed in the laboratory of Imogen Coe were used to verify how the HCV-induced autophagy response alters cell surface expression of ENT1 through the clathrin heavy chain.…”

Section: Ribavirin Antiviral Activity Is Impaired In Persistently Hcvmentioning

confidence: 99%

Persistent Hepatitis C Virus Infection Impairs Ribavirin Antiviral Activity through Clathrin-Mediated Trafficking of Equilibrative Nucleoside Transporter 1

Panigrahi

Chandra

Ferraris

et al. 2015

J Virol

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Ribavirin (RBV) continues to be an important component of interferon-free hepatitis C treatment regimens, as RBV alone does not inhibit hepatitis C virus (HCV) replication effectively; the reason for this ineffectiveness has not been established. In this study, we investigated the RBV resistance mechanism using a persistently HCV-infected cell culture system. The antiviral activity of RBV against HCV was progressively impaired in the persistently infected culture, whereas interferon lambda 1 (IFN-1), a type III IFN, showed a strong antiviral response and induced viral clearance. We found that HCV replication in persistently infected cultures induces an autophagy response that impairs RBV uptake by preventing the expression of equilibrative nucleoside transporter 1 (ENT1). The Huh-7.5 cell line treated with an autophagy inducer, Torin 1, downregulated membrane expression of ENT1 and terminated RBV uptake. In contrast, the autophagy inhibitors hydroxychloroquine (HCQ), 3-methyladenine (3-MA), and bafilomycin A1 (BafA1) prevented ENT1 degradation and enhanced RBV antiviral activity. The HCV-induced autophagy response, as well as treatment with Torin 1, degrades clathrin heavy chain expression in a hepatoma cell line. Reduced expression of the clathrin heavy chain by HCV prevents ENT1 recycling to the plasma membrane and forces ENT1 to the lysosome for degradation. This study provides a potential mechanism for the impairment of RBV antiviral activity in persistently HCV-infected cell cultures and suggests that inhibition of the HCV-induced autophagy response could be used as a strategy for improving RBV antiviral activity against HCV infection. IMPORTANCEThe results from this work will allow a review of the competing theories of antiviral therapy development in the field of HCV virology. Ribavirin (RBV) remains an important component of interferon-free hepatitis C treatment regimens. The reason why RBV alone does not inhibit HCV replication effectively has not been established. This study provides a potential mechanism for why RBV antiviral activity is impaired in persistently HCV-infected cell cultures and suggests that inhibition of the HCV-induced autophagy response could be used as a strategy to increase RBV antiviral activity against HCV infection. Therefore, it is anticipated that this work would generate a great deal of interest, not only among virologists but also among the general public. H epatitis C virus (HCV) is estimated to infect Ͼ185 million people worldwide (1). Infection by HCV leads to a high likelihood of chronic liver disease, which often progresses to liver cirrhosis and hepatocellular carcinoma; HCV is therefore a major public health problem. Interferon alpha (IFN-␣) and ribavirin (RBV) (a guanosine analogue) have been used as standard therapy for chronic HCV infection for over a decade, with a sustained virologic response rate of 50% for genotype 1a virus. In 2011, two HCV-specific direct-acting antivirals (DAAs) targeting to NS3 protease (telaprevir and boceprevir) received FDA appro...

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“…A recent study has provided an important insight into the life cycle of human equilibrative nucleoside transporters (Nivillac et al, 2011). In this study, green fluorescence protein-tagged or FLAG-tagged hENT1 was transiently transfected into mammalian cells and the sequence of events regulating the hENT1 life cycle was studied; protein translocation to the plasma membrane was examined using fixed and live cell confocal microscopy (Nivillac et al, 2011). This study revealed that that the entire life cycle of the tagged-hENT1 protein was approximately 14 hours following translation, folding and ER export (Nivillac et al, 2011).…”

Section: Molecular Properties Expression and Mechanism Of Transport mentioning

confidence: 99%

“…Glycosylation probably plays a significant role in trafficking and function for a number of transporters including ENTs (Cai et al, 2005, Hendriks et al, 2004, Tanaka et al, 2004. hENT1 was then trafficked to the plasma membrane in association with the microtubule network in a variety of vesicles; in the plasma membrane hENT1 was co-localized with actin, which suggested that this transporter was anchored in the membrane by the actin cytoskeleton (Nivillac et al, 2011). This finding was consistent with previous observations for some other transporters, such as mouse GABA transporter 1 (Moss et al, 2009).…”

Section: Molecular Properties Expression and Mechanism Of Transport mentioning

confidence: 99%

Transport Mechanisms of Nucleosides and Nucleoside Analogues ReverseTranscriptase Inhibitors in the Brain

Redžić¹,

Denčić²

2011

Recent Translational Research in HIV/AIDS

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The life cycle of human equilibrative nucleoside transporter 1: From ER export to degradation

Cited by 20 publications

References 46 publications

Human supraphysiological gestational weight gain and fetoplacental vascular dysfunction

Human supraphysiological gestational weight gain and fetoplacental vascular dysfunction

Persistent Hepatitis C Virus Infection Impairs Ribavirin Antiviral Activity through Clathrin-Mediated Trafficking of Equilibrative Nucleoside Transporter 1

Transport Mechanisms of Nucleosides and Nucleoside Analogues ReverseTranscriptase Inhibitors in the Brain

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