Cholesterol biosynthesis modulation regulates dengue viral replication

Rothwell, Christopher; LeBreton, Aude; Ng, Choon Ta; Lim, Joanne Y.H.; Liu, Wei; Vasudevan, Subhash G.; Labow, Mark; Gu, Feng; Gaither, L. Alex

doi:10.1016/j.virol.2009.03.025

Cited by 235 publications

(223 citation statements)

References 34 publications

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“…In addition, several studies on WNV have reported the cellular redistribution of cholesterol and its requirement for viral entry and replication (43,44). Finally, using DENV subgenomic luciferase replicon-expressing cell lines, treatment with various anti-cholesterol pharmacological drugs were shown to affect replication (45). These findings, along with those presented in this study, lead us to hypothesize that signaling through the ER via IRE1-JNK pathway might be important during the DENV life cycle.…”

Section: Discussionsupporting

confidence: 69%

Dengue Virus Modulates the Unfolded Protein Response in a Time-dependent Manner

Peña

Harris

2011

Journal of Biological Chemistry

170

203

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Flaviviruses, such as dengue virus (DENV), depend on the host endoplasmic reticulum for translation, replication, and packaging of their genomes. Here we report that DENV-2 infection modulates the unfolded protein response in a time-dependent manner. We show that early DENV-2 infection triggers and then suppresses PERK-mediated eIF2␣ phosphorylation and that in mid and late DENV-2 infection, the IRE1-XBP1 and ATF6 pathways are activated, respectively. Activation of IRE1-XBP1 correlated with induction of downstream targets GRP78, CHOP, and GADD34. Furthermore, induction of CHOP did not induce apoptotic markers, such as suppression of anti-apoptotic protein Bcl-2, activation of caspase-9 or caspase-3, and cleavage of poly(ADPribose) polymerase. Finally, we show that DENV-2 replication is affected in PERK ؊/؊ and IRE1 ؊/؊ mouse embryo fibroblasts when compared with wild-type mouse embryo fibroblasts. These results demonstrate that time-dependent activation of the unfolded protein response by DENV-2 can override inhibition of translation, prevent apoptosis, and prolong the viral life cycle.

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Section: Discussionsupporting

confidence: 69%

Dengue Virus Modulates the Unfolded Protein Response in a Time-dependent Manner

Peña

Harris

2011

Journal of Biological Chemistry

170

203

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“…Host kinases have been shown to be involved in DENV and WNV assembly and secretion (8,19). The cholesterol biosynthesis pathway has been linked to DENV entry and replication as well as to the host immune response (29,42). We recently showed that brequinar inhibits DENV through depletion of the intracellular level of pyrimidine (39).…”

mentioning

confidence: 99%

Inhibition of Dengue Virus through Suppression of Host Pyrimidine Biosynthesis

Wang

Bushell

Qing

et al. 2011

J Virol

151

131

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Viral replication relies on the host to supply nucleosides. Host enzymes involved in nucleoside biosynthesis are potential targets for antiviral development. Ribavirin (a known antiviral drug) is such an inhibitor that suppresses guanine biosynthesis; depletion of the intracellular GTP pool was shown to be the major mechanism to inhibit flavivirus. Along similar lines, inhibitors of the pyrimidine biosynthesis pathway could be targeted for potential antiviral development. Here we report on a novel antiviral compound (NITD-982) that inhibits host dihydroorotate dehydrogenase (DHODH), an enzyme required for pyrimidine biosynthesis. The inhibitor was identified through screening 1.8 million compounds using a dengue virus (DENV) infection assay. The compound contains an isoxazole-pyrazole core structure, and it inhibited DENV with a 50% effective concentration (EC 50 ) of 2.4 nM and a 50% cytotoxic concentration (CC 50 ) of >5 M. NITD-982 has a broad antiviral spectrum, inhibiting both flaviviruses and nonflaviviruses with nanomolar EC 90 s. We also show that (i) the compound inhibited the enzymatic activity of recombinant DHODH, (ii) an NITD-982 analogue directly bound to the DHODH protein, (iii) supplementing the culture medium with uridine reversed the compoundmediated antiviral activity, and (iv) DENV type 2 (DENV-2) variants resistant to brequinar (a known DHODH inhibitor) were cross resistant to NITD-982. Collectively, the results demonstrate that the compound inhibits DENV through depleting the intracellular pyrimidine pool. In contrast to the in vitro potency, the compound did not show any efficacy in the DENV-AG129 mouse model. The lack of in vivo efficacy is likely due to the exogenous uptake of pyrimidine from the diet or to a high plasma protein-binding activity of the current compound.

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“…Lipid rafts consisting of sphingolipids and cholesterol and distributing to the outer leaflet of the cell membrane have been shown to be involved in the infection of not only many viruses but also several bacteria and parasites (24), in addition to playing roles in various functions such as lipid sorting, protein trafficking (26,47), cell polarity, and signal transduction (38). With respect to cholesterol itself, various aspects of the life cycle of flaviviruses have been shown to involve this lipid, including the entry of DENV (34), hepatitis C virus (HCV) (16), and WNV (27), the membrane fusion of tick-borne encephalitis virus (40), and the replication of HCV (14,17), WNV (23), and DENV (35). Recently Lee et al (20) showed that treatment with cholesterol efficiently impairs both the entry and replication steps of JEV and DENV-2 but enhances infection with the Sindbis virus (22).…”

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confidence: 99%

Involvement of Ceramide in the Propagation of Japanese Encephalitis Virus

Tani

Mai

Kaname

et al. 2010

J Virol

116

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Japanese encephalitis virus (JEV) is a small, enveloped virus belonging to the family Flaviviridae and the genus Flavivirus, which also includes Dengue virus (DENV), West Nile virus (WNV), Yellow fever virus, and Tick-borne encephalitis virus (11). JEV is the most common agent of viral encephalitis, causing approximately 50,000 cases annually, of which 15,000 will die, and up to 50% of survivors are left with severe residual neurological complications. JEV has a single-stranded positive-sense RNA genome of approximately 11 kb, encoding a single large polyprotein, which is cleaved by the host-and virus-encoded proteases into three structural proteins, capsid (C), premembrane (PrM), and envelope (E), and seven nonstructural proteins. The structural proteins are components of viral particles, and the E protein is suggested to interact with a cell surface receptor molecule(s). Although a number of cellular components, including heat shock cognate protein 70 (33), glycosaminoglycans, such as heparin or heparan sulfate (21, 41), and laminin (3), have been shown to participate in JEV infection, the precise mechanisms by which these receptor candidates participate in JEV infection remain largely unclear.In addition to the many studies identifying and characterizing receptor molecules in numerous viruses, data suggesting the involvement of membrane lipids, such as sphingolipids and cholesterol, in viral infection have also been accumulating. Lipid rafts consisting of sphingolipids and cholesterol and distributing to the outer leaflet of the cell membrane have been shown to be involved in the infection of not only many viruses but also several bacteria and parasites (24), in addition to playing roles in various functions such as lipid sorting, protein trafficking (26, 47), cell polarity, and signal transduction (38). With respect to cholesterol itself, various aspects of the life cycle of flaviviruses have been shown to involve this lipid, including the entry of DENV (34), hepatitis C virus (HCV) (16), and WNV (27), the membrane fusion of tick-borne encephalitis virus (40), and the replication of HCV (14, 17), WNV (23), and DENV (35). Recently Lee et al. (20) showed that treatment with cholesterol efficiently impairs both the entry and replication steps of JEV and DENV-2 but enhances infection with the Sindbis virus (22).On the other hand, sphingolipids, including sphingomyelins and glycosphingolipids, are ubiquitous components of eukaryotic cell membrane structures, providing integrity to cellular membranes. Ceramide is one of the intermediates of sphingolipids and plays roles in cell differentiation, regulation of apoptosis and protein secretion, induction of cellular senescence, and other processes (2). Ceramide is generated from the hydrolysis of sphingomyelin by sphingomyelinase (SMase) or from catalysis by serine-palmitoyl-coenzyme A (CoA) transferase and ceramide synthase. Ceramide spontaneously selfassociates to form ceramide-enriched microdomains and then to form larger ceramide-enriched membrane platforms which...

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Cholesterol biosynthesis modulation regulates dengue viral replication

Cited by 235 publications

References 34 publications

Dengue Virus Modulates the Unfolded Protein Response in a Time-dependent Manner

Dengue Virus Modulates the Unfolded Protein Response in a Time-dependent Manner

Inhibition of Dengue Virus through Suppression of Host Pyrimidine Biosynthesis

Involvement of Ceramide in the Propagation of Japanese Encephalitis Virus

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