Immunolocalization of the Dengue Virus Nonstructural Glycoprotein NS1 Suggests a Role in Viral RNA Replication

Mackenzie, Jason M.; Jones, Malcolm K.; Young, Paul R.

doi:10.1006/viro.1996.0307

Cited by 394 publications

(385 citation statements)

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“…Conceivably, it could be the consequence of NN-DNJ decreasing the amounts of flaviviral NS1 glycoprotein (Fig. 5), which has been suggested to play a role in flavivirus RNA replication (28,29,36,37). Alternatively, NN-DNJ may have an indirect effect on the microenvironment of the ER, the major site for flavivirus replication (40), making it no longer favorable for the accomplishment of the flavivirus life cycle.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, a few misfolded envelope proteins may become dominant enough to disrupt the proper process of viral envelope formation, thereby amplifying the effect of NN-DNJ inhibition on virus assembly and subsequently infectivity. Alternatively, this ␣-glucosidase inhibitor might act directly to block the biosynthesis of the flaviviral glycoprotein NS1, which has been suggested to play a role in viral RNA replication (28,29,36,37). In the present study, intracellular NS1 levels were greatly reduced by NN-DNJ treatment, especially for DEN-2 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…NS1 carries 12 invariant cysteine residues, which are highly conserved among the flaviviruses. While no precise function has been ascribed to NS1, it clearly plays some critical role in viral RNA replication (28,29,36,37). An additional NS1-2A-related protein (named NS1Ј) with a molecular size of 53 kDa is often observed in JEV-infected cells; it is presumably generated by an unknown cellular protease that recognizes an alternative cleavage site within NS2A (7).…”

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confidence: 99%

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Antiviral Effects of an Iminosugar Derivative on Flavivirus Infections

Lee

Liao

et al. 2002

J Virol

204

164

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Endoplasmic reticulum (ER) ␣-glucosidase inhibitors, which block the trimming step of N-linked glycosylation, have been shown to eliminate the production of several ER-budding viruses. Here we investigated the effects of one such inhibitor, N-nonyl-deoxynojirimycin (NN-DNJ), a 9-carbon alkyl iminosugar derivative, on infection by Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2). In the presence of NN-DNJ, JEV and DEN-2 infections were suppressed in a dose-dependent manner. This inhibitory effect appeared to influence DEN-2 infection more than JEV infection, since lower concentrations of NN-DNJ substantially blocked DEN-2 replication. Secretion of the flaviviral glycoproteins E and NS1 was greatly reduced, and levels of DEN-2 viral RNA replication measured by fluorogenic reverse transcription-PCR were also decreased, by NN-DNJ. Notably, the viral glycoproteins, prM, E, and NS1 were found to associate transiently with the ER chaperone calnexin, and this interaction was affected by NN-DNJ, suggesting a potential role of calnexin in the folding of flaviviral glycoproteins. Additionally, in a mouse model of lethal challenge by JEV infection, oral delivery of NN-DNJ reduced the mortality rate. These findings show that NN-DNJ has an antiviral effect on flavivirus infection, likely through interference with virus replication at the posttranslational modification level, occurring mainly in the ER.The Flaviviridae family includes the three genera Hepacivirus (e.g., Hepatitis C virus), Flavivirus, and Pestivirus (e.g., Bovine viral diarrhea virus [BVDV]). The genus Flavivirus comprises more than 70 viruses, many of which are potent human pathogens that can cause severe encephalitic, hemorrhagic, hepatic, or febrile illnesses (35). Of particular importance for public health are the mosquito-borne flaviviruses, such as Yellow fever virus (41, 48), Japanese encephalitis virus (JEV) (45), West Nile virus (25), and dengue viruses (DENs) (16). Severe forms of dengue-related diseases, such as dengue hemorrhagic fever and dengue shock syndrome, have recently become the most serious vector-borne viral diseases in humans. It is estimated that more than 50 million people suffer DEN infection annually, with approximately 2.5 billion people living in at-risk areas (16,34). Even though these flaviviruses have a major clinical impact, there is still no vaccine for DENs, nor are there any specific antiviral therapeutics available for treatment of infections with JEV or DENs.Flaviviral virions are composed of a lipid bilayer with two or more envelope proteins surrounding a nucleocapsid, which consists of a single-stranded positive-sense genome RNA associated with multiple copies of capsid proteins. After entering a host cell, flaviviral RNA first translates into a long polyprotein, which is cleaved by cellular and viral proteases into individual structural and nonstructural proteins. RNA replication begins with the synthesis of complementary negative strands, which are then used as templates for reproduction of positiv...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Antiviral Effects of an Iminosugar Derivative on Flavivirus Infections

Lee

Liao

et al. 2002

J Virol

204

164

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“…Part of NS1 resides in virally induced intracellular organelles, where it plays an essential role in viral replication (12)(13)(14)(15)(16). The protein, possibly modified by GPI, also associates to lipid rafts at the plasma membrane and mediates a signaling pattern common to GPI-anchored proteins in the presence of specific antibodies (17)(18)(19).…”

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confidence: 99%

Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein

Gutsche

Coulibaly

Voss

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

264

294

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Dengue virus (DENV) causes the major arboviral disease of the tropics, characterized in its severe forms by signs of hemorrhage and plasma leakage. DENV encodes a nonstructural glycoprotein, NS1, that associates with intracellular membranes and the cell surface. NS1 is eventually secreted as a soluble hexamer from DENV-infected cells and circulates in the bloodstream of infected patients. Extracellular NS1 has been shown to modulate the complement system and to enhance DENV infection, yet its structure and function remain essentially unknown. By combining cryoelectron microscopy analysis with a characterization of NS1 amphipathic properties, we show that the secreted NS1 hexamer forms a lipoprotein particle with an open-barrel protein shell and a prominent central channel rich in lipids. Biochemical and NMR analyses of the NS1 lipid cargo reveal the presence of triglycerides, bound at an equimolar ratio to the NS1 protomer, as well as cholesteryl esters and phospholipids, a composition evocative of the plasma lipoproteins involved in vascular homeostasis. This study suggests that DENV NS1, by mimicking or hijacking lipid metabolic pathways, contributes to endothelium dysfunction, a key feature of severe dengue disease.arbovirus | dengue hemorrhagic fever | amphiphilic proteins | secretion

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“…NS1 is a highly conserved, Ϸ48-kDa glycoprotein that is essential for flavivirus RNA replication, although its precise function remains poorly defined (10,11). It exists in the cell as a heatlabile homodimer that associates with cellular organelle membranes and is transported to the mammalian cell surface (12,13) where it is vulnerable to immunological recognition.…”

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confidence: 99%

Flavivirus nonstructural protein NS1: Complementary surprises

Schlesinger

2006

Proc. Natl. Acad. Sci. U.S.A.

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Immunolocalization of the Dengue Virus Nonstructural Glycoprotein NS1 Suggests a Role in Viral RNA Replication

Cited by 394 publications

References 0 publications

Antiviral Effects of an Iminosugar Derivative on Flavivirus Infections

Antiviral Effects of an Iminosugar Derivative on Flavivirus Infections

Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein

Flavivirus nonstructural protein NS1: Complementary surprises

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