Highly Sulfated Forms of Heparin Sulfate Are Involved in Japanese Encephalitis Virus Infection

Su, Chin Cheng; Liao, Ching‐Len; Lee, Yi-Ling; Lin, Yi‐Ling

doi:10.1006/viro.2001.0986

Cited by 86 publications

(76 citation statements)

References 47 publications

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“…Although no definitive host-cell receptor has yet been identified, a large number of binding molecules on the surface of a range of cell types have been reported in the literature including DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) (Navarro-Sanchez et al, 2003;Tassaneetrithep et al, 2003) Germi et al, 2002;Kroschewski et al, 2003;Su et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Antibody neutralization-and peptide-based studies have further supported a critical role for DIII in host-cell binding (Abd-Jamil et al, 2008;Hiramatsu et al, 1996;Lin et al, 1994;Roehrig et al, 1998;Thullier et al, 2001). In addition to these studies, investigation of sequence variation among cell cultureadapted, serially passed and mutant viruses has also supported a receptor-binding role for DIII (Erb et al, 2010;Lee & Lobigs, 2000, 2002Lee et al, 2004).Although no definitive host-cell receptor has yet been identified, a large number of binding molecules on the surface of a range of cell types have been reported in the literature including DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) (Navarro-Sanchez et al, 2003;Tassaneetrithep et al, 2003) Germi et al, 2002;Kroschewski et al, 2003;Su et al, 2001).At an atomic level, electrostatic interactions between the negatively charged sulphate groups within GAGs and solvent-exposed basic residues such as lysine and arginine on the protein ligand are thought to mediate the molecular recognition process (Hileman et al, 1998). A number of studies have demonstrated adaptive mutations to acidic amino acids in serial passaging of flaviviruses under cellculture conditions, with these changes thought to play a role in facilitating enhanced GAG binding (Lee & Lobigs, 2002;Lee et al, 2006).…”

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confidence: 99%

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Residues in domain III of the dengue virus envelope glycoprotein involved in cell-surface glycosaminoglycan binding

Watterson

Kobe

Young

2012

Journal of General Virology

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The dengue virus (DENV) envelope (E) protein mediates virus entry into cells via interaction with a range of cell-surface receptor molecules. Cell-surface glycosaminoglycans (GAGs) have been shown to play an early role in this interaction, and charged oligosaccharides such as heparin bind to the E protein. We have examined this interaction using site-directed mutagenesis of a recombinant form of the putative receptor-binding domain III of the DENV-2E protein expressed as an MBP (maltose-binding protein)-fusion protein. Using an ELISA-based GAG-binding assay, cell-based binding analysis and antiviral-activity assays, we have identified two critical residues, K291 and K295, that are involved in GAG interactions. These studies have also demonstrated differential binding between mosquito and human cells. INTRODUCTIONDengue virus (DENV) belongs to the medically important genus Flavivirus. Spread by the mosquito vector Aedes aegypti, DENV has re-emerged as the most globally significant arthropod-borne viral pathogen in terms of annual incidence and morbidity. Antiviral and vaccine development against DENV is therefore a priority (Mackenzie et al., 2004). There are four distinct serotypes of DENV (DENV-1-DENV-4) and reinfection with a heterologous serotype is associated with an increased risk of severe disease, thereby complicating effective vaccine strategies (WHO, 2009).Flaviviruses are small (50 nm), positive-strand RNA, enveloped viruses with a smooth, spherical morphology. The mature virion comprises three structural proteins: a capsid protein (C), which associates with the viral RNA genome; a membrane protein (M), which is derived from a structural precursor (prM); and the glycosylated envelope protein (E), which is the major surface protein and mediates both cell attachment and fusion of the viral and cellular membranes. The atomic structure of E has been solved for tick-borne encephalitis virus (TBEV), DENV-2, DENV-3, West Nile virus (WNV) and Japanese encephalitis virus (JEV) by X-ray crystallography of recombinant proteins comprising the first approximately 400 residues of E, referred to as the soluble E ectodomain (sE) (Kanai et al., 2006;Modis et al., 2003Modis et al., , 2005Rey et al., 1995; JEV E, PDB accession no. 3P54). This recombinant lacks the Cterminal membrane-spanning anchors and the associated 'stem' region. These structural studies demonstrated a conserved global fold across the entire family, suggesting a shared mode of action with respect to the two functional roles of receptor binding and membrane fusion. The structures also revealed that the E glycoprotein forms a head-to-tail homodimer and is composed of three distinct domains, referred to as domains I (DI), II (DII) and III (DIII), that reflect the earlier determined antigenic domains (Guirakhoo et al., 1989). DIII consists of the Cterminal region (residues 292-395) of sE, which adopts an immunoglobulin-like fold of seven anti-parallel b-sheets linked by flexible loops (Huang et al., 2008;Mukherjee et al., 2006;Volk et al., 2004 Volk et a...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Residues in domain III of the dengue virus envelope glycoprotein involved in cell-surface glycosaminoglycan binding

Watterson

Kobe

Young

2012

Journal of General Virology

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“…Studies have shown that heparan sulfate proteoglycans (HSPGs) and glycosaminoglycans (GAGs) serve as attachment factors for JEV (10)(11)(12). These interactions are charge driven, with the negatively charged HSPGs serving to concentrate the positively charged E glycoprotein-containing virions on the cell membrane, thus facilitating the receptor interaction.…”

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confidence: 99%

GRP78 Is an Important Host Factor for Japanese Encephalitis Virus Entry and Replication in Mammalian Cells

Nain

Mukherjee

Karmakar

et al. 2017

J Virol

120

126

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Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is the leading cause of viral encephalitis in Southeast Asia with potential to become a global pathogen. Here, we identify glucose-regulated protein 78 (GRP78) as an important host protein for virus entry and replication. Using the plasma membrane fractions from mouse neuronal (Neuro2a) cells, mass spectroscopy analysis identified GRP78 as a protein interacting with recombinant JEV envelope protein domain III. GRP78 was found to be expressed on the plasma membranes of Neuro2a cells, mouse primary neurons, and human epithelial Huh-7 cells. Antibodies against GRP78 significantly inhibited JEV entry in all three cell types, suggesting an important role of the protein in virus entry. Depletion of GRP78 by small interfering RNA (siRNA) significantly blocked JEV entry into Neuro2a cells, further supporting its role in virus uptake. Immunofluorescence studies showed extensive colocalization of GRP78 with JEV envelope protein in virus-infected cells. This interaction was also confirmed by immunoprecipitation studies. Additionally, GRP78 was shown to have an important role in JEV replication, as treatment of cells post-virus entry with subtilase cytotoxin that specifically cleaved GRP78 led to a substantial reduction in viral RNA replication and protein synthesis, resulting in significantly reduced extracellular virus titers. Our results indicate that GRP78, an endoplasmic reticulum chaperon of the HSP70 family, is a novel host factor involved at multiple steps of the JEV life cycle and could be a potential therapeutic target.IMPORTANCE Recent years have seen a rapid spread of mosquito-borne diseases caused by flaviviruses. The flavivirus family includes West Nile, dengue, Japanese encephalitis, and Zika viruses, which are major threats to public health with potential to become global pathogens. JEV is the major cause of viral encephalitis in several parts of Southeast Asia, affecting a predominantly pediatric population with a high mortality rate. This study is focused on identification of crucial host factors that could be targeted to cripple virus infection and ultimately lead to development of effective antivirals. We have identified a cellular protein, GRP78, that plays a dual role in virus entry and virus replication, two crucial steps of the virus life cycle, and thus is a novel host factor that could be a potential therapeutic target.

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“…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.…”

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confidence: 99%

Involvement of Ceramide in the Propagation of Japanese Encephalitis Virus

Tani

Mai

Kaname

et al. 2010

J Virol

110

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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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Highly Sulfated Forms of Heparin Sulfate Are Involved in Japanese Encephalitis Virus Infection

Cited by 86 publications

References 47 publications

Residues in domain III of the dengue virus envelope glycoprotein involved in cell-surface glycosaminoglycan binding

Residues in domain III of the dengue virus envelope glycoprotein involved in cell-surface glycosaminoglycan binding

GRP78 Is an Important Host Factor for Japanese Encephalitis Virus Entry and Replication in Mammalian Cells

Involvement of Ceramide in the Propagation of Japanese Encephalitis Virus

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