Mucin-like Region of Herpes Simplex Virus Type 1 Attachment Protein Glycoprotein C (gC) Modulates the Virus-Glycosaminoglycan Interaction

Altgärde, Noomi; Eriksson, Charlotta E.; Peerboom, Nadia; Phan-Xuan, Tuan; Moeller, Stephanie; Schnabelrauch, Matthias; Svedhem, Sofia; Trybala, Edward; Bergström, Tomas; Bally, Marta

doi:10.1074/jbc.m115.637363

Cited by 33 publications

(79 citation statements)

References 55 publications

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“…Mucins have typically high molecular weight and contain a large central region formed of multiple tandem repeats of a serine or threonine-rich motif which is usually heavily glycosylated. They are found in eukaryotes but also in some viruses, such as in Filoviridae (Hashiguchi et al 2015), Herpesviridae (Altgärde et al 2015), Paramyxoviridae (respiratory syncitial virus, RSV), and HIV, where they are incorporated into the envelope. ORF61 may thus also be a structural protein of LbFV.…”

Section: Resultsmentioning

confidence: 99%

“…ORF61 may thus also be a structural protein of LbFV. Mucin-like proteins found in viruses mediate the binding with host cell surface by interacting with host glycosaminoglycans, such as chondroitin sulfate and sulfated hyaluronan (Altgärde et al 2015). Because ORF61 has a putative glycosaminoglycan-ligand activity and ORF106 has putative glycosaminoglycan-breaking activity, we can speculate that both ORFs may work in conjunction to facilitate LbFV entry into the cell.…”

Section: Resultsmentioning

confidence: 99%

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Genome Sequencing of the Behavior Manipulating Virus LbFV Reveals a Possible New Virus Family

Lepetit

Gillet

Hughes

et al. 2016

Genome Biology and Evolution

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Parasites are sometimes able to manipulate the behavior of their hosts. However, the molecular cues underlying this phenomenon are poorly documented. We previously reported that the parasitoid wasp Leptopilina boulardi which develops from Drosophila larvae is often infected by an inherited DNA virus. In addition to being maternally transmitted, the virus benefits from horizontal transmission in superparasitized larvae (Drosophila that have been parasitized several times). Interestingly, the virus forces infected females to lay eggs in already parasitized larvae, thus increasing the chance of being horizontally transmitted. In a first step towards the identification of virus genes responsible for the behavioral manipulation, we present here the genome sequence of the virus, called LbFV. The sequencing revealed that its genome contains an homologous repeat sequence (hrs) found in eight regions in the genome. The presence of this hrs may explain the genomic plasticity that we observed for this genome. The genome of LbFV encodes 108 ORFs, most of them having no homologs in public databases. The virus is however related to Hytrosaviridae, although distantly. LbFV may thus represent a member of a new virus family. Several genes of LbFV were captured from eukaryotes, including two anti-apoptotic genes. More surprisingly, we found that LbFV captured from an ancestral wasp a protein with a Jumonji domain. This gene was afterwards duplicated in the virus genome. We hypothesized that this gene may be involved in manipulating the expression of wasp genes, and possibly in manipulating its behavior.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Genome Sequencing of the Behavior Manipulating Virus LbFV Reveals a Possible New Virus Family

Lepetit

Gillet

Hughes

et al. 2016

Genome Biology and Evolution

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“…The function of these densely glycosylated areas are not clear, but it is proposed that O-glycans in the distally located mucin-like region in gC has a direct role in modulating the interaction with cell surface proteoglycans (21). In a similar way it can be speculated that the abundant O-glycosylation found on the unique N-terminal domain of VZV gE affects the multiple functions specified by the region, including interactions with cell entry receptor insulin-degrading enzyme and binding partner gI (50).…”

Section: Discussionmentioning

confidence: 99%

“…Important biological functions are associated with both types of glycans. For instance, clustered O-glycans of the distinct HSV-1 glycoprotein C have been found to be necessary not only for adjusting viral binding to its initial receptor, heparan sulfate, but also for preventing progeny virus from entrapment on the dying cell in which the virus replicated (21). An example of the functional role of single O-glycans emerged with the demonstration of a few O-glycosites on HSV-1 gB involved in the interaction with entry receptor paired immunoglobulin-like type 2 receptor ␣, possibly important for immune evasion (20,31).…”

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confidence: 99%

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Bagdonaite

Nordén

Joshi

et al. 2016

Journal of Biological Chemistry

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Herpesviruses are among the most complex and widespread viruses, infection and propagation of which depend on envelope proteins. These proteins serve as mediators of cell entry as well as modulators of the immune response and are attractive vaccine targets. Although envelope proteins are known to carry glycans, little is known about the distribution, nature, and functions of these modifications. This is particularly true for O-glycans; thus we have recently developed a "bottom up" mass spectrometry-based technique for mapping O-glycosylation sites on herpes simplex virus type 1. We found wide distribution of O-glycans on herpes simplex virus type 1 glycoproteins and demonstrated that elongated O-glycans were essential for the propagation of the virus. Here, we applied our proteome-wide discovery platform for mapping O-glycosites on representative and clinically significant members of the herpesvirus family: varicella zoster virus, human cytomegalovirus, and Epstein-Barr virus. We identified a large number of O-glycosites distributed on most envelope proteins in all viruses and further demonstrated conserved patterns of O-glycans on distinct homologous proteins. Because glycosylation is highly dependent on the host cell, we tested varicella zoster virus-infected cell lysates and clinically isolated virus and found evidence of consistent O-glycosites. These results present a comprehensive view of herpesvirus O-glycosylation and point to the widespread occurrence of O-glycans in regions of envelope proteins important for virus entry, formation, and recognition by the host immune system. This knowledge enables dissection of specific functional roles of individual glycosites and, moreover, provides a framework for design of glycoprotein vaccines with representative glycosylation.

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“…These residues are situated directly C-terminal to the HBD, which has been described as a region of G that binds GAG (73,123,124,370). It has been shown that removal of a cluster of O-linked sites that sit proximal to a GAG-binding domain on the gC attachment protein of herpes simplex virus (HSV) type 1, affects binding of the virus to GAG and reduces the production of new viral particles (389).…”

Section: Discussionmentioning

confidence: 99%

Structural characterisation of glycosylation of paramyxovirus attachment and fusion proteins by mass spectrometry

Pegg¹

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The family Paramyxoviridae (paramyxovirus) contains several significant human and animal pathogens.Represented within this family are human respiratory syncytial virus (hRSV) and Newcastle disease virus (NDV). The former contributes significantly to severe respiratory tract disease in infants, children and immunocompromised individuals. At present, highly efficacious therapeutics or safe and effective vaccines are not available for hRSV. NDV is the causative agent of Newcastle disease, afflicting a wide range of avian species. The desire to study NDV is due not only to the significant economic impact it has on the poultry industry worldwide, but also its potential use as an oncolytic agent and vaccine vector in humans and animals. Additionally, findings on NDV may be translated to closely related viruses that cause disease in humans, such as parainfluenza viruses.As outlined in Chapter 1 of this thesis, the infectious processes of all members of this family are driven by two major membrane glycoproteins whose ectodomains project from the viral envelope: the fusion (F) and attachment glycoproteins. The F glycoprotein is responsible for viral entry by means of fusion with host cell membranes while the variable attachment glycoproteins, haemagglutinin, haemagglutininneuraminidase (HN) and major surface glycoprotein (G), are involved in viral attachment to host cells.Previous studies have shown that altering the glycosylation profile of these proteins can modulate the ability of the virus to infect host cells and stimulate the host immune system. As yet, site-specific glycan heterogeneity of hRSV and NDV surface glycoproteins has not been defined at a chemical level. As described in Chapter 2, reverse-phase liquid chromatography tandem mass spectrometry (MS) strategies were implemented to characterise intact glycopeptides from the attachment and F glycoproteins of hRSV and NDV. Site-occupancy and monosaccharide compositions at a given site were determined using collision-induced dissociation, higher-energy collision dissociation, electron-transfer dissociation and electron-transfer dissociation combined with collision dissociation. As described in Chapter 3, a spectral processing program was developed called OxoExtract to aid identification of intact glycopeptides that were fragmented with higher-energy collision dissociation.The F and HN proteins of NDV were derived from virions propagated in embryonic eggs. Analyses of HN in Chapter 4 revealed high mannose N-linked glycans and complex or hybrid N-linked glycans that were variably fucosylated, sialylated and sulfated or phosphorylated. In total 63, 58, and 37 glycans were identified at sites N341, N433 and N481, respectively. In addition, a previously undocumented Olinked glycosylation site was identified in the stalk domain of the protein. Observed glycans from NDV F described in Chapter 5 were mainly high mannose, containing variations of five to nine mannose ii residues across four sites, N85, N191, N366 and N471. There was also evidence of fucosylated c...

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Mucin-like Region of Herpes Simplex Virus Type 1 Attachment Protein Glycoprotein C (gC) Modulates the Virus-Glycosaminoglycan Interaction

Cited by 33 publications

References 55 publications

Genome Sequencing of the Behavior Manipulating Virus LbFV Reveals a Possible New Virus Family

Genome Sequencing of the Behavior Manipulating Virus LbFV Reveals a Possible New Virus Family

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Structural characterisation of glycosylation of paramyxovirus attachment and fusion proteins by mass spectrometry

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