O-Linked Glycosylation of the Mucin Domain of the Herpes Simplex Virus Type 1-specific Glycoprotein gC-1 Is Temporally Regulated in a Seed-and-spread Manner

Nordén, Rickard; Halim, Adnan; Nyström, Kristina; Bennett, Eric; Mandel, Ulla; Olofsson, Sigvard; Nilsson, Jonas; Larson, Göran

doi:10.1074/jbc.m114.616409

Cited by 21 publications

(23 citation statements)

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“…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). Altogether, such data, including our recent demonstration of the importance of O-glycans for HSV-1 and HSV-2 propagation as well as HSV-2 immune sensing (31,33,34), emphasize important functions of O-glycans on herpesvirus envelope glycoproteins.…”

mentioning

confidence: 65%

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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confidence: 65%

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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“…The recent advances in mass spectrometry-based proteomics have resulted in numerous studies addressing O-glycosylation of individual viral glycoproteins. O-glycoproteomic analyses have been performed for several recombinant or isolated viral glycoproteins, including HIV-1 gp120, influenza A virus HA1, HCV E2, HSV-1 gC and Hendra virus glycoprotein G (Colgrave et al 2012;Brautigam et al 2013;Go et al 2013;Yang W et al 2014;Norden et al 2015;Stansell et al 2015). Recombinantly expressed gp120 and HA1 were glycosylated at a single position each, which in both cases was modified with core 1 or core 2 elongated O-glycans (Stansell et al 2015).…”

Section: O-glycoproteomicsmentioning

confidence: 99%

“…Only a few of these proteins have merited more thorough investigation with most attention devoted to proteins containing mucin-like domains. HSV-1 attachment factor gC was the first envelope glycoprotein described to carry O-glycans, acquiring distinct structures in different cell types (Olofsson et al 1981(Olofsson et al , 1983Dall'Olio et al 1985;Lundstrom et al 1987), and specific O-glycosites have recently been mapped to the mucin-like region (Bagdonaite et al 2015;Norden et al 2015). Furthermore, the HSV-2 and VZV orthologs were also found to be O-glycosylated (Zezulak and Spear 1983;Bagdonaite et al 2016).…”

Section: Global O-glycoproteomicsmentioning

confidence: 99%

Global aspects of viral glycosylation

2018

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Enveloped viruses encompass some of the most common human pathogens causing infections of different severity, ranging from no or very few symptoms to lethal disease as seen with the viral hemorrhagic fevers. All enveloped viruses possess an envelope membrane derived from the host cell, modified with often heavily glycosylated virally encoded glycoproteins important for infectivity, viral particle formation and immune evasion. While N-linked glycosylation of viral envelope proteins is well characterized with respect to location, structure and site occupancy, information on mucin-type O-glycosylation of these proteins is less comprehensive. Studies on viral glycosylation are often limited to analysis of recombinant proteins that in most cases are produced in cell lines with a glycosylation capacity different from the capacity of the host cells. The glycosylation pattern of the produced recombinant glycoproteins might therefore be different from the pattern on native viral proteins. In this review, we provide a historical perspective on analysis of viral glycosylation, and summarize known roles of glycans in the biology of enveloped human viruses. In addition, we describe how to overcome the analytical limitations by using a global approach based on mass spectrometry to identify viral O-glycosylation in virus-infected cell lysates using the complex enveloped virus herpes simplex virus type 1 as a model. We underscore that glycans often pay important contributions to overall protein structure, function and immune recognition, and that glycans represent a crucial determinant for vaccine design. High throughput analysis of glycosylation on relevant glycoprotein formulations, as well as data compilation and sharing is therefore important to identify consensus glycosylation patterns for translational applications.

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“…Developments in MS‐based proteomics have enabled sensitive detection and comprehensive analysis of proteins and their post‐translational modifications. It has been widely used for discovery and analysis of glycosylation on viral envelope glycoproteins . Several types of information are desired when investigating glycosylation of proteins.…”

Section: Mass Spectrometry‐based Glycoproteomics In Virologymentioning

confidence: 99%

Viral glycoproteomes: technologies for characterization and outlook for vaccine design

et al. 2018

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It has long been known that surface proteins of most enveloped viruses are covered with glycans. It has furthermore been demonstrated that glycosylation is essential for propagation and immune evasion for many viruses. The recent development of high-resolution mass spectrometry techniques has enabled identification not only of the precise structures but also the positions of such post-translational modifications on viruses, revealing substantial differences in extent of glycosylation and glycan maturation for different classes of viruses. In-depth characterization of glycosylation and other post-translational modifications of viral envelope glycoproteins is essential for rational design of vaccines and antivirals. In this Review, we provide an overview of techniques used to address viral glycosylation and summarize information on glycosylation of enveloped viruses representing ongoing public health challenges. Furthermore, we discuss how knowledge on glycosylation can be translated to means to prevent and combat viral infections.

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O-Linked Glycosylation of the Mucin Domain of the Herpes Simplex Virus Type 1-specific Glycoprotein gC-1 Is Temporally Regulated in a Seed-and-spread Manner

Cited by 21 publications

References 50 publications

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

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

Global aspects of viral glycosylation

Viral glycoproteomes: technologies for characterization and outlook for vaccine design

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