Research Article: Multiple Novel Functions of Henipavirus O-glycans: The First O-glycan Functions Identified in the Paramyxovirus Family

Date Published: February 11, 2016

Publisher: Public Library of Science

Author(s): Jacquelyn A. Stone, Anthony V. Nicola, Linda G. Baum, Hector C. Aguilar, Sean Whelan.

http://doi.org/10.1371/journal.ppat.1005445

Abstract

O-linked glycosylation is a ubiquitous protein modification in organisms belonging to several kingdoms. Both microbial and host protein glycans are used by many pathogens for host invasion and immune evasion, yet little is known about the roles of O-glycans in viral pathogenesis. Reportedly, there is no single function attributed to O-glycans for the significant paramyxovirus family. The paramyxovirus family includes many important pathogens, such as measles, mumps, parainfluenza, metapneumo- and the deadly Henipaviruses Nipah (NiV) and Hendra (HeV) viruses. Paramyxoviral cell entry requires the coordinated actions of two viral membrane glycoproteins: the attachment (HN/H/G) and fusion (F) glycoproteins. O-glycan sites in HeV G were recently identified, facilitating use of the attachment protein of this deadly paramyxovirus as a model to study O-glycan functions. We mutated the identified HeV G O-glycosylation sites and found mutants with altered cell-cell fusion, G conformation, G/F association, viral entry in a pseudotyped viral system, and, quite unexpectedly, pseudotyped viral F protein incorporation and processing phenotypes. These are all important functions of viral glycoproteins. These phenotypes were broadly conserved for equivalent NiV mutants. Thus our results identify multiple novel and pathologically important functions of paramyxoviral O-glycans, paving the way to study O-glycan functions in other paramyxoviruses and enveloped viruses.

Partial Text

Many microbial pathogens utilize protein glycosylation for host invasion and immune evasion [1]. Although many N-glycan functions have been reported, relatively little is known about the roles of O-glycans in microbial pathogenesis or biology, particularly for viruses. O-linked glycosylation is a ubiquitous protein modification in organisms belonging to several kingdoms. For example, O-glycans play roles in protein trafficking, signaling, cell-cell interactions, and receptor binding for host proteins [2–4], and O-glycans are important for developmental processes and immune system functions [3]. Additionally, altered O-glycosylation has been linked to illnesses such as autoimmune diseases and cancer [5–7], as well as pathogen virulence [8–10]. Yet currently the specific functions of O-glycans on viral glycoproteins are not well understood, and to our knowledge there is no single function attributed to O-glycans for the important paramyxovirus family.

Viral O-glycans remain understudied, and the present study is the first to show functions for paramyxoviral O-glycans. In mammalian cells, O-glycans have functions in receptor binding, cell-cell interactions, cellular trafficking, and immune system regulation [2–4]. Viruses use glycosylation for protein trafficking, signaling, folding, immune evasion, and receptor interactions [1], but the majority of these functions have been described for N-glycans. The lack of clear O-glycosylation prediction motifs, and the fact that utilization of some O-glycan sites can affect O-glycosylation of neighboring sites [21], makes analysis of specific O-glycan functions much more complex. O-glycans are present on HIV, SIV, Marburg, MHV, and vaccinia virus glycoproteins [28–32] but their functions are still unknown. While some studies have shown that O-glycans are involved in immune evasion, receptor binding, plaque formation, and possibly cell detachment [22,25,27], this has not been described for paramyxoviruses, although prior work has shown that O-glycans do not play roles in RSV-G oligomerization [33] nor NDV receptor binding [34]. The present work is the first to show functions for paramyxoviral O-glycans, and one of only a handful of studies demonstrating functions of O-glycans for any virus.

 

Source:

http://doi.org/10.1371/journal.ppat.1005445

 

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