title: Cytoplasmic Motifs in the Nipah Virus Fusion Protein Modulate Virus Particle Assembly and Egress.
abstract: Nipah virus (NiV), a paramyxovirus in the genusHenipavirus, has a mortality rate in humans of approximately 75%. While several studies have begun our understanding of NiV particle formation, the mechanism of this process remains to be fully elucidated. For many paramyxoviruses, M proteins drive viral assembly and egress; however, some paramyxoviral glycoproteins have been reported as important or essential in budding. For NiV the matrix protein (M), the fusion glycoprotein (F) and, to a much lesser extent, the attachment glycoprotein (G) autonomously induce the formation of virus-like particles (VLPs). However, functional interactions between these proteins during assembly and egress remain to be fully understood. Moreover, if the F-driven formation of VLPs occurs through interactions with host cell machinery, the cytoplasmic tail (CT) of F is a likely interactive domain. Therefore, we analyzed NiV F CT deletion and alanine mutants and report that several but not all regions of the F CT are necessary for efficient VLP formation. Two of these regions contain YXXØ or dityrosine motifs previously shown to interact with cellular machinery involved in F endocytosis and transport. Importantly, our results showed that F-driven, M-driven, and M/F-driven viral particle formation enhanced the recruitment of G into VLPs. By identifying key motifs, specific residues, and functional viral protein interactions important for VLP formation, we improve our understanding of the viral assembly/egress process and point to potential interactions with host cell machinery.IMPORTANCEHenipaviruses can cause deadly infections of medical, veterinary, and agricultural importance. With recent discoveries of new henipa-like viruses, understanding the mechanisms by which these viruses reproduce is paramount. We have focused this study on identifying the functional interactions of three Nipah virus proteins during viral assembly and particularly on the role of one of these proteins, the fusion glycoprotein, in the incorporation of other viral proteins into viral particles. By identifying several regions in the fusion glycoprotein that drive viral assembly, we further our understanding of how these viruses assemble and egress from infected cells. The results presented will likely be useful toward designing treatments targeting this aspect of the viral life cycle and for the production of new viral particle-based vaccines.
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, Washington, USA.
authors.forename: Gunner P
authors.initials: GP
authors.lastname: Johnston
authors.affiliation: Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, USA.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Contreras
authors.affiliation: Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Dabundo
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, Washington, USA.|Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, USA.
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Henderson
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, Washington, USA.
authors.forename: Keesha M
authors.initials: KM
authors.lastname: Matz
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, Washington, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Ortega
authors.affiliation: Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Arnold
authors.identifier: http://orcid.org/0000-0001-8916-2230
authors.initials: A
authors.lastname: Park
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, Washington, USA haguilar@vetmed.wsu.edu.|Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, USA.
authors.forename: Hector C
authors.initials: HC
authors.lastname: Aguilar
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D003593:Cytoplasm / Q000737:chemistry* / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry; D006801:Humans; D045405:Nipah Virus / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D000072417:Protein Domains; D058425:Vaccines, Virus-Like Particle; D014759:Viral Envelope Proteins / Q000378:metabolism; D014760:Viral Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000378:metabolism*; D019065:Virus Assembly; D053586:Virus Internalization; D057074:Virus Release
chemical_list: C510755:F protein, Nipah virus; D006023:Glycoproteins; D058425:Vaccines, Virus-Like Particle; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins; D014763:Viral Matrix Proteins
keywords: Nipah virus; Paramyxoviridae; attachment; budding; cytoplasmic tail; fusion protein; glycoprotein; matrix; paramyxovirus; viral assembly