Recognition by host nuclear transport proteins drives disorder-to-order transition in Hendra virus V.

Abstract

Hendra virus (HeV) is a paramyxovirus that causes lethal disease in humans, for which no vaccine or antiviral agent is available. HeV V protein is central to pathogenesis through its ability to interact with cytoplasmic host proteins, playing key antiviral roles. Here we use immunoprecipitation, siRNA knockdown and confocal laser scanning microscopy to show that HeV V shuttles to and from the nucleus through specific host nuclear transporters. Spectroscopic and small angle X-ray scattering studies reveal HeV V undergoes a disorder-to-order transition upon binding to either importin α/β1 or exportin-1/Ran-GTP, dependent on the V N-terminus. Importantly, we show that specific inhibitors of nuclear transport prevent interaction with host transporters, and reduce HeV infection. These findings emphasize the critical role of host-virus interactions in HeV infection, and potential use of compounds targeting nuclear transport, such as the FDA-approved agent ivermectin, as anti-HeV agents.

• Authors: Sarah C Atkinson, Michelle D Audsley, Kim G Lieu, Glenn A Marsh, David R Thomas, Steven M Heaton, Jason J Paxman, Kylie M Wagstaff, Ashley M Buckle, Gregory W Moseley, David A Jans, Natalie A Borg
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 358 (01 10 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29321677 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Karyopherins
• Nucleocytoplasmic Transport Proteins
• Receptors, Cytoplasmic and Nuclear
• V protein, Hendra virus
• Viral Proteins

Topics

• Antiviral Agents (chemistry, pharmacology)
• Cell Nucleus (metabolism)
• Drug Discovery
• Gene Knockdown Techniques
• Hendra Virus (drug effects, physiology)
• Henipavirus Infections (genetics, metabolism, virology)
• Host-Pathogen Interactions
• Humans
• Karyopherins (chemistry, genetics, metabolism)
• Models, Molecular
• Molecular Conformation
• Nucleocytoplasmic Transport Proteins (metabolism)
• Protein Binding
• Protein Interaction Domains and Motifs
• Protein Transport
• Receptors, Cytoplasmic and Nuclear (chemistry, genetics, metabolism)
• Structure-Activity Relationship
• Viral Proteins (chemistry, metabolism)
• Exportin 1 Protein