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

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

doi:10.1038/s41598-017-18742-8

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

Sci Rep. 2018 Jan 10;8(1):358. doi: 10.1038/s41598-017-18742-8.

Affiliations

¹ Infection & Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
² CSIRO Livestock Industries, Australian Animal Health Laboratory, Victoria, Australia.
³ La Trobe Institute for Molecular Sciences and Department of Biochemistry and Genetics, La Trobe University, Melbourne, Victoria, Australia.
⁴ Infection & Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. [email protected].
⁵ Infection & Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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