title: Quantitative Analysis of the Microtubule Interaction of Rabies Virus P3 Protein: Roles in Immune Evasion and Pathogenesis.
abstract: Although microtubules (MTs) are known to have important roles in intracellular transport of many viruses, a number of reports suggest that specific viral MT-associated proteins (MAPs) target MTs to subvert distinct MT-dependent cellular processes. The precise functional importance of these interactions and their roles in pathogenesis, however, remain largely unresolved. To assess the association with disease of the rabies virus (RABV) MAP, P3, we quantitatively compared the phenotypes of P3 from a pathogenic RABV strain, Nishigahara (Ni) and a non-pathogenic Ni-derivative strain, Ni-CE. Using confocal/live-cell imaging and dSTORM super-resolution microscopy to quantify protein interactions with the MT network and with individual MT filaments, we found that the interaction by Ni-CE-P3 is significantly impaired compared with Ni-P3. This correlated with an impaired capacity to effect association of the transcription factor STAT1 with MTs and to antagonize interferon (IFN)/STAT1-dependent antiviral signaling. Importantly, we identified a single mutation in Ni-CE-P3 that is sufficient to inhibit MT-association and IFN-antagonist function of Ni-P3, and showed that this mutation alone attenuates the pathogenicity of RABV. These data provide evidence that the viral protein-MT interface has important roles in pathogenesis, suggesting that this interface could provide targets for vaccine/antiviral drug development.
authors.affiliation: Viral Pathogenesis Laboratory, Department of Biochemistry and Molecular Biology, Bio21 Institute, The University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: Aaron
authors.initials: A
authors.lastname: Brice
authors.affiliation: School of Chemistry, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Donna R
authors.initials: DR
authors.lastname: Whelan
authors.affiliation: Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.|The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ito
authors.affiliation: The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.|Viral Pathogenesis Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Wiltzer-Bach
authors.affiliation: Monash Micro Imaging, 27-31 Wright Street, Clayton, Victoria, 3168, Australia.
authors.forename: Camden Y
authors.initials: CY
authors.lastname: Lo
authors.affiliation: Unité de Virologie Moleculaire et Structurale, CNRS, UPR 3296, 91198 Gif sur Yvette Cedex, France.
authors.forename: Danielle
authors.initials: D
authors.lastname: Blondel
authors.affiliation: Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Jans
authors.affiliation: School of Chemistry, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Toby D M
authors.initials: TD
authors.lastname: Bell
authors.affiliation: Viral Pathogenesis Laboratory, Department of Biochemistry and Molecular Biology, Bio21 Institute, The University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Moseley
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D057131:Immune Evasion; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D055503:Protein Multimerization; D011818:Rabies / Q000276:immunology* / Q000821:virology*; D011820:Rabies virus / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D014764:Viral Proteins