Dual modes of rabies P-protein association with microtubules: a novel strategy to suppress the antiviral response.
Conventional nuclear import is independent of the cytoskeleton, but recent data have shown that the import of specific proteins can be either facilitated or inhibited by microtubules (MTs). Nuclear import of the P-protein from rabies virus involves a MT-facilitated mechanism, but here, we show that P-protein is unique in that it also undergoes MT-inhibited import, with the mode of MT-interaction being regulated by the oligomeric state of the P-protein. This is the first demonstration that a protein can utilise both MT-inhibited and MT-facilitated import mechanisms, and can switch between these different modes of MT interaction to regulate its nuclear trafficking. Importantly, we show that the P-protein exploits MT-dependent mechanisms to manipulate host cell processes by switching the import of the interferon-activated transcription factor STAT1 from a conventional to a MT-inhibited mechanism. This prevents STAT1 nuclear import and signalling in response to interferon, which is vital to the host innate antiviral response. This is the first report of MT involvement in the viral subversion of interferon signalling that is central to virus pathogenicity, and identifies novel targets for the development of antiviral drugs or attenuated viruses for vaccine applications.
Moseley
Gregory W
GW
Department of Biochemistry and Molecular Biology, Nuclear Signalling Laboratory, Monash University, Clayton, Victoria 3800, Australia. greg.moseley@med.monash.edu.au
Lahaye
Xavier
X
Roth
Daniela M
DM
Oksayan
Sibil
S
Filmer
Richard P
RP
Rowe
Caitlin L
CL
Blondel
Danielle
D
Jans
David A
DA
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D000072159:Dynactin Complex; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D018832:Molecular Chaperones; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011818:Rabies / Q000378:metabolism / Q000821:virology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015678:Viral Structural Proteins / Q000737:chemistry / Q000378:metabolism*
D000998:Antiviral Agents; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; C103961:P phosphoprotein, Rabies virus; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D015678:Viral Structural Proteins; D049452:Green Fluorescent Proteins; D007372:Interferons