Nucleocytoplasmic distribution of rabies virus P-protein is regulated by phosphorylation adjacent to C-terminal nuclear import and export signals.
Nucleocytoplasmic distribution of the rabies virus phosphoprotein is implicated in the evasion of cellular antiviral mechanisms by rabies virus and has been reported to depend on an N-terminal nuclear export sequence and a C-terminal nuclear localization sequence. This paper identifies a second nuclear export sequence that is located between key residues of the nuclear localization sequence in the phosphoprotein C-terminal domain. The C-terminal domain confers predominantly nuclear localization in unstimulated transfected cells, indicating that the nuclear localization sequence is the dominant signal at steady state. However, protein kinase-C activation or mutagenesis to mimic protein kinase-C phosphorylation at a site proximal to the C-terminal nuclear localization/export sequences shifts the targeting activity of the C-terminal domain toward nuclear exclusion, indicating that the nuclear export sequence becomes the dominant signal in activated cells. Mapping of these sequences within the three-dimensional structure of the C-terminal domain indicates that their activities may be coregulated by phosphorylation and/or conformational changes in the domain. The data are consistent with a model in which intimate positioning of the nuclear localization sequence, export sequence, and phosphorylation site within a single domain provides a switch mechanism to rapidly and efficiently balance the reciprocal import and export signals in response to cellular stimuli.
Moseley
Gregory W
GW
Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Monash, Victoria 3800, Australia. greg.moseley@med.monash.edu.au
Filmer
Richard P
RP
DeJesus
Michelle A
MA
Jans
David A
DA
D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D018832:Molecular Chaperones; D009154:Mutation; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D015398:Signal Transduction; D015678:Viral Structural Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D018832:Molecular Chaperones; C103961:P phosphoprotein, Rabies virus; D010750:Phosphoproteins; D015678:Viral Structural Proteins