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Implication of the nuclear trafficking of rabies virus P3 protein in viral pathogenicity
Aaron M Brice1, Ericka Watts1, Bevan Hirst1
1Viral Pathogenesis Laboratory, Department of Microbiology, Monash University, Clayton, Victoria, Australia.
Abstract:
Although the majority of viruses of the family Mononegvirales replicate exclusively in the host cell cytoplasm, many of these viruses encode proteins that traffic between the nucleus and cytoplasm, which is believed to enable accessory functions in modulating the biology of the infected host cell. Among these, the P3 protein of rabies virus localizes to the nucleus through the activity of several specific nuclear localization and nuclear export signals. The major defined functions of P3 are in evasion of interferon (IFN)-mediated antiviral responses, including through inhibition of DNA-binding by IFN-activated STAT1. P3 also localizes to nucleoli and promyelocytic leukemia (PML) nuclear bodies, and interacts with nucleolin and PML protein, indicative of several intranuclear roles. The relationship of P3 nuclear localization with pathogenicity, however, is unresolved. We report that nucleocytoplasmic localization of P3 proteins from a pathogenic RABV strain, Nishigahara (Ni) and a non-pathogenic Ni-derived strain, Ni-CE, differs significantly, with nuclear accumulation defective for Ni-CE-P3. Molecular mapping indicates that altered localization derives from a coordinated effect, including two residue substitutions that independently disable nuclear localization and augment nuclear export signals, collectively promoting nuclear exclusion. Intriguingly, this appears to relate to effects on protein conformation or regulatory mechanisms, rather than direct modification of defined trafficking signal sequences. These data provide new insights into the role of regulated nuclear trafficking of a viral protein in the pathogenicity of a virus that replicates in the cytoplasm.
Insights
Rabies virus P3 protein nuclear localization differs between pathogenic and non-pathogenic strains. Altered trafficking, not direct signal changes, impacts nuclear exclusion and potentially pathogenicity.
Area of Science:
- Virology
- Cell Biology
- Molecular Biology
Background:
- Mononegavirales viruses replicate in the cytoplasm but possess proteins that traffic to the nucleus.
- The P3 protein of rabies virus (RABV) is known to localize to the nucleus and plays roles in immune evasion.
- The connection between P3 nuclear localization and RABV pathogenicity remains unclear.
Purpose of the Study:
- To investigate the differences in nucleocytoplasmic localization of P3 proteins from pathogenic and non-pathogenic RABV strains.
- To elucidate the molecular mechanisms underlying altered P3 protein trafficking.
- To understand the role of P3 nuclear localization in viral pathogenicity.
Main Methods:
- Comparative analysis of P3 protein localization in cells infected with pathogenic (Nishigahara, Ni) and non-pathogenic (Ni-CE) RABV strains.
- Molecular mapping and mutational analysis to identify regions responsible for altered nucleocytoplasmic transport.
- Investigation of potential effects on protein conformation or regulatory mechanisms.
Main Results:
- Significant differences in nucleocytoplasmic localization were observed between Ni P3 and Ni-CE P3 proteins.
- Nuclear accumulation of Ni-CE P3 was defective compared to Ni P3.
- Molecular mapping revealed that two residue substitutions contribute to altered localization by disabling nuclear localization signals and enhancing nuclear export signals, leading to nuclear exclusion.
- These changes appear to affect protein conformation or regulatory mechanisms rather than directly altering defined trafficking signals.
Conclusions:
- Nucleocytoplasmic trafficking of RABV P3 protein is significantly altered in a non-pathogenic strain.
- Specific residue substitutions, affecting protein conformation or regulation, underlie the altered P3 localization and nuclear exclusion.
- Regulated nuclear trafficking of viral proteins may play a crucial role in the pathogenicity of viruses that replicate in the host cell cytoplasm.
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