Implication of the nuclear trafficking of rabies virus P3 protein in viral pathogenicity

Aaron M. Brice, Ericka Watts, Bevan Hirst, David A. Jans, Naoto Ito, Gregory W. Moseley

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)482-489
Number of pages8
JournalTraffic
Volume22
Issue number12
DOIs
Publication statusPublished - Dec 2021

Keywords

  • cell nucleus
  • lyssavirus
  • nuclear export signal
  • nuclear localization signal
  • nuclear transport
  • pathogenicity
  • phosphoprotein
  • rabies virus
  • virus-host interactions

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