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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)\u2010mediated antiviral responses, including through inhibition of DNA\u2010binding by IFN\u2010activated 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\u2010pathogenic Ni\u2010derived strain, Ni\u2010CE, differs significantly, with nuclear accumulation defective for Ni\u2010CE\u2010P3. 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.<\/jats:p>","DOI":"10.1111\/tra.12821","type":"journal-article","created":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T06:01:25Z","timestamp":1633759285000},"page":"482-489","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Implication of the nuclear trafficking of rabies virus <scp>P3<\/scp> protein in viral pathogenicity"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2999-186X","authenticated-orcid":false,"given":"Aaron M.","family":"Brice","sequence":"first","affiliation":[{"name":"Viral Pathogenesis Laboratory, Department of Microbiology Monash University  Clayton Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ericka","family":"Watts","sequence":"additional","affiliation":[{"name":"Viral Pathogenesis Laboratory, Department of Microbiology Monash University  Clayton Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bevan","family":"Hirst","sequence":"additional","affiliation":[{"name":"Viral Pathogenesis Laboratory, Department of Microbiology Monash University  Clayton Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Jans","sequence":"additional","affiliation":[{"name":"Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology Monash University  Clayton Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoto","family":"Ito","sequence":"additional","affiliation":[{"name":"Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences, and United Graduate School of 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