Nucleolar targeting of lyssavirus P-protein is isoform- and phylogroup-specific

TL;DR

This study shows that certain versions of a virus protein target the nucleolus in a specific way, which could help develop new treatments.

Contribution

The study identifies isoform- and phylogroup-specific nucleolar targeting of lyssavirus P-proteins and their interactions with nucleolar proteins.

Findings

P3–P5 isoforms accumulate in nucleoli, while P1 and P2 are excluded.

P3 nucleolar targeting is conserved in phylogroup I but absent in phylogroup II lyssaviruses.

P3 interacts with nucleolin and NPM1 but shows divergent binding to Treacle and NOLC1.

Abstract

The nucleolus is a multifunctional hub and a common target of viral proteins, yet its role in infections by cytoplasmically replicating RNA viruses remains poorly defined. In rabies virus (RABV), the phosphoprotein (P-protein) isoform P3 localizes to nucleoli and inhibits rRNA biogenesis, whereas P1 lacks nucleolar targeting, even when forced into the nucleus. Here, we show that nucleolar targeting is an isoform- and phylogroup-specific property of lyssavirus P-proteins. Isoforms P3–P5 accumulate in nucleoli, whereas P1 and P2 are excluded. Comparative analyses revealed that P3 nucleolar targeting is conserved in phylogroup I but absent in phylogroup II lyssaviruses. Co-immunoprecipitation assays identified conserved interactions with nucleolin and nucleophosmin (NPM1) but divergent binding to Treacle and nucleolar and coiled-body phosphoprotein 1 (NOLC1). These findings define nucleolar targeting as a gain-of-function of truncated P isoforms, demonstrate its conservation across phylogroup I lyssaviruses and suggest broader engagement with membraneless compartments, highlighting potential therapeutic vulnerabilities.

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