Viral hijacking of the nucleolar DNA-damage response machinery: a novel mechanism to regulate host cell biology

Recent landmark studies indicate that the nucleolus plays key roles in stress responses including the DNA-damage response (DDR). The latter involves interactions of components of the DDR machinery including NBS1 with the sub-nucleolar protein Treacle, a key mediator of ribosomal RNA (rRNA) transcription and processing, implicated in Treacher-Collins syndrome. Using comparative proteomics, confocal and single molecule super-resolution imaging, and infection under BSL-4 containment, we have shown for the first time that the nucleolar DDR pathway is targeted by infectious pathogens [1]. We found that the matrix (M) proteins of Hendra virus and Nipah virus, highly lethal viruses of the Henipavirus genus (order Mononegavirales), target Treacle to inhibit its function, thereby silencing rRNA biogenesis, consistent with mimicking NBS1-Treacle interaction during a DDR. Furthermore, inhibition of Treacle expression/function enhanced henipavirus production. These data identify a novel mechanism for viral subversion of host cell biology by appropriating the nucleolar DDR and represent, to our knowledge, the first direct intra-nucleolar function for proteins of any mononegavirus [1, 2]. For the presentation I will discuss our new data, which is advancing our understanding both of the mechanisms impacted by the Henipavirus-Treacle interaction, and potential roles of such interactions in infection by other viruses, including highly lethal lyssaviruses [3].

[1] Rawlinson et al. Nature Communications 2018.9 : 3057 (2018)

[2] Rawlinson et al. Cellular Microbiology 2015. 17(8):1108–20

[3] Oksayan et al. Journal of Virology 2015.89(3):1939–43