Viral regulation of host cell biology by hijacking of the nucleolar DNA-damage response

Stephen M. Rawlinson, Tianyue Zhao, Ashley M. Rozario, Christina L. Rootes, Paul J. McMillan, Anthony W. Purcell, Amanda Woon, Glenn A. Marsh, Kim G. Lieu, Lin-Fa Wang, Hans J. Netter, Toby D.M. Bell, Cameron R. Stewart, Gregory W. Moseley

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Recent studies indicate that nucleoli play critical roles in the DNA-damage response (DDR) via interaction of DDR machinery including NBS1 with nucleolar Treacle protein, a key mediator of ribosomal RNA (rRNA) transcription and processing. Here, using proteomics, confocal and single molecule super-resolution imaging, and infection under biosafety level-4 containment, we show that this nucleolar DDR pathway is targeted by infectious pathogens. We find that the matrix proteins of Hendra virus and Nipah virus, highly pathogenic viruses of the Henipavirus genus in the order Mononegavirales, interact with Treacle and inhibit its function, thereby silencing rRNA biogenesis, consistent with mimicking NBS1–Treacle interaction during a DDR. Furthermore, inhibition of Treacle expression/function enhances henipavirus production. These data identify a mechanism for viral modulation of host cells by appropriating the nucleolar DDR and represent, to our knowledge, the first direct intranucleolar function for proteins of any mononegavirus.

Original languageEnglish
Article number3057
Number of pages12
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 3 Aug 2018

Keywords

  • DNA damage response
  • nucleolus
  • super-resolution microscopy
  • virus-host interactions

Cite this

Rawlinson, Stephen M. ; Zhao, Tianyue ; Rozario, Ashley M. ; Rootes, Christina L. ; McMillan, Paul J. ; Purcell, Anthony W. ; Woon, Amanda ; Marsh, Glenn A. ; Lieu, Kim G. ; Wang, Lin-Fa ; Netter, Hans J. ; Bell, Toby D.M. ; Stewart, Cameron R. ; Moseley, Gregory W. / Viral regulation of host cell biology by hijacking of the nucleolar DNA-damage response. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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abstract = "Recent studies indicate that nucleoli play critical roles in the DNA-damage response (DDR) via interaction of DDR machinery including NBS1 with nucleolar Treacle protein, a key mediator of ribosomal RNA (rRNA) transcription and processing. Here, using proteomics, confocal and single molecule super-resolution imaging, and infection under biosafety level-4 containment, we show that this nucleolar DDR pathway is targeted by infectious pathogens. We find that the matrix proteins of Hendra virus and Nipah virus, highly pathogenic viruses of the Henipavirus genus in the order Mononegavirales, interact with Treacle and inhibit its function, thereby silencing rRNA biogenesis, consistent with mimicking NBS1–Treacle interaction during a DDR. Furthermore, inhibition of Treacle expression/function enhances henipavirus production. These data identify a mechanism for viral modulation of host cells by appropriating the nucleolar DDR and represent, to our knowledge, the first direct intranucleolar function for proteins of any mononegavirus.",
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Viral regulation of host cell biology by hijacking of the nucleolar DNA-damage response. / Rawlinson, Stephen M.; Zhao, Tianyue; Rozario, Ashley M.; Rootes, Christina L.; McMillan, Paul J.; Purcell, Anthony W.; Woon, Amanda; Marsh, Glenn A.; Lieu, Kim G.; Wang, Lin-Fa; Netter, Hans J.; Bell, Toby D.M.; Stewart, Cameron R.; Moseley, Gregory W.

In: Nature Communications, Vol. 9, No. 1, 3057, 03.08.2018.

Research output: Contribution to journalArticleResearchpeer-review

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