Poxviruses Evade Cytosolic Sensing through Disruption of an mTORC1-mTORC2 Regulatory Circuit

Nathan Meade, Colleen Furey, Hua Li, Rita Verma, Qingqing Chai, Madeline G. Rollins, Stephen DiGiuseppe, Mojgan H. Naghavi, Derek Walsh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Viruses employ elaborate strategies to coopt the cellular processes they require to replicate while simultaneously thwarting host antiviral responses. In many instances, how this is accomplished remains poorly understood. Here, we identify a protein, F17 encoded by cytoplasmically replicating poxviruses, that binds and sequesters Raptor and Rictor, regulators of mammalian target of rapamycin complexes mTORC1 and mTORC2, respectively. This disrupts mTORC1-mTORC2 crosstalk that coordinates host responses to poxvirus infection. During infection with poxvirus lacking F17, cGAS accumulates together with endoplasmic reticulum vesicles around the Golgi, where activated STING puncta form, leading to interferon-stimulated gene expression. By contrast, poxvirus expressing F17 dysregulates mTOR, which localizes to the Golgi and blocks these antiviral responses in part through mTOR-dependent cGAS degradation. Ancestral conservation of Raptor/Rictor across eukaryotes, along with expression of F17 across poxviruses, suggests that mTOR dysregulation forms a conserved poxvirus strategy to counter cytosolic sensing while maintaining the metabolic benefits of mTOR activity. Poxviruses disrupt an mTOR regulatory circuit via a small protein that sequesters Raptor and Rictor, allowing the virus to evade cGAS-STING sensing while reaping the metabolic benefits of mTOR activity.

Original languageEnglish (US)
Pages (from-to)1143-1157.e17
JournalCell
Volume174
Issue number5
DOIs
StatePublished - Aug 23 2018

Keywords

  • STING
  • cGAS
  • innate immunity
  • interferon
  • mTOR
  • poxvirus
  • protein synthesis
  • sensor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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