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 Naghavi, Derek Walsh*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

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

Fingerprint

Poxviridae
Viruses
Antiviral Agents
Raptors
Poxviridae Infections
Networks (circuits)
Sirolimus
Crosstalk
Gene expression
Interferons
Conservation
Proteins
Degradation
Eukaryota
Endoplasmic Reticulum
mechanistic target of rapamycin complex 1
TOR complex 2
Gene Expression

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Meade, Nathan ; Furey, Colleen ; Li, Hua ; Verma, Rita ; Chai, Qingqing ; Rollins, Madeline G. ; DiGiuseppe, Stephen ; Naghavi, Mojgan ; Walsh, Derek. / Poxviruses Evade Cytosolic Sensing through Disruption of an mTORC1-mTORC2 Regulatory Circuit. In: Cell. 2018 ; Vol. 174, No. 5. pp. 1143-1157.e17.
@article{82fe6b36370b4e8687b79bc185f0477e,
title = "Poxviruses Evade Cytosolic Sensing through Disruption of an mTORC1-mTORC2 Regulatory Circuit",
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.",
keywords = "STING, cGAS, innate immunity, interferon, mTOR, poxvirus, protein synthesis, sensor",
author = "Nathan Meade and Colleen Furey and Hua Li and Rita Verma and Qingqing Chai and Rollins, {Madeline G.} and Stephen DiGiuseppe and Mojgan Naghavi and Derek Walsh",
year = "2018",
month = "8",
day = "23",
doi = "10.1016/j.cell.2018.06.053",
language = "English (US)",
volume = "174",
pages = "1143--1157.e17",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",

}

Meade, N, Furey, C, Li, H, Verma, R, Chai, Q, Rollins, MG, DiGiuseppe, S, Naghavi, M & Walsh, D 2018, 'Poxviruses Evade Cytosolic Sensing through Disruption of an mTORC1-mTORC2 Regulatory Circuit', Cell, vol. 174, no. 5, pp. 1143-1157.e17. https://doi.org/10.1016/j.cell.2018.06.053

Poxviruses Evade Cytosolic Sensing through Disruption of an mTORC1-mTORC2 Regulatory Circuit. / Meade, Nathan; Furey, Colleen; Li, Hua; Verma, Rita; Chai, Qingqing; Rollins, Madeline G.; DiGiuseppe, Stephen; Naghavi, Mojgan; Walsh, Derek.

In: Cell, Vol. 174, No. 5, 23.08.2018, p. 1143-1157.e17.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Poxviruses Evade Cytosolic Sensing through Disruption of an mTORC1-mTORC2 Regulatory Circuit

AU - Meade, Nathan

AU - Furey, Colleen

AU - Li, Hua

AU - Verma, Rita

AU - Chai, Qingqing

AU - Rollins, Madeline G.

AU - DiGiuseppe, Stephen

AU - Naghavi, Mojgan

AU - Walsh, Derek

PY - 2018/8/23

Y1 - 2018/8/23

N2 - 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.

AB - 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.

KW - STING

KW - cGAS

KW - innate immunity

KW - interferon

KW - mTOR

KW - poxvirus

KW - protein synthesis

KW - sensor

UR - http://www.scopus.com/inward/record.url?scp=85053846326&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053846326&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.06.053

DO - 10.1016/j.cell.2018.06.053

M3 - Article

VL - 174

SP - 1143-1157.e17

JO - Cell

JF - Cell

SN - 0092-8674

IS - 5

ER -

Meade N, Furey C, Li H, Verma R, Chai Q, Rollins MG et al. Poxviruses Evade Cytosolic Sensing through Disruption of an mTORC1-mTORC2 Regulatory Circuit. Cell. 2018 Aug 23;174(5):1143-1157.e17. https://doi.org/10.1016/j.cell.2018.06.053