Viral sensing by epithelial cells involves PKR- and caspase-3-dependent generation of gasdermin E pores

Coralie Guy; Marcin Baran; Pau Ribó-Molina; Bernadette G. van den Hoogen; Andrew G. Bowie

doi:10.1016/j.isci.2023.107698

Viral sensing by epithelial cells involves PKR- and caspase-3-dependent generation of gasdermin E pores

Coralie Guy
, Marcin Baran
, Pau Ribó-Molina
, Bernadette G. van den Hoogen
, Andrew G. Bowie^*

^*Corresponding author for this work

Virology

Trinity College Dublin

Research output: Contribution to journal › Article › Academic › peer-review

20 Citations (Scopus)

79 Downloads (Pure)

Abstract

Viral sensing in myeloid cells involves inflammasome activation leading to gasdermin pore formation, cytokine release, and cell death. However, less is known about viral sensing in barrier epithelial cells, which are critical to the innate immune response to RNA viruses. Here, we show that poly(I:C), a mimic of viral dsRNA, is sensed by NLRP1 in human bronchial epithelial cells, leading to inflammasome-dependent gasdermin D (GSDMD) pore formation via caspase-1. DsRNA also stimulated a parallel sensing pathway via PKR which activated caspase-3 to cleave gasdermin E (GSDME) to form active pores. Influenza A virus (IAV) infection of cells caused GSDME activation, cytokine release, and cell death, in a PKR-dependent but NLRP1-independent manner, involving caspase-8 and caspase-3. Suppression of GSDMD and GSDME expression increased IAV replication. These data clarify mechanisms of gasdermin cleavage in response to viral sensing and reveal that gasdermin pore formation is intrinsically antiviral in human epithelial cells.

Original language	English
Article number	107698
Journal	iScience
Volume	26
Issue number	9
DOIs	https://doi.org/10.1016/j.isci.2023.107698
Publication status	Published - 15 Sept 2023

Bibliographical note

Funding Information:
This work was funded by the Marie Sklodowska-Curie Actions (MSCA) Innovative Training Networks (ITN): H2020-MSCA-ITN-2019 (Grant No 813343 ), and by Science Foundation Ireland ( 16/IA/4376 to A.G.B.). We thank Ryoichi Sugisawa for technical help with the PI uptake assay.

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© 2023 The Authors

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Viral sensing by epithelial cells involves PKR- and caspase-3-dependent generation of gasdermin E poresFinal published version, 4.56 MBLicence: CC BY

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title = "Viral sensing by epithelial cells involves PKR- and caspase-3-dependent generation of gasdermin E pores",

abstract = "Viral sensing in myeloid cells involves inflammasome activation leading to gasdermin pore formation, cytokine release, and cell death. However, less is known about viral sensing in barrier epithelial cells, which are critical to the innate immune response to RNA viruses. Here, we show that poly(I:C), a mimic of viral dsRNA, is sensed by NLRP1 in human bronchial epithelial cells, leading to inflammasome-dependent gasdermin D (GSDMD) pore formation via caspase-1. DsRNA also stimulated a parallel sensing pathway via PKR which activated caspase-3 to cleave gasdermin E (GSDME) to form active pores. Influenza A virus (IAV) infection of cells caused GSDME activation, cytokine release, and cell death, in a PKR-dependent but NLRP1-independent manner, involving caspase-8 and caspase-3. Suppression of GSDMD and GSDME expression increased IAV replication. These data clarify mechanisms of gasdermin cleavage in response to viral sensing and reveal that gasdermin pore formation is intrinsically antiviral in human epithelial cells.",

author = "Coralie Guy and Marcin Baran and Pau Rib{\'o}-Molina and \{van den Hoogen\}, \{Bernadette G.\} and Bowie, \{Andrew G.\}",

note = "Funding Information: This work was funded by the Marie Sklodowska-Curie Actions (MSCA) Innovative Training Networks (ITN): H2020-MSCA-ITN-2019 (Grant No 813343 ), and by Science Foundation Ireland ( 16/IA/4376 to A.G.B.). We thank Ryoichi Sugisawa for technical help with the PI uptake assay. Publisher Copyright: {\textcopyright} 2023 The Authors",

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doi = "10.1016/j.isci.2023.107698",

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AU - Guy, Coralie

AU - Baran, Marcin

AU - Ribó-Molina, Pau

AU - van den Hoogen, Bernadette G.

AU - Bowie, Andrew G.

N1 - Funding Information: This work was funded by the Marie Sklodowska-Curie Actions (MSCA) Innovative Training Networks (ITN): H2020-MSCA-ITN-2019 (Grant No 813343 ), and by Science Foundation Ireland ( 16/IA/4376 to A.G.B.). We thank Ryoichi Sugisawa for technical help with the PI uptake assay. Publisher Copyright: © 2023 The Authors

PY - 2023/9/15

Y1 - 2023/9/15

N2 - Viral sensing in myeloid cells involves inflammasome activation leading to gasdermin pore formation, cytokine release, and cell death. However, less is known about viral sensing in barrier epithelial cells, which are critical to the innate immune response to RNA viruses. Here, we show that poly(I:C), a mimic of viral dsRNA, is sensed by NLRP1 in human bronchial epithelial cells, leading to inflammasome-dependent gasdermin D (GSDMD) pore formation via caspase-1. DsRNA also stimulated a parallel sensing pathway via PKR which activated caspase-3 to cleave gasdermin E (GSDME) to form active pores. Influenza A virus (IAV) infection of cells caused GSDME activation, cytokine release, and cell death, in a PKR-dependent but NLRP1-independent manner, involving caspase-8 and caspase-3. Suppression of GSDMD and GSDME expression increased IAV replication. These data clarify mechanisms of gasdermin cleavage in response to viral sensing and reveal that gasdermin pore formation is intrinsically antiviral in human epithelial cells.

AB - Viral sensing in myeloid cells involves inflammasome activation leading to gasdermin pore formation, cytokine release, and cell death. However, less is known about viral sensing in barrier epithelial cells, which are critical to the innate immune response to RNA viruses. Here, we show that poly(I:C), a mimic of viral dsRNA, is sensed by NLRP1 in human bronchial epithelial cells, leading to inflammasome-dependent gasdermin D (GSDMD) pore formation via caspase-1. DsRNA also stimulated a parallel sensing pathway via PKR which activated caspase-3 to cleave gasdermin E (GSDME) to form active pores. Influenza A virus (IAV) infection of cells caused GSDME activation, cytokine release, and cell death, in a PKR-dependent but NLRP1-independent manner, involving caspase-8 and caspase-3. Suppression of GSDMD and GSDME expression increased IAV replication. These data clarify mechanisms of gasdermin cleavage in response to viral sensing and reveal that gasdermin pore formation is intrinsically antiviral in human epithelial cells.

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DO - 10.1016/j.isci.2023.107698

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Viral sensing by epithelial cells involves PKR- and caspase-3-dependent generation of gasdermin E pores

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