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

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
15 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 languageEnglish
Article number107698
JournaliScience
Volume26
Issue number9
DOIs
Publication statusPublished - 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.

Publisher Copyright:
© 2023 The Authors

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