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

iScience. 2023 Aug 21;26(9):107698. doi: 10.1016/j.isci.2023.107698. eCollection 2023 Sep 15.

Authors

Coralie Guy¹, Marcin Baran¹, Pau Ribó-Molina², Bernadette G van den Hoogen², Andrew G Bowie¹

Affiliations

¹ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
² Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands.

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.

Keywords: Immunology; Virology.