2. Academic Validation
  3. Caspase-7 activates ASM to repair gasdermin and perforin pores

Caspase-7 activates ASM to repair gasdermin and perforin pores

  • Nature. 2022 Jun;606(7916):960-967. doi: 10.1038/s41586-022-04825-8.
Kengo Nozaki # 1 2,  Vivien I Maltez # 3,  Manira Rayamajhi 3,  Alan L Tubbs 3,  Joseph E Mitchell 3 4,  Carolyn A Lacey 1 2,  Carissa K Harvest 1 2 3,  Lupeng Li 1 2 3,  William T Nash 5,  Heather N Larson 1 2,  Benjamin D McGlaughon 3,  Nathaniel J Moorman 3,  Michael G Brown 5,  Jason K Whitmire 3 4,  Edward A Miao 6 7
Affiliations

Affiliations

  • 1 Department of Immunology, Duke University School of Medicine, Durham, NC, USA.
  • 2 Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
  • 3 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 4 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 5 Department of Medicine, Division of Nephrology and the Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA.
  • 6 Department of Immunology, Duke University School of Medicine, Durham, NC, USA. edward.miao@duke.edu.
  • 7 Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA. edward.miao@duke.edu.
  • # Contributed equally.
PMID: 35705808 DOI: 10.1038/s41586-022-04825-8
Abstract

Among the caspases that cause regulated cell death, a unique function for caspase-7 has remained elusive. Caspase-3 performs Apoptosis, whereas caspase-7 is typically considered an inefficient back-up. Caspase-1 activates gasdermin D pores to lyse the cell; however, Caspase-1 also activates caspase-7 for unknown reasons1. Caspases can also trigger cell-type-specific death responses; for example, Caspase-1 causes the extrusion of intestinal epithelial cell (IECs) in response to Infection with Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium)2,3. Here we show in both organoids and mice that caspase-7-deficient IECs do not complete extrusion. Mechanistically, caspase-7 counteracts gasdermin D pores and preserves cell integrity by cleaving and activating acid sphingomyelinase (ASM), which thereby generates copious amounts of ceramide to enable enhanced membrane repair. This provides time to complete the process of IEC extrusion. In parallel, we also show that caspase-7 and ASM cleavage are required to clear Chromobacterium violaceum and Listeria monocytogenes after perforin-pore-mediated attack by natural killer cells or cytotoxic T lymphocytes, which normally causes Apoptosis in infected hepatocytes. Therefore, caspase-7 is not a conventional executioner but instead is a death facilitator that delays pore-driven lysis so that more-specialized processes, such as extrusion or Apoptosis, can be completed before cell death. Cells must put their affairs in order before they die.

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