Caspase-7 activates ASM to repair gasdermin and perforin pores

Kengo Nozaki, Vivien I. Maltez, Manira Rayamajhi, Alan L. Tubbs, Joseph E. Mitchell, Carolyn A. Lacey, Carissa K. Harvest, Lupeng Li, William T. Nash, Heather N. Larson, Benjamin D. McGlaughon, Nathaniel J. Moorman, Michael G. Brown, Jason K. Whitmire and Edward A. Miao ()
Additional contact information
Kengo Nozaki: Duke University School of Medicine
Vivien I. Maltez: University of North Carolina at Chapel Hill
Manira Rayamajhi: University of North Carolina at Chapel Hill
Alan L. Tubbs: University of North Carolina at Chapel Hill
Joseph E. Mitchell: University of North Carolina at Chapel Hill
Carolyn A. Lacey: Duke University School of Medicine
Carissa K. Harvest: Duke University School of Medicine
Lupeng Li: Duke University School of Medicine
William T. Nash: University of Virginia
Heather N. Larson: Duke University School of Medicine
Benjamin D. McGlaughon: University of North Carolina at Chapel Hill
Nathaniel J. Moorman: University of North Carolina at Chapel Hill
Michael G. Brown: University of Virginia
Jason K. Whitmire: University of North Carolina at Chapel Hill
Edward A. Miao: Duke University School of Medicine

Nature, 2022, vol. 606, issue 7916, 960-967

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04825-8

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