2. Academic Validation
  3. The formation of the 'footprint of death' as a mechanism for generating large substrate-bound extracellular vesicles that mark the site of cell death

The formation of the 'footprint of death' as a mechanism for generating large substrate-bound extracellular vesicles that mark the site of cell death

  • Nat Commun. 2025 Oct 15;16(1):9160. doi: 10.1038/s41467-025-64206-3.
Stephanie F Rutter 1 2,  Taeyoung Kang 1 2,  Gemma F Ryan 1 2,  Bo Shi 1 2,  Caitlin L Vella 1 2 3,  Pradeep Rajasekhar 4 5,  Sean W Cutter 1,  Amy L Hodge 1,  Dilara C Ozkocak 1 2,  Ching-Seng Ang 6,  Julian Ratcliffe 7,  Katrina J Binger 1,  Pamali Foneska 1 2,  Suresh Mathivanan 1 2,  Niall D Geoghegan 4 5,  Kelly L Rogers 4 5,  Michael F Olson 8,  Georgia K Atkin-Smith # 9 10,  Ivan K H Poon # 11 12
Affiliations

Affiliations

  • 1 Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia.
  • 2 Research Centre for Extracellular Vesicles, La Trobe University, Melbourne, VIC, Australia.
  • 3 Centre for Cardiovascular Biology and Disease Research, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.
  • 4 The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC, Australia.
  • 5 University of Melbourne, Melbourne, VIC, Australia.
  • 6 The Bio21 Institute of Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia.
  • 7 Bioimaging Platform, La Trobe University, Melbourne, VIC, Australia.
  • 8 Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON, Canada.
  • 9 The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC, Australia. atkinsmith.g@wehi.edu.au.
  • 10 University of Melbourne, Melbourne, VIC, Australia. atkinsmith.g@wehi.edu.au.
  • 11 Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia. i.poon@latrobe.edu.au.
  • 12 Research Centre for Extracellular Vesicles, La Trobe University, Melbourne, VIC, Australia. i.poon@latrobe.edu.au.
  • # Contributed equally.
PMID: 41093830 DOI: 10.1038/s41467-025-64206-3
Abstract

Apoptotic cells communicate to phagocytic cells through releasing soluble factors and apoptotic cell-derived extracellular vesicles. However, whether there are additional factors that remain attached at the site of cell death to signal to phagocytic cells is currently unknown. Here we show that apoptotic cell retraction generates a membrane-encased, F-actin-rich 'footprint' tightly anchored to the substrate that marks the site of cell death, coined 'the FOotprint Of Death' or FOOD. Formation of FOOD is observed frequently across many different cell types, apoptotic stimuli and surface composition. Mechanistically, FOOD formation is regulated by the protein kinase ROCK1. 3D time-lapse microscopy studies revealed that FOOD vesicularises into distinct large extracellular vesicles. These extracellular vesicles expose the 'eat-me' signal phosphatidylserine and can function to 'flag' the site of cell death to neighbouring phagocytes for efferocytosis. Under a viral Infection setting, FOOD can harbour Viral Proteins and virions, and propagate Infection to healthy cells. Together, this study has revealed another route of apoptotic cell-phagocyte communication.

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