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

Stephanie F. Rutter, Taeyoung Kang, Gemma F. Ryan, Bo Shi, Caitlin L. Vella, Pradeep Rajasekhar, Sean W. Cutter, Amy L. Hodge, Dilara C. Ozkocak, Ching-Seng Ang, Julian Ratcliffe, Katrina J. Binger, Pamali Foneska, Suresh Mathivanan, Niall D. Geoghegan, Kelly L. Rogers, Michael F. Olson, Georgia K. Atkin-Smith () and Ivan K. H. Poon ()
Additional contact information
Stephanie F. Rutter: La Trobe University
Taeyoung Kang: La Trobe University
Gemma F. Ryan: La Trobe University
Bo Shi: La Trobe University
Caitlin L. Vella: La Trobe University
Pradeep Rajasekhar: The Walter and Eliza Hall Institute of Medial Research
Sean W. Cutter: La Trobe University
Amy L. Hodge: La Trobe University
Dilara C. Ozkocak: La Trobe University
Ching-Seng Ang: University of Melbourne
Julian Ratcliffe: La Trobe University
Katrina J. Binger: La Trobe University
Pamali Foneska: La Trobe University
Suresh Mathivanan: La Trobe University
Niall D. Geoghegan: The Walter and Eliza Hall Institute of Medial Research
Kelly L. Rogers: The Walter and Eliza Hall Institute of Medial Research
Michael F. Olson: Toronto Metropolitan University
Georgia K. Atkin-Smith: The Walter and Eliza Hall Institute of Medial Research
Ivan K. H. Poon: La Trobe University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64206-3

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