Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

Corey Rogers, Teresa Fernandes-Alnemri, Lindsey Mayes, Diana Alnemri, Gino Cingolani and Emad S. Alnemri ()
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Corey Rogers: Kimmel Cancer Center, Thomas Jefferson University
Teresa Fernandes-Alnemri: Kimmel Cancer Center, Thomas Jefferson University
Lindsey Mayes: Kimmel Cancer Center, Thomas Jefferson University
Diana Alnemri: Schreyer Honors College, Pennsylvania State University
Gino Cingolani: Kimmel Cancer Center, Thomas Jefferson University
Emad S. Alnemri: Kimmel Cancer Center, Thomas Jefferson University

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Apoptosis is a genetically regulated cell suicide programme mediated by activation of the effector caspases 3, 6 and 7. If apoptotic cells are not scavenged, they progress to a lytic and inflammatory phase called secondary necrosis. The mechanism by which this occurs is unknown. Here we show that caspase-3 cleaves the GSDMD-related protein DFNA5 after Asp270 to generate a necrotic DFNA5-N fragment that targets the plasma membrane to induce secondary necrosis/pyroptosis. Cells that express DFNA5 progress to secondary necrosis, when stimulated with apoptotic triggers such as etoposide or vesicular stomatitis virus infection, but disassemble into small apoptotic bodies when DFNA5 is deleted. Our findings identify DFNA5 as a central molecule that regulates apoptotic cell disassembly and progression to secondary necrosis, and provide a molecular mechanism for secondary necrosis. Because DFNA5-induced secondary necrosis and GSDMD-induced pyroptosis are dependent on caspase activation, we propose that they are forms of programmed necrosis.

Date: 2017
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DOI: 10.1038/ncomms14128

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