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Published on: January 20, 2023
Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death
Corey Rogers1, Teresa Fernandes-Alnemri1, Lindsey Mayes1
1Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
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.
Insights
Unscavenged apoptotic cells can undergo secondary necrosis. Researchers discovered that caspase-3 cleaves DFNA5, generating a fragment that triggers this inflammatory cell death, revealing a key mechanism in programmed necrosis.
Area of Science:
- Cellular biology
- Molecular mechanisms of cell death
Background:
- Apoptosis is a regulated cell suicide process.
- Unclear mechanisms link apoptosis to secondary necrosis, an inflammatory cell death phase.
- DFNA5 is a GSDMD-related protein.
Purpose of the Study:
- To elucidate the molecular mechanism driving secondary necrosis.
- To identify the role of DFNA5 in the progression from apoptosis to secondary necrosis.
Main Methods:
- Investigated caspase-3 cleavage of DFNA5.
- Analyzed the function of the DFNA5-N fragment.
- Compared cell death pathways in DFNA5-expressing and DFNA5-deleted cells.
Main Results:
- Caspase-3 cleaves DFNA5 at Asp270, producing a necrotic DFNA5-N fragment.
- This fragment targets the plasma membrane, inducing secondary necrosis or pyroptosis.
- DFNA5 expression is essential for secondary necrosis progression following apoptotic triggers.
- DFNA5 deletion leads to apoptotic body formation instead of secondary necrosis.
Conclusions:
- DFNA5 is a central regulator of apoptotic cell disassembly and secondary necrosis.
- Identified a molecular mechanism for secondary necrosis.
- Proposed DFNA5-induced secondary necrosis and GSDMD-induced pyroptosis as forms of programmed necrosis due to caspase dependence.
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