Cleavage of DFNA5 by caspase-3 During Apoptosis Mediates Progression to Secondary necrotic/pyroptotic Cell Death

Nat Commun. 2017 Jan 3;8:14128. doi: 10.1038/ncomms14128.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Caspase 3 / genetics*
  • Caspase 3 / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Membrane / virology
  • Etoposide / pharmacology
  • Gene Expression Regulation
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necrosis / chemically induced
  • Necrosis / genetics*
  • Necrosis / metabolism
  • Primary Cell Culture
  • Pyroptosis / drug effects
  • Pyroptosis / genetics*
  • Receptors, Estrogen / genetics*
  • Receptors, Estrogen / metabolism
  • Vesicular stomatitis Indiana virus / growth & development
  • Vesicular stomatitis Indiana virus / pathogenicity

Substances

  • Apoptosis Regulatory Proteins
  • Dfna5h protein, mouse
  • Gsdmd protein, mouse
  • Receptors, Estrogen
  • Etoposide
  • Casp3 protein, mouse
  • Caspase 3