title: Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Rogers
authors.affiliation: Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Fernandes-Alnemri
authors.affiliation: Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Mayes
authors.affiliation: Schreyer Honors College, Pennsylvania State University, 10 E College Ave, University Park, Pennsylvania 16802, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Alnemri
authors.affiliation: Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Gino
authors.initials: G
authors.lastname: Cingolani
authors.affiliation: Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D061251:Primary Cell Culture; D000069292:Pyroptosis / Q000187:drug effects / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000254:growth & development / Q000472:pathogenicity; D000094524:Gasdermins
chemical_list: D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D005047:Etoposide; D047908:Intracellular Signaling Peptides and Proteins; D028044:Phosphate-Binding Proteins; D011960:Receptors, Estrogen; C498368:Gsdmd protein, mouse; D000094524:Gasdermins; C491747:Gsdme protein, mouse; C505409:Casp3 protein, mouse