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

By Corey Rogers, T. Fernandes-Alnemri, Lindsey Mayes, Diana Alnemri, G. Cingolani, E. Alnemri. Nature Communications, 2017

1,339 citations recorded by the source corpus.

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. DFNA5 is related to the caspase-dependent pyroptosis inducer gasdermin D. Here the authors find that DFNA5 is cleaved by caspase 3 and show this cleavage skews cells away from apoptosis into secondary necrosis, a form of cell death characterized by membrane ballooning similar to pyroptosis.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/849f960b3e0742e5e1109eed8dae0768d207816a

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Citations in the corpus

Caspases in Cell Death, Inflammation, and Gasdermin-Induced Pyroptosis (2020, background): “GSDME by caspase-3 switches TNF- or chemotherapeutic-induced apoptosis to pyroptosis by releasing the GN-term, which also exhibits pore-forming activity (120, 121).”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “apoptosis in vitro (in the absence of proficient phagocytosis) [39], further demonstrating the elevated degree of”
Pyroptosis in inflammatory diseases and cancer (2022, background): “Chemotherapy can activate caspase-3 to trigger pyroptosis in GSDME-expressing cancer cells [16, 39].”
Role of pyroptosis in inflammation and cancer (2022, background): “Granzyme B is also the most abundant granzyme in cytotoxic granules and is transported to cancer cells, where it cleaves caspase-3 and perforin to induce apoptosis [128, 129].”
PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumor Necrosis (2020, background): “The N-terminal domain (1-365) of GSDMC is sufficient to induce pyroptosis (a) 3-D structural modeling of GSDMC.”
Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis. (2020, background): “, 2018), and caspase-3 cleaves GSDME at a DMPD site to induce pyroptosis (Rogers et al., 2017; Wang et al., 2017).”
Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells (2020, background): “GSDME, the other well-characterized gasdermin, is cleaved and activated by caspase-3 similarly as GSDMD by caspase-1/11 (32, 33).”
From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways (2021, background): “For example, at the executioner level, apoptotic CASP3 can cleave GSDME, another member of the gasdermin family, to induce pyroptosis in multiple cell types, which causes tissue damage during chemotherapy [99,100].”