Pyroptosis is a unique, pro‐inflammatory form of lytic cell death that is initiated by the activation of inflammatory caspases. The caspase substrate gasdermin D (GSDMD) plays a critical function in pyroptosis, yet the precise mode of action of this molecule in cell death execution remained unclear. Several recent reports, including a The EMBO Journal article, show that the caspase‐matured N‐terminal fragment of GSDMD is recruited to lipid membranes to form pore‐like structures, which constitutes the key effector mechanism of pyroptotic cell death.
See also: L Sborgi et al (August 2016)
The term pyroptosis (pyro greek for fire or fever) has been originally coined to describe the non‐apoptotic, caspase‐1‐dependent cell death of Salmonella‐infected macrophages that would alarm and recruit neighboring cells to the site of infection (Cookson & Brennan, 2001). Later it became apparent that the activation of caspase‐1 to induce pyroptosis is controlled by a subset of PRRs that can induce inflammasome activation (e.g. NLRP3, AIM2 or NLRC4/NAIP). Upon recognition of their cognate ligands, these sensors seed the prion‐like assembly of the inflammasome adapter ASC into a high molecular weight cytosolic complex to which caspase‐1 becomes recruited and is activated by. Auto‐processed caspase‐1 then matures the cytokines IL‐1β and IL‐18 to render them bioactive and induce pyroptotic cell death. Besides this canonical inflammasome activation leading to caspase‐1 maturation, other pro‐inflammatory caspases, murine caspase‐11 and human caspase‐4 and caspase‐5, directly sense cytosolic LPS to induce pyroptosis and activate the NLRP3 inflammasome via the so‐called non‐canonical pathway (Broz & Dixit, 2016). Recently, …
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