The gasdermin-D pore: Executor of pyroptotic cell death

Pyroptosis is a lytic type of programmed cell death that is initiated in response to pathogenor host-derived perturbations of the cytosol. It is characterized by cell swelling, lysis, and the release of cytoplasmic content; thus restricting the replication of intracellular pathogens and attracting effector cells of the immune system. The name pyroptosis derives from the Greek pyro (fire or fever) and ptosis (to fall), illustrating its intrinsic pro-inflammatory properties. Pyroptosis is induced by a dedicated set of proteases, the so-called inflammatory caspases, such as caspase-1, -4 and -5 in humans, and caspase-1 and -11 in mice. These caspases are activated within inflammasomes, multi-protein complexes that are assembled by cytosolic pattern-recognition receptors upon recognition various cytosolic dangeror pathogen-associated molecular patterns [1]. While the basis of inflammasome assembly and caspase activation has been well established, the exact mechanism of pyroptosis remained unclear for over a decade. This picture changed dramatically in 2015 when Shi et al. and Kayagaki et al. independently discovered that the orphan protein gasdermin D (GSDMD) was the central mediator of pyroptotic cell death downstream of both caspase-1 and caspase-11 [2, 3]. The two groups also found that GSDMD is cleaved by these caspases into a 31 kDa N-terminal fragment (GSDMDNterm) and a 22 kDa C-terminal fragment (GSDMDCterm), and that the N-terminus by itself had the ability to induce pyroptosis when expressed ectopically. A series of papers by us and other groups has now shown that the cytotoxicity of this N-terminal fragment is due to its ability to target, insert and permeabilize cellular membranes, therefore representing a novel class of pore forming proteins (Figure 1) [4, 5, 6, 7]. To understand how the GSDMDNterm induces pyroptosis, we started by investigating its subcellular localization using biochemical fractionation and membrane extraction methods. We found that that Editorial: Autophagy and Cell Death