A single cut to pyroptosis

Pyroptosis is a form of inflammatory cell death mediated by inflammatory caspases. Two independent studies have recently demonstrated that inflammatory caspases cleave gasdermin D and the resulting N-terminal fragment of this protein mediates pyroptosis. Here we summarize the key findings reported in these important publications. Caspases are cysteine proteases that function in apoptosis and other forms of cell deaths, such as pyroptosis, a form of proinflammatory programmed necrosis [1]. Pyroptosis is a critical innate immune defence system against microbial pathogens and features pore formation in the plasma membrane and its subsequent rupture, resulting in the release of cytosolic inflammatory contents. Activation of the inflammatory caspases caspase-1 and caspase-11, of which caspase-4 and caspase-5 are the human homologs, play a pivotal role in the execution and regulation of pyroptosis (Figure 1). In the canonical inflammasome (a multi-protein complex) pathway, caspase-1 is activated by inflammasome formation upon proinflammatory stimuli, such as microbial infection, and processes proinflammatory cytokines such as IL-1β and IL-18, triggering pyroptosis [1]. In contrast to the canonical inflammasome pathway, direct binding of caspase-11 to cytoplasmic lipopolysaccharide (LPS), a strong innate immune system stimulator, leads to noncanonical inflammasome activation to induce pyroptosis [2, 3]. While the mechanisms of inflammasome assembly are well understood, until recently, the mechanisms of how inflammatory caspases bring about pyroptosis have been unclear. Two papers recently published in Nature [4, 5] now describe that caspase-1 and caspase-11 mediated cleavage of a previously unsuspected culprit gasdermin D (GSDMD), is a critical step in the execution of pyroptosis. The two groups used different strategies to arrive at their findings. Shi et al. [4] performed a genomewide screen using CRISPR/Cas9 to identify essential factors in caspase-1 and caspase-11-induced pyroptosis in immortalized bone marrow-derived macrophages. Kayagaki et al. [5] conducted a genetic screen in mice randomly mutated by ethyl-N-nitrosourea to identify down-stream molecules of capase-11-mediated noncanonical inflammasome signalling. Both groups identified the Gsdmd that encodes GSDMD a protein of unknown function. The genetic screening results were confirmed through several experiments in mouse and human cells, showing that GSDMD is an essential molecule for noncanonical inflammasome-mediated pyroptosis (Figure 1). Kayagaki et al. also demonstrate that LPS-induced lethality is dramatically reduced in both Gsdmd-/and Casp11-/mice, which is critical in vivo data supporting that GSDMD is indeed a key substrate of caspase-11 in pyroptosis. While data from both groups show that GSDMD is necessary for caspase-4, caspase-5 or caspse-11-induced pyroptosis, their experimental results differ on the exact requirement of GSDMD in caspse-1induced canonical pyroptosis (Figure 1). Shi et al. generated Gsdmd-/macrophages to confirm that GSDMD is essential in Editorial