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Pyroptosis is a form of lytic inflammatory programmed cell death that is triggered by microbial infection or pathological stimuli, such as stroke or cancer (reviewed in Shi J et al. 2017; Man SM et al. 2017; Tang D et al. 2020; Zheng Z & Li G 2020). The process of pyroptosis protects the host from microbial infection but can also lead to pathological inflammation if overactivated. The morphologic characteristics of pyroptosis include cell swelling, rupture of the cell membrane and release of intracellular contents into the immediate cellular environment. Pyroptosis is also characterized by chromatin condensation (reviewed in Man SM et al. 2017; Tang D et al. 2019). Pyroptosis is executed by proteins of the gasdermin family, which mediate formation of membrane pores (Liu X et al. 2016; Ding J et al. 2016; Mulvihill E et al. 2018). Pyroptosis can be defined as gasdermin-mediated programmed necrotic cell death (Shi J et al. 2017; Galluzzi L et al. 2018). The gasdermin (GSDM) superfamily includes GSDMA, GSDMB, GSDMC, GSDMD, GSDME (or DFNA5) and PJVK (DFNB59) (Kovacs SB & Miao EA 2018). Each protein contains an N-terminal domain with intrinsic necrotic activity and a C‑terminal domain reported to inhibit cell death through intramolecular domain association (Liu X et al. 2016; Ding J et al. 2016; Liu Z et al. 2018, 2019; Kuang S et al. 2017). Proteolytic cleavage in the linker connecting the N‑ and C‑terminal domains of gasdermins releases the C‑terminus, allowing the gasdermin N‑terminus to translocate to the cell membrane and oligomerize to form pores (Shi J et al. 2015; Ding J et al. 2016; Sborgi L et al. 2016; Feng S et al. 2018; Yang J et al. 2018; Mulvihill E et al. 2018). Although PJVK (DFNB59) is included to the gasdermin family, it is not known whether PJVK is cleaved and whether the full length or the N-terminal portion of PJVK is responsible for forming membrane pores. The N‑terminal fragments of GSDMs strongly bind to phospholipids, such as phosphatidylserine and phosphatidylinositol phosphates, found on the inner leaflet of the plasma membrane (Liu X et al. 2016; Ding J et al. 2016; Mulvihill E et al. 2018). GSDMD and GSDME are also able to target cardiolipin, which is often found in mitochondrial membranes and membranes of bacteria (Liu X et al. 2016; Rogers C et al. 2019). Mitochondrial permeabilization by GSDME or GSDMD leads to activation of the intrinsic apoptotic pathway (Rogers C et al. 2019). The size of the GSDMD pore is estimated to be 10–20 nm (Ding J et al. 2016; Sborgi L et al. 2016). The pore‑forming activity of GSDMs in the cell membrane facilitates the release of inflammatory molecules such as interleukin (IL)‑1β and IL‑18 (mainly in GSDMD-mediated pyroptosis), and eventually leads to cytolysis in mammalian cells, releasing additional proinflammatory cellular contents including danger signals such as high mobility group box‑1 (HMGB1) (Shi J et al. 2015; He W et al. 2015; Evavold CL et al. 2017; Semino C et al. 2018; Volchuk A et al. 2020). Pyroptosis can occur in immune cells such as macrophages, monocytes and dendritic cells and non‑immune cell types such as intestinal epithelial cells, trophoblasts and hepatocytes (Taabazuing CY et al. 2017; Li H et al. 2019; Jia C et al. 2019). GSDME can be cleaved by caspase‑3 (CASP3) to induce pyroptosis downstream of apoptosis (Wang Y et al. 2017; Rogers C et al. 2017), whereas GSDMD is cleaved by inflammatory CASP1, CASP4 and CASP5 in humans, and CASP1, CASP11 in mice to induce pyroptosis associated with inflammasome activation (Shi J et al. 2015; Kayagaki N et al. 2015). CASP3 cleavage of GSDMD results in its inactivation (Taabazuing et al. 2017). In mouse macrophages, CASP8 can also cleave GSDMD and cause pyroptosis when TAK1 is inhibited (Malireddi R et al. 2018; Orning P et al. 2018; Sarhan J et al. 2018), and TAK1 inhibition also leads to GSDME cleavage (Sarhan J et al. 2018). Furthermore, activated CASP8 can drive inflammasome-independent cleavage of both pro-IL-1β and GSDMD downstream of the extrinsic cell death receptor signaling pathway switching apoptotic signaling to GSDMD-dependent pyroptotic-like cell death (Donado CA et al. 2020). The cleavage and activation of GSDMD in neutrophils is mediated by neutrophil elastase (NE or ELANE), which is released from azurophil granules into the cytosol during neutrophil extracellular trap (NET) formation (Kambara H et al. 2018). Further, granzyme B (GZMB) released from cytotoxic T lymphocytes and natural killer (NK) cells, may induce GSDME‑dependent lytic cell death in tumor targets by directly cleaving GSDME or via the CASP3‑mediated cleavage of GSDME (Zhang Z et al. 2020).

This Reactome module describes pyroptotic activities of GSDMD and GSDME. While the N‑terminal domains of mammalian GSDMA, GSDMB, and GSDMC also have the ability to form pores (Feng S et al. 2018; Ruan J et al. 2018), their functions in the induction of pyroptosis, secretion of proinflammatory cytokines or in bactericidal activity in host remain poorly studied and are not covered by this Reactome module.

Literature References
PubMed ID Title Journal Year
28462526 Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases

Man, SM, Karki, R, Kanneganti, TD

Immunol. Rev. 2017
29362479 Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Galluzzi, L, Vitale, I, Aaronson, SA, Abrams, JM, Adam, D, Agostinis, P, Alnemri, ES, Altucci, L, Amelio, I, Andrews, DW, Annicchiarico-Petruzzelli, M, Antonov, AV, Arama, E, Baehrecke, EH, Barlev, NA, Bazan, NG, Bernassola, F, Bertrand, MJM, Bianchi, K, Blagosklonny, MV, Blomgren, K, Borner, C, Boya, P, Brenner, C, Campanella, M, Candi, E, Carmona-Gutierrez, D, Cecconi, F, Chan, FK, Chandel, NS, Cheng, EH, Chipuk, JE, Cidlowski, JA, Ciechanover, A, Cohen, GM, Conrad, M, Cubillos-Ruiz, JR, Czabotar, PE, D'Angiolella, V, Dawson, TM, Dawson, VL, De Laurenzi, V, De Maria, R, Debatin, KM, DeBerardinis, RJ, Deshmukh, M, Di Daniele, N, Di Virgilio, F, Dixit, VM, Dixon, SJ, Duckett, CS, Dynlacht, BD, El-Deiry, WS, Elrod, JW, Fimia, GM, Fulda, S, Garcia-Saez, AJ, Garg, AD, Garrido, C, Gavathiotis, E, Golstein, P, Gottlieb, E, Green, DR, Greene, LA, Gronemeyer, H, Gross, A, Hajnóczky, G, Hardwick, JM, Harris, IS, Hengartner, MO, Hetz, C, Ichijo, H, Jäättelä, M, Joseph, B, Jost, PJ, Juin, PP, Kaiser, WJ, Karin, M, Kaufmann, T, Kepp, O, Kimchi, A, Kitsis, RN, Klionsky, DJ, Knight, RA, Kumar, S, Lee, SW, Lemasters, JJ, Levine, B, Linkermann, A, Lipton, SA, Lockshin, RA, López-Otín, C, Lowe, SW, Luedde, T, Lugli, E, MacFarlane, M, Madeo, F, Malewicz, M, Malorni, W, Manic, G, Marine, JC, Martin, SJ, Martinou, JC, Medema, JP, Mehlen, P, Meier, P, Melino, S, Miao, EA, Molkentin, JD, Moll, UM, Muñoz-Pinedo, C, Nagata, S, Nuñez, G, Oberst, A, Oren, M, Overholtzer, M, Pagano, M, Panaretakis, T, Pasparakis, M, Penninger, JM, Pereira, DM, Pervaiz, S, Peter, ME, Piacentini, M, Pinton, P, Prehn, JHM, Puthalakath, H, Rabinovich, GA, Rehm, M, Rizzuto, R, Rodrigues, CMP, Rubinsztein, DC, Rudel, T, Ryan, KM, Sayan, E, Scorrano, L, Shao, F, Shi, Y, Silke, J, Simon, HU, Sistigu, A, Stockwell, BR, Strasser, A, Szabadkai, G, Tait, SWG, Tang, D, Tavernarakis, N, Thorburn, A, Tsujimoto, Y, Turk, B, Vanden Berghe, T, Vandenabeele, P, Vander Heiden, MG, Villunger, A, Virgin, HW, Vousden, KH, Vucic, D, Wagner, EF, Walczak, H, Wallach, D, Wang, Y, Wells, JA, Wood, W, Yuan, J, Zakeri, Z, Zhivotovsky, B, Zitvogel, L, Melino, G, Kroemer, G

Cell Death Differ 2018
33033617 Emerging insights on the role of gasdermins in infection and inflammatory diseases

Tang, L, Lu, C, Zheng, G, Burgering, BM

Clin Transl Immunology 2020
27932073 Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death

Shi, J, Gao, W, Shao, F

Trends Biochem Sci 2017
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