Written by Emily Locke
Imagine a house engulfed in flames. But this is no uncontrolled inferno – it is a planned demolition to prevent something worse, a strategic sacrifice to protect the surroundings. This is exactly how pyroptosis works – a special form of programmed cell death, often described as "burning down the house" [1]. In this highly effective yet drastic mechanism, infected or damaged cells deliberately sacrifice themselves to alert the immune system and trigger a strong defensive response. Once the affected cell detects danger, specific proteins are activated, leading to a controlled rupture of the cell and the release of pro-inflammatory signaling molecules [2]. This "fiery" death alarms the immune system, enabling a rapid response to the threat – sometimes, targeted destruction is the best defense mechanism.
At the heart of this process are the gasdermins – a family of proteins that increase cell membrane permeability and ultimately lead to cell rupture. In recent years, gasdermin D (GSDMD) and gasdermin E (GSDME) have increasingly become the focus of research, proving to be key players in these complex biological mechanisms. Our partner AdipoGen Life Sciences, a specialist in inflammasome research, continuously develops innovative products to support you in studying these fascinating molecules. In this article, you will learn about the role of gasdermins in the immune system, their significance in infections, inflammation, and even cancer – and how AdipoGen’s high-quality ELISA kits can help advance your inflammasome research
These topics await you:
1) Self-Destruction Mode Activated: The Highly Inflammatory Death Program Pyroptosis
2) The Conductor of Pyroptosis: Gasdermin D
3) Gasdermin E as a Bridge Between Apoptosis and Pyroptosis
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Self-Destruction Mode Activated: The Highly Inflammatory Death Program Pyroptosis
While terms like apoptosis and necrosis are widely known in cell biology, pyroptosis is less familiar – despite its crucial role in rapid immune responses, especially following bacterial infections. For a cell to initiate its self-destruction program, it must first recognize the danger. This often occurs through Toll-like receptors on the cell surface or within endosomes, which detect pathogens and subsequently stimulate the production of pro-inflammatory cytokines [3]. Additionally, NOD-like receptors (NLRs), a specialized class of pattern recognition receptors (PRRs), play a key role. They recognize both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [4]. This enables the detection of not only bacterial toxins inside the cell but also viral genomes and other cellular threats. Upon NLR activation, a cytosolic multiprotein complex of the innate immune system – the inflammasome – is formed (Fig. 1).
Figure 1: Induction of pyroptosis via the canonical and non-canonical inflammasome pathway [4]. Left (Canonical Inflammasome): Various danger signals, such as bacterial toxins, PAMPs, DAMPs, flagellin, or cytosolic DNA, activate inflammasome sensors (e.g., NLRP3, NLRC4, AIM2). These sensors form an inflammasome oligomer that activates caspase-1. Caspase-1 cleaves the pro-form of IL-1β into its active form and activates gasdermin D. Gasdermin D then forms pores in the cell membrane, leading to the release of IL-1β. Right (Non-canonical Inflammasome): Gram-negative bacteria release lipopolysaccharides (LPS), which directly activate caspase-11, -4, or -5. These caspases also cleave gasdermin D, whose N-terminal fragment forms pores in the cell membrane, leading to cell lysis and the release of inflammatory signals.
Inflammasomes are primarily expressed in specialized immune cells of the innate immune system, such as macrophages [5]. However, recent studies indicate that they also play a significant role in epithelial tissues [6]. Inflammasomes always consist of a sensor (e.g., NLRP3), an adaptor protein (ASC/PYCARD), and a protease (pro-caspase-1) [4]. The inflammasome receptors interact with the adaptor protein, which subsequently recruits the inactive form of caspase-1 (pro-caspase-1) and activates it through proteolytic cleavage (Fig. 1). Activated caspase-1 then catalyzes the maturation of the pro-inflammatory cytokines IL-1β and IL-18. In addition to the classical, canonical inflammasome, a non-canonical inflammasome has recently been described [7]. In this pathway, cytosolic lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria is directly recognized by a different caspase – caspase-11 in mice and caspase-4 and caspase-5 in human cells (Fig. 1).
The Conductor of Pyroptosis: Gasdermin D
In both the canonical and non-canonical inflammasome pathways, gasdermins play a crucial role. Gasdermin D, encoded by the gsdmd gene, consists of an N-terminal (GSDMD-N) and an autoinhibitory C-terminal (GSDMD-C) domain, which are cleaved by inflammatory caspases at Asp-275 (Fig. 1) [8, 9]. Following proteolytic cleavage, the C-terminal fragment remains in the cytosol, while the N-terminal fragment is transported to the plasma membrane with the help of lipid anchor groups. At the membrane, GSDMD-N primarily interacts with membrane lipids such as phosphatidylinositol 4-phosphate (PI(4)P) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P), inducing the formation of large pores (Fig. 1). These pores disrupt the cell’s osmotic balance, leading to swelling and ultimately cell rupture. Additionally, the pores act as gateways for the release of inflammatory cytokines, which trigger an immune response (Fig. 1). In this way, pyroptosis helps limit the spread of intracellular infections [10].
While the role of GSDMD-N in pore formation is now well characterized, the fate of GSDMD-C remains largely unknown. The detection of GSDMD-C in the supernatant of cells undergoing pyroptosis suggests that the C-terminal fragment is released (Fig. 1). However, whether this occurs passively through the pores or serves a specific function is still unclear [4]. Further research is needed to unravel the precise mechanisms of gasdermin D and deepen our understanding of inflammatory processes. For scientists studying gasdermins, precise measurement methods are essential. Our partner AdipoGen Life Sciences offers ELISA kits specifically designed to meet these needs. The Gasdermin D (mouse) ELISA Kit enables the quantitative detection of murine C-terminal and full-length gasdermin D in cell culture supernatants and cell lysates. With an impressive sensitivity of 14 pg/ml and a measurement range of 15.6 to 1000 pg/ml, this kit is an indispensable tool for GSDMD research [11].
Figure 2: Specific detection of gasdermin D using the ELISA kit from AdipoGen Life Sciences [11]. Gasdermin D was analyzed in the supernatants of bone marrow-derived macrophages (BMDMs) from various knockout mouse strains transfected with LPS. The results show that only the supernatants from wild-type (WT) and NLRP3-/- mice contain gasdermin D.
View Gasdermin D (mouse) ELISA Kit
Gasdermin E as a Bridge Between Apoptosis and Pyroptosis
Since gasdermin D was identified as a key player in the classical pyroptotic signaling pathway, it has garnered significant attention in research. However, gradually, one of its relatives in the gasdermin family is also gaining some spotlight: Gasdermin E (GSDME), also known as DFNA5 (deafness, autosomal dominant 5), because mutations in GSDME are associated with the development of hereditary, non-syndromic deafness in humans [4]. Recent studies have shown that gasdermin E is also involved in membrane pore formation and, thus, pyroptotic cell death. The protein contains a caspase-3 cleavage site in its linker region and is cleaved similarly to gasdermin D. This results in the separation of the N-terminal, pyroptosis-inducing domain (GSDME-N) from the C-terminal regulatory domain. Caspase-3 is traditionally considered a key enzyme in apoptosis – it ensures a controlled, non-inflammatory form of cell death. However, in cells expressing GSDME, activation of caspase-3 does not lead to apoptosis but instead triggers pyroptosis [12].
Gasdermin E can determine whether a cell "dies quietly" (apoptosis) or "explodes" with a strong immune response (pyroptosis). This makes it a central player at the intersection of programmed cell death and immune regulation. This is particularly relevant in cancer: many cancer cells downregulate the expression of GSDME to avoid pyroptosis and escape immune detection [13]. Restoring GSDME in tumor cells, combined with chemotherapy-induced caspase-3 activation, could therefore represent a promising new strategy in cancer therapy [14]. The interest in gasdermin E is growing – not only in the field of cancer but also in other areas such as autoimmune diseases and neurodegeneration [4]. Scientists are working intensively to better understand the function of this fascinating protein to develop potential therapeutic approaches. Their research is supported by our partner AdipoGen Life Sciences, which offers a high-quality Gasdermin E ELISA Kit that allows for precise quantification of GSDME in human samples. The kit is characterized by high specificity and reliability [15].
View Gasdermin E (human) ELISA Kit
The study of gasdermins promises fascinating insights into inflammation and cell death processes. With the precise measurement tools provided by our partner AdipoGen Life Sciences, researchers can dive even deeper into this captivating field and potentially pave the way for new therapeutic approaches. Are you interested in more tools for your inflammasome research? Take a look at AdipoGen’s extensive portfolio or browse their inflammasome catalog! Additionally, you can request a poster of the NLRP3 inflammasome here to decorate your lab wall!
Sources
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[2] https://flexikon.doccheck.com/de/Pyroptose, 23.02.2025.
[3] Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009 Feb;7(2):99-109.
[4] https://adipogen.com/gasdermin-d, 23.02.2025.
[5] https://de.wikipedia.org/wiki/Inflammasom, 23.02.2025.
[6] Winsor N, Krustev C, Bruce J, Philpott DJ, Girardin SE. Canonical and noncanonical inflammasomes in intestinal epithelial cells. Cell Microbiol. 2019 Nov;21(11):e13079.
[7] Downs KP, Nguyen H, Dorfleutner A, Stehlik C. An overview of the non-canonical inflammasome. Mol Aspects Med. 2020 Dec;76:100924.
[8] Kuang S, Zheng J, Yang H, Li S, Duan S, Shen Y, Ji C, Gan J, Xu XW, Li J. Structure insight of GSDMD reveals the basis of GSDMD autoinhibition in cell pyroptosis. Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10642-10647.
[9] https://en.wikipedia.org/wiki/GSDMD, 23.02.2025.
[10] https://de.wikipedia.org/wiki/Pyroptose, 23.02.2025.
[11] https://adipogen.com/ag-45b-0011-gasdermin-mouse-elisa-kit.html, 23.02.2025.
[12] Tsuchiya, K. Switching from Apoptosis to Pyroptosis: Gasdermin-Elicited Inflammation and Antitumor Immunity. Int. J. Mol. Sci. 2021, 22, 426.
[13] Zhang, Z., Zhang, Y., Xia, S. et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 579, 415–420 (2020).
[14] Wang, Y., Gao, W., Shi, X. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103 (2017).
[15] https://adipogen.com/ag-45b-0024-gasdermin-e-human-elisa-kit.html, 23.02.2025.
