It is evident that the gasdermin family is central to pyroptosis. This is because the gasdermin family members are the executioners of pyroptosis, and their pore-forming function is a necessary condition for pyroptosis to occur. This family generally includes a cytotoxic N-terminal domain and a C-terminal inhibitory domain. After cleavage, the N-terminal domain is released and can assemble into pores in the membrane. Gasdermin pores disrupt the integrity of the cell membrane, leading to inflammatory cell death, with cell contents, including inflammatory cytokines, being released into the extracellular space.
The name "Gasdermins" comes from the combination of "gastro" and "dermato," as these proteins were initially discovered in the gastrointestinal tract and skin. The Gasdermin (GSDM) protein family comprises six members: GSDMA, GSDMB, GSDMC, GSDMD, GSDME (also known as DFNA5), and DFNB59 (also known as PJVK). Except for DFNB59, GSDMA-E proteins all have three types of domains: the N-terminal domain (NT), a linker domain, and the C-terminal domain (CT). The NT and CT domains of these proteins are relatively conserved within the family, with significant differences in the linker domain.[1]
Fig. 1 Significant milestones in the development of gasdermins[2]
- GSDMA Gsdma3 induces catagen-associated apoptosis in hair follicle keratinocytes by directly increasing the expression of caspase-3. [3] The DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) enhances the expression of GSDMA in these cancer cell lines, indicating that DNA methylation may play a role in the suppression of GSDMA expression. [4] While mutations in GSDMA have not been associated with human alopecia, polymorphisms of GSDMA have been linked to systemic sclerosis (an autoimmune fibrotic disease affecting the skin and internal organs), inflammatory bowel disease (IBD), and childhood asthma. [5-8]
- GSDMB Genome-wide association studies (GWAS) have identified a significant link between GSDMB and the risk of chronic inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and type I diabetes. [9-13] Additionally, a specific single nucleotide polymorphism that is associated with heightened expression of GSDMB has been correlated with asthma susceptibility. [9] GSDMB expression is significantly elevated in several types of cancer, including cervical, breast, gastrointestinal, and liver cancers. This heightened expression is linked to a poorer prognosis for patients. [14-17] GSDMB plays a significant role in noncanonical pyroptosis by enhancing the activity of caspase 4, indicating its involvement in inflammatory processes. [10] A recent study revealed that granzyme A, released from cytotoxic T cells and natural killer cells, cleaves and activates gasdermin B, leading to pyroptosis in tumor cells. [18]
- GSDMC GSDMC is notably elevated in colorectal cancer, where it promotes cancer cell proliferation [19], suggesting its potential role as an oncogene. It can also be activated by hypoxia, leading to STAT3 phosphorylation and its association with nuclear-localized PDL1. [20] Additionally, GSDMC contributes to UV-induced MMP1 expression through the activation of ERK and JNK pathways. [21] In death receptor signaling, GSDMC is cleaved and activated by caspase 8, which converts apoptosis into pyroptosis in cells expressing GSDMC. [20]
- GSDMD The functional role of GSDMD and its cleavage was not fully understood until 2015, when two independent research groups identified it as a central executor of inflammasome-driven pyroptosis. This discovery was made through chemical mutagenesis and CRISPR screens in both mouse and cell models. [22, 23] GSDMD forms pores with a diameter of 10–15 nm, which allows the release of smaller molecules like IL-1β (4.5 nm) and IL-18 (5.0 nm) [24, 25], while restricting the passage of larger structures such as ribosomes (25–30 nm) [26]. GSDMD is expressed in a variety of tissues, including immune cells (particularly macrophages and dendritic cells) [27], as well as the placenta, gastrointestinal epithelium, and in several cancers, such as oesophageal, gastric, pancreatic, prostate, melanoma, and salivary gland tumors. It is also found in Jurkat T cells and Ramos B cells [28-30]. The expression of GSDMD is regulated by IRF2, a transcriptional repressor of interferons [31].
- GSDME GSDME is cleaved and activated by caspase 3, and potentially by other apoptotic effector caspases such as caspases 6 and 7, when cells that express GSDME are induced to undergo apoptosis. This cleavage shifts the process from noninflammatory apoptosis to inflammatory pyroptosis. Compared to normal tissue, GSDME expression is often epigenetically repressed by DNA methylation in cancers such as gastric, colorectal, and breast cancers, as well as in many human cancer cell lines. Importantly, mutations in the N-terminal domain of GSDME found in cancer are mainly loss-of-function mutations, which impair its ability to form pores. [32]
- DFNB59 DFNB59 is a more distantly related member of the GSDM family, distinguished by a truncated, non-homologous CT domain. Its transcripts are present in several tissues, including the brain, eye, inner ear, heart, lung, kidney, liver, intestine, and testis. Like GSDME, DFNB59 is associated with hereditary hearing loss in humans due to familial mutations. [33, 34]
Fig. 2 Activation Mechanisms of GSDMs and the Programmed Cell Death They Induce [1]
GSDM family recommended products:
|
Catalog # |
Product Name |
Application |
Reactivity |
|
Cleaved Gasdermin B（C Terminal） Rabbit mAb |
WB |
Human |
|
|
[KO Validated] Cleaved Gasdermin E（N terminal) Rabbit mAb |
WB IHC |
Human
|
|
|
|
Gasdermin D (Full Length+C terminal) Rabbit mAb |
WB |
Human
|
| A24059 |
Cleaved Gasdermin D (N Terminal) Rabbit mAb |
WB |
Human |
|
PJVK Rabbit mAb |
WB |
Human |
A26197 [KO Validated] Cleaved Gasdermin E (N terminal) Rabbit mAb A24059 [KO Validated] Gasdermin D (N Terminal) Rabbit mAb
