Members of the gasdermin (GSDM) family are widely expressed and may play tissue-specific roles. For 15 years, scientists have been trying to determine the structure and function of GSDM family members, and some progress has been made. Multiple lines of evidence indicate that the GSDM family plays diverse roles in biological and pathological processes, including cell differentiation, cell proliferation, cell death, mitochondrial homeostasis, antimicrobial resistance, inflammation, and tumorigenesis. In recent years, the direct role of GSDM family members in promoting cell pyroptosis has also been intensively studied, sparking great interest among researchers.
(Data source: Molina L, et al. Semin Liver Dis. 2022)
GSDM family proteins:
The human and mouse genomes encode 6 (GSDMA, GSDMB, GSDMC, GSDMD, GSDME, DFNB59) and 10 (GSDMA1, GSDMA2, GSDMA3, GSDMC, GSDMC2, GSDMC3, GSDMC4, GSDMD, GSDME, DFNB59) family members of the GSDM family, respectively.
(Data source: Broz P, et al. Nat Rev Immunol. 2020)
GSDM functional mechanism:
All members of the GSDM family (except DFNB59) contain a cytotoxic N-terminal domain and a C-terminal repressor domain connected by a flexible linker. The protein cleavage site between the two domains can be processed by caspase to release the intramolecular inhibition of the cytotoxic N-terminal domain, enabling the N-terminal domain of the GSDM protein to insert into the cell membrane and form large oligomeric pores, thereby disrupting ion homeostasis and inducing cell death.
(Data source: Wang K, et al. Cell. 2020)
GSDM activity is regulated at multiple levels to prevent spontaneous pore formation and control the abundance of pores on the cell surface. These mechanisms include autoinhibitory structures, proteolytic cleavage events that promote (or prevent) pore assembly, post-translational modifications that regulate lipid binding and oligomerization, and pore removal through membrane repair mechanisms.
(Data source: Cao A, et al. J Mol Biol. 2022)
GSDMD protein:
Among the GSMD family members, GSDMD has garnered significant attention. As the first identified pyroptosis executor, it acts downstream of inflammatory caspases in response to cellular inflammation. GSDMD transcription may be regulated by multiple molecules: a. NF-κB activation promotes GSDMD transcription in adipocytes; b. DNMT (DNA methyltransferase)-mediated hypermethylation of the promoter region leads to reduced GSDMD expression in NK92 cells; c. In endothelial cells or macrophages, GSDMD expression is significantly enhanced through activation of IRF1 and IRF2.
(Data source: Li Z, et al. Front Immunol. 2022)
In the typical inflammasome-induced cell pyroptosis process, GSDMD is proteolytically cleaved by activated Caspase -1 to produce an active fragment with membrane pore-forming ability, thereby allowing the release of IL-1β and IL-18 through unconventional protein secretion; the non-canonical inflammasome pathway leads to the activation of human Caspase-4/5 and mouse Caspase-11, and the GSDMD pore allows potassium release, leading to the activation of NLRP3 inflammasome and the maturation of IL-1β/IL-18, and then the GSDMD pore causes pyroptosis and promotes the release of mature cytokines.
(Data source: Broz P, et al. Nat Rev Immunol. 2020)
Currently, numerous reports have revealed that GSDMD plays a key role in autoimmune or inflammatory diseases.
GSDMD acts as a co-effector of the inflammasome. Small molecules that block GSDMD by inhibiting its cleavage or oligomerization have been shown to be effective in a variety of diseases. So far, GSDMD inhibitors (such as NAS, DMF, and disulfiram) also affect upstream signaling pathways of GSDMD, such as NF-κB and covalent cleavage of modified reactive cysteines in caspase-1. A deeper understanding of the pyroptosis-regulating mechanisms and executive functions of GSDMD will not only expand our current knowledge but also enable the development of novel and more specific inhibitors.
(Data source: Li Z, et al. Front Immunol. 2022)
Summary:
As a star member of the GSDM family, GSDMD has made significant progress in understanding its regulatory mechanisms. However, the unique patterns of GSDMD activation in different cell types and diseases require further exploration. Although multiple GSDMD inhibitors have been identified, more selective and tolerable inhibitors are needed for clinical translation. GSDMD is becoming a highly attractive checkpoint in various diseases, opening new opportunities for therapeutic intervention in GSDMD-related disorders.
Wuhan Mabnus Bio's R&D team has over a decade of experience in recombinant protein and antibody development, focusing on recombinant protein expression in eukaryotic mammalian cells and recombinant rabbit monoclonal antibody development in single B cells. We provide simpler and more efficient recombinant protein and antibody product development services. Our current GSDM-related protein products include human and mouse GSDMD, as well as human GSDM B and GSDM C.
