Molecular and structural aspects of gasdermin family pores and insights into gasdermin-elicited programmed cell death

Abstract

Pyroptosis is a highly inflammatory and lytic type of programmed cell death (PCD) commenced by inflammasomes, which sense perturbations in the cytosolic environment. Recently, several ground-breaking studies have linked a family of pore-forming proteins known as gasdermins (GSDMs) to pyroptosis. The human genome encodes six GSDM proteins which have a characteristic feature of forming pores in the plasma membrane resulting in the disruption of cellular homeostasis and subsequent induction of cell death. GSDMs have an N-terminal cytotoxic domain and an auto-inhibitory C-terminal domain linked together through a flexible hinge region whose proteolytic cleavage by various enzymes releases the N-terminal fragment that can insert itself into the inner leaflet of the plasma membrane by binding to acidic lipids leading to pore formation. Emerging studies have disclosed the involvement of GSDMs in various modalities of PCD highlighting their role in diverse cellular and pathological processes. Recently, the cryo-EM structures of the GSDMA3 and GSDMD pores were resolved which have provided valuable insights into the pore formation process of GSDMs. Here, we discuss the current knowledge regarding the role of GSDMs in PCD, structural and molecular aspects of autoinhibition, and pore formation mechanism followed by a summary of functional consequences of gasdermin-induced membrane permeabilization.

Relevance of pyroptosis‐associated genes in nasopharyngeal carcinoma diagnosis and subtype classification

“…41 A member of the GSDM family, GSDMB, can induce pyroptosis by being cleaved by caspase-1/3/4/5/6/7/11; however, further research is needed to determine the precise mechanism by which GSDMB is cleaved by caspase-3/6/7 and engaged in pyroptosis. 15,16,42 According to previous studies, GSDMB is located in genomic regions that are frequently amplified during cancer development and is highly expressed in a variety of cancer tissues, such as cervical, gastric, pancreatic and breast cancers, amongst others. 43 However, the role of GSDMB in cancer development, invasion, and metastasis and the specific mechanisms involved are not yet clear.…”

The role of ROS-induced pyroptosis in CVD

“…There are few studies on GSDMC-related functions. Currently, only the mechanism by which GSDMD induces pyroptosis has been clarified (14)(15)(16). Furthermore, GSMDE can convert tumor necrosis factor α (TNFα) or chemotherapeutic drug -induced caspase-3 -mediated classical apoptosis into pyroptosis.…”

Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3

“…Before revealing its full necrotic potential, gasdermin lies dormant in a deactivated form consisting of covalently bound Cand N-terminus. Across all variants, the three-dimensional structure is very similar, despite diverging sequences (45% homology Zahid et al (2021)). Upon inflammation, enzymatic cleavage of gasdermins releases the functional N-terminus of its inhibitory C-terminus, enabling membrane insertion and pore formation.…”

“…Pyroptosis is a proinflammatory form of programmed cell death Walle and Lamkanfi (2016) following a range of pathways, either the canonical or noncanonical inflammasome pathway, where the inflammasomes detect cytosolic contamination Kovacs and Miao (2017), or via granzymes. In the final step of pyroptosis, transmembrane lytic pores are formed causing swelling of the cell, followed by the efflux of cytoplasmic content, and cell rupture Zahid et al (2021). Recently, GSDMs have been shown to be the sole executors of pyroptosis by forming lytic pores Kovacs and Miao (2017).…”