Gasdermins: New Therapeutic Targets in Host Defense, Inflammatory Diseases, and Cancer

Abstract

Gasdermins (GSDMs) are a class of pore-forming proteins related to pyroptosis, a programmed cell death pathway that is induced by a range of inflammatory stimuli. Small-scale GSDM activation and pore formation allow the passive release of cytokines, such as IL-1β and IL-18, and alarmins, but, whenever numerous GSDM pores are assembled, osmotic lysis and cell death occur. Such GSDM-mediated pyroptosis promotes pathogen clearance and can help restore homeostasis, but recent studies have revealed that dysregulated pyroptosis is at the root of many inflammation-mediated disease conditions. Moreover, new homeostatic functions for gasdermins are beginning to be revealed. Here, we review the newly discovered mechanisms of GSDM activation and their prominent roles in host defense and human diseases associated with chronic inflammation. We also highlight the potential of targeting GSDMs as a new therapeutic approach to combat chronic inflammatory diseases and cancer and how we might overcome the current obstacles to realize this potential.

Keywords: cancer; gasdermins; host defense; inflammasome; pyroptosis; therapeutics.

Figure 1

Mechanisms of Gasdermin D activation following canonical and non-canonical inflammasome stimulation. Left. Canonical inflammasome activation is a well-structured process involving several steps. Upon sensing specific inflammatory stimuli (microbes, danger signals, and environmental factors), the inflammasome sensor (i.e., NOD-like receptor protein 3, NLRP3) recruits the precursor of caspase-1 (pro-caspase-1) via the protein adaptor apoptosis-associated speck-like protein containing a CARD (ASC). Upon inflammasome complex formation, pro-caspase-1 is activated by autocatalytic processing and converts the pro-IL-1β and pro-IL-18 precursors into their bioactive forms. Matured caspase-1 also cleaves the pore-forming protein gasdermin D (GSDMD), generating the N-terminal domain of GSDMD (GSDMD-NT), which relocates to the plasma membrane and oligomerizes to form a pore. Pore formation allows the release of mature IL-1β and IL-18 and drives a type of inflammatory cell death known as pyroptosis. Right. The non-canonical inflammasome pathway is activated by intracellular sensing of Gram-negative bacteria or lipopolysaccharides (LPS). It involves the activation of human caspase 4/5 or caspase-11 in mice. Active caspases directly process the pro-IL-1β and pro-IL-18 precursors and GSDMD. Like the canonical inflammasome activation mode, GSDMD pores allow the passive release of IL-1β/IL-18 cytokines and pyroptosis.

Figure 2

Gasdermin-related functions in infectious and non-infectious diseases and cancer. Infectious diseases. During infections, GSDM-mediated pyroptosis is, in general, beneficial for the host because it leads to successful pathogens eradication by mediating innate immune cell recruitment, NET- and MET-osis. However, under some circumstances, detrimental pyroptosis occurs which causes unwarranted and permanent tissue damage. Non-infectious diseases. GSDMA and GSDMB polymorphisms are associated with asthma susceptibility, bronchial hyperresponsiveness, and increased risk of multiple sclerosis. GSDMD and GSDME mediate pyroptosis and cytokine release associated with many immune-mediated inflammatory diseases such as Cryopyrin-associated periodic syndrome (CAPS), Familial Mediterranean fever (FMF), rheumatoid arthritis, and type 1 diabetes. PJVK-deficiency triggers excessive generation of reactive oxygen species (ROS), which cause hearing impairment due to cell death of auditory cells and sensory neurons. Cancer. GSDMA reduces the growth of gastric cancer cells by promoting apoptosis. On the other hand, GSDMB overexpression has been linked to metastatic and invasive properties of breast cancer cells. Tumor-infiltrating immune cells (i.e., M1 macrophages, CD8⁺ T cells, and NK cells) promote cell death of cancer cells via a mechanism mediated by the granzyme-GSDMB/D/E pathway.