Pyroptosis Modulators: New Insights of Gasdermins in Health and Disease

Abstract

Pyroptosis is an inflammation-dependent type of cell death that has been in the spotlight for the scientific community in the last few years. Crucial players in the process of pyroptosis are the members of the gasdermin family of proteins, which have been parallelly studied. Upon induction of pyroptosis, gasdermins suffer from structural changes leading to the formation of pores in the membrane that subsequently cause the release of pro-inflammatory contents. Recently, it has been discovered that oxidation plays a key role in the activation of certain gasdermins. Here, we review the current knowledge on pyroptosis and human gasdermins, focusing on the description of the different members of the family, their molecular structures, and their influence on health and disease directly or non-directly related to inflammation. Noteworthy, we have focused on the existing understanding of the role of this family of proteins in cancer, which could translate into novel promising strategies aimed at benefiting human health. In conclusion, the modulation of pyroptosis and gasdermins by natural and synthetic compounds through different mechanisms, including modification of the redox state of cells, has been proven effective and sets precedents for future therapeutic strategies.

Keywords: gasdermin; natural compounds; non-apoptotic cell death; pyroptosis.

Figure 1

Year-distribution profile of publications in Pubmed containing the term “gasdermi*” from 1999 to 30 April 2023.

Figure 2

Structure of human gasdermins. The colored figures correspond to the predicted structures by AlphaFold, with the following model of confidence: blue, Very high (pLDDT > 90); cyan, Confident (90 > pLDDT > 70); yellow, Low (70 > pLDDT > 50), and orange, Very low (pLDDT < 50). For gasdermin D, the most studied one, the structure of the crystallized protein from PDB is also shown (in grey).

Figure 3

Molecular mechanism of the pore formation by GSDMD. When the canonical pathway is activated (a) by stimuli such as bacterial flagellin, potassium efflux, or cytosolic DNA, the canonical inflammasome forms, promoting cleavage of pro-caspase-1 into the inflammatory caspase-1. A similar procedure occurs throughout the non-canonical pathway (b), induced by stimuli like LPS from Gram-negative bacteria or oxidized lipids and involving caspase-11 instead. Both pathways converge in (c) the gasdermin D (GSDMD) oxidation-dependent cleavage and release of the N-terminal domain, together with the maduration of IL-1β. Finally, the N-terminal domain of GSDMD is transported to the membrane, where it oligomerizes with other N-terminal domains to eventually form a pore in the plasma membrane that leads to the release of pro-inflammatory content to the extracellular media.