Gasdermin Pore Forming Activities that Promote Inflammation from Living and Dead Cells

Abstract

Gasdermins are proteins that can self-assemble into membrane channels (also known as pores). These pores can serve as conduits for the secretion of cytosolic molecules, with the most commonly studied being members of the interleukin-1 family of cytokines. However, gasdermin pore forming activities must be tightly regulated, as the channels that they form can lead to a lytic form of cell death known as pyroptosis. Recent studies have revealed multiple mechanisms that control gasdermin activities within cells and identified gasdermin proteins in organisms as diverse as bacteria, humans and yeast. In this Review, we discuss the molecular and cellular mechanisms that regulate gasdermin pore formation. These mechanisms of gasdermin regulation likely explain the flexibility of these proteins to display cell type specific (and potentially organism specific) functions.

Keywords: IL-1; gasdermin; inflammasomes; innate immunity; pyroptosis.

Figure 1.

Intermediate steps regulating gasdermins activation of pore formation. 1) Autoinhibition - most gasdermins contain a pore-forming fragment and an inhibitory fragment, which through intramolecular interactions mask the surfaces required for lipid-binding and oligomerization. 2) Proteolytic cleavage - proteases are required to cleave the linker between the pore-forming and inhibitory fragments. These proteases include proinflammatory caspases like caspase-1/4/5/11, proapoptotic caspases like caspase-8/3, granules-associated proteases like elastase and cathepsin G. Cells can regulate the rate of gasdermin pore formation by controlling the degree of proteolytic activity. 3. Lipid selectivity - the pore-forming fragment of most gasdermins shows selectivity toward negatively charged phospholipids, which associate with the inner leaflet of the plasma membrane and the outer leaflet of intracellular vesicles. The pore-forming fragments of human and murine gasdermins also bind to cardiolipin, a phospholipid found in mitochondria and the plasma membrane of bacteria. The lipid preference ensures that gasdermin activation only kills the cells in which they are activated. 4. Oligomerizations - the pore-forming fragments oligomerize to form pore-like structures on cellular membranes. The oligomerization step requires covalent modifications on conserved cysteines and reactive oxygen species (ROS). However, the exact mechanism and the nature of the covalent modifications remain largely unknown. 5. Amplifications - the formation of gasdermins pores usually leads to further cleavages of gasdermins through feed-forward loops by releasing proteases into the cytosol or activating pathways responsible for gasdermin cleavage. 6. Membrane repair - there are mechanisms to remove perforated membranes and organelles, such as membrane remodeling by the ESCRT-III complex and autophagy, which may establish an equilibrium with the pore-forming activities to prevent cell death to preserve other cellular functions.