Gasdermins: Effectors of Pyroptosis

Abstract

Pyroptosis is a form of lytic programmed cell death initiated by inflammasomes, which detect cytosolic contamination or perturbation. This drives activation of caspase-1 or caspase-11/4/5, which cleave gasdermin D, separating its N-terminal pore-forming domain (PFD) from the C-terminal repressor domain (RD). The PFD oligomerizes to form large pores in the membrane that drive swelling and membrane rupture. Gasdermin D is one of six (in humans) gasdermin family members; several other gasdermins have also been shown to form pores that cause pyroptosis after cleavage to activate their PFDs. One of these, gasdermin E, is activated by caspase-3 cleavage. We review our current understanding of pyroptosis as well as current knowledge of the gasdermin family.

Keywords: apoptosis; gasdermin; inflammasome; programmed cell death; pyroptosis.

Figure I

Considering the gasdermin pore and methods to detect pyroptosis

Figure 1. Pyroptosis converts cells into pore-induced intracellular traps (PITs)

Whereas apoptosis converts cells into apoptotic bodies, pyroptosis converts cells into PITs. The membrane rupture event that defines pyroptosis immediately disperses soluble cytosolic contents. However, although torn, the plasma membrane remains largely intact such that organelles and live intracellular bacteria remain trapped within. This is different from the image of cellular debris, where all cellular contents are dispersed. Efferocytosis is the process whereby one cell phagocytoses another. Apoptotic bodies are typically efferocytosed by macrophages. In contrast, PITs are efferocytosed by neutrophils. These neutrophils then kill the previously intracellular, now PIT-trapped, bacteria. Pictures of neutrophils (marked by Ly6G, white) that have efferocytosed macrophage PITs (marked by CD68, red) that entrap intracellular bacteria (GFP, green) after the engineered bacteria are prompted to express flagellin and trigger pyroptosis of macrophages in vivo [2].

Key Figure: Figure 2. Caspase-1/11 activate the gasdermin D pore to cause pyroptosis

Caspase-1 is activated by various inflammasomes in response to contamination of the cytosol or perturbation of basic cellular homeostasis. Caspase-11 (mice) and caspase-4 and -5 (humans) activate by direct sensing of cytosolic LPS. Upon activation, these caspases cleave pro-IL-1β, pro-IL-18, and gasdermin D. Gasdermin D is composed of an amino-terminal pore-forming domain (PFD, green), a linker (red), and a carboxy-terminal repression domain (RD). The amino-terminal pore-forming domain (PFD) of gasdermin D then interacts with the plasma membrane and approximately 16 monomers oligomerize to form a gasdermin pore. The diameter of this pore is estimated in the range of 10–15 nm, which is large enough to release small proteins, including mature IL-1β (4.5 nm diameter), probably at a relatively slow rate. Simultaneously, sodium enters the cell, bringing with it water that causes the cell volume to increase. This can rapidly exceed the volume capacity of the membrane, resulting in membrane rupture that is larger in size than the gasdermin pore, but smaller or on par with most organelles and intracellular bacteria. Upon membrane rupture, all remaining soluble cytosolic contents are released so rapidly as to be essentially instantaneous.