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.

Lysosomal membrane permeabilization and cell death

“…At the molecular level, pyroptosis generally involves activation of inflammasome sensor molecules, such as AIM2 or NLRP3. These proteins trigger the prion‐like assembly of the inflammasome adaptor ASC into a pyroptosome, a filamentous helical structure that recruits caspase‐1, leading to the maturation of IL‐1β‐family cytokines and gasdermin‐D, and consequent release of cytokines into the extracellular space . Cholesterol crystals, protein aggregates such as β‐amyloid, and bacterial products disrupt lysosomal integrity and activate the NRLP3 inflammasome, inducing cytokine release and cell death .…”

Bromodomain‐containing protein 4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity in NP cells

“…Pyroptosis is a form of inflammatory programmed cell death (Bergsbaken et al, 2009; Shi et al, 2017) that regulates immune responses and disease pathogenesis (Franchi, Eigenbrod, Munoz‐Planillo, & Nunez, 2009). It is characterized by activation of caspase‐1/4/5/11, cleavage, and activation of the pore‐forming effector GSDMD and release of the pro‐inflammatory cytokines IL‐1β and IL‐18 (Kovacs & Miao, 2017; Liu & Lieberman, 2017). Previous studies have reported that the NLRP3/caspase‐1/IL‐1β axis is active in human cartilaginous endplate degeneration and associated with the grade of IDD (Chen et al, 2015; Tang et al, 2016).…”

“…Activated by the inflammasome, caspase‐1 (or caspase‐4, caspase‐5, or caspase‐11) causes cleavage of GSDMD. The N‐terminal cleavage products then form membrane pores, causing cell lysis and release of the inflammatory factor IL‐1β, which is essential for immune responses (Aglietti & Dueber, 2017; Kovacs & Miao, 2017; Man & Kanneganti, 2015; Shi, Gao, & Shao, 2017; Upton & Chan, 2014). Importantly, it has been demonstrated that the NLRP3/caspase‐1/IL‐1β axis is associated with the grade of disc degeneration, and that the NLRP3 inflammasome is involved in IDD(Chen et al, 2015; Tang et al, 2016).…”

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

“…In non‐canonical pyroptosis, caspases‐4 and caspases‐5 can act as direct sensors of intracellular LPS . The mentioned caspases are activated and then cleave gasdermin (GSDM) D, thereby separating the inhibitory C‐terminal domain and the N‐terminal domain of GSDMD, which subsequently forms pores in the cell membrane . In addition, proforms of the cytokines IL‐1β and IL‐18 are cleaved by caspases to allow their full biological activity.…”

“…[22] The mentioned caspases are activated and then cleave gasdermin (GSDM) D, thereby separating the inhibitory C-terminal domain and the N-terminal domain of GSDMD, which subsequently forms pores in the cell membrane. [22,27] In addition, . There is evidence that GSDMD forms also pores in organelles, leading to the decay of mitochondria and lysosomes prior to the rupture of the plasma membrane.…”