Gasdermin D in pyroptosis

Abstract

Pyroptosis is the process of inflammatory cell death. The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection. Excessive pyroptosis, however, leads to several inflammatory diseases, including sepsis and autoimmune disorders. Pyroptosis can be canonical or noncanonical. Upon microbe infection, the canonical pathway responds to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), while the noncanonical pathway responds to intracellular lipopolysaccharides (LPS) of Gram-negative bacteria. The last step of pyroptosis requires the cleavage of gasdermin D (GsdmD) at D275 (numbering after human GSDMD) into N- and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11 (caspase 4/5 in humans, caspase 11 in mice) in the noncanonical pathway. Upon cleavage, the N-terminus of GsdmD (GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1β and IL-18 and disturbs the regulation of ions and water, eventually resulting in strong inflammation and cell death. Since GsdmD is the effector of pyroptosis, promising inhibitors of GsdmD have been developed for inflammatory diseases. This review will focus on the roles of GsdmD during pyroptosis and in diseases.

Keywords: 7DG, 7-desacetoxy-6,7-dehydrogedunin; ADRA2B, α-2B adrenergic receptor; AIM, absent in melanoma; ASC, associated speck-like protein; Ac-FLTD-CMK, acetyl-FLTD-chloromethylketone; BMDM, bone marrow-derived macrophages; CARD, caspase activation; CD, Crohn’s disease; CTM, Chinese traditional medicine; CTSG, cathepsin G; Caspase; DAMP, damage-associated molecular pattern; DFNA5, deafness autosomal dominant 5; DFNB59, deafness autosomal recessive type 59; DKD, diabetic kidney disease; DMF, dimethyl fumarate; Damage-associated molecular patterns (DAMPs); ELANE, neutrophil expressed elastase; ESCRT, endosomal sorting complexes required for transport; FADD, FAS-associated death domain; FDA, U.S. Food and Drug Administration; FIIND, function to find domain; FMF, familial Mediterranean fever; GI, gastrointestinal; GPX, glutathione peroxidase; Gasdermin; GsdmA/B/C/D/E, gasdermin A/B/C/D/E; HAMP, homeostasis altering molecular pattern; HIN, hematopoietic expression, interferon-inducible nature, and nuclear localization; HIV, human immunodeficiency virus; HMGB1, high mobility group protein B1; IBD, inflammatory bowel disease; IFN, interferon; ITPR1, inositol 1,4,5-trisphosphate receptor type 1; Inflammasome; Inflammation; LPS, lipopolysaccharide; LRR, leucine-rich repeat; MAP3K7, mitogen-activated protein kinase kinase kinase 7; MCC950, N-[[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino]carbonyl]-4-(1-hydroxy-1-methylethyl)-2-furansulfonamide; NAIP, NLR family apoptosis inhibitory protein; NBD, nucleotide-binding domain; NEK7, NIMA-related kinase 7; NET, neutrophil extracellular trap; NIK, NF-κB inducing kinase; NLR, NOD-like receptor; NLRP, NLR family pyrin domain containing; NSAID, non-steroidal anti-inflammatory drug; NSCLC, non-small cell lung cancer; NSP, neutrophil specific serine protease; PAMP, pathogen-associated molecular pattern; PKA, protein kinase A; PKN1/2, protein kinase1/2; PKR, protein kinase-R; PRR, pattern recognition receptors; PYD, pyrin domain; Pathogen-associated molecular patterns (PAMPs); Pyroptosis; ROS, reactive oxygen species; STING, stimulator of interferon genes; Sepsis; TLR, Toll-like receptor; UC, ulcerative colitis; cAMP, cyclic adenosine monophosphate; cGAS, cyclic GMP–AMP synthase; mtDNA, mitochondrial DNA.

Graphical abstract

Figure 1

Activation of either caspase 1 or caspase 11 can lead to pyroptosis. Pro-caspase 11 is directly activated by LPS, which leads to activated caspase 11 that cleaves GsdmD. Pro-caspase 1 is activated by the CARD recruiting domain after receptor activation and inflammasome formation. Caspase 1 can activate GsdmD and IL-1β/IL-18.

Figure 2

Inflammasomes in canonical pyroptosis pathway. Ligands are differentially recognized by PRRs, which then assembles corresponding inflammasome complexes to activate caspase 1. Activated caspase 1 subsequently cleaves GsdmD to free its N-terminus, which forms the transmembrane pore and functions as the executor of pyroptosis. Note: the oligomerization of inflammasome proteins is not shown.

Figure 3

Similarities of the N-termini of hGsdmD, mGsdmD, and mGsdmA3, and the structure of the transmembrane pore of mGsdmA3. (A) The sequence and (B) structural alignments of the unactivated N-termini of hGsdmD, mGsdmD, and mGSDMA3 suggest the three proteins adopt similar structures after pore formation. Green: hGsdmD, PDB:6N9O; Pink: mGsdmD, PDB:6N9N; Cyan: mGsdmA3, PDB:5B5R. Note: There are ∼30 amino acids at the end of N-terminal domain that are not all structurally available for all three proteins, and these amino acids are not shown in (A) and (B). The (C) top to bottom and (D) side views show the symmetric assembly of mGsdmA3 pore.