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Gasdermin D in pyroptosis

Brandon E Burdette1, Ashley N Esparza1, Hua Zhu2

  • 1Biology Department, University of Arkansas at Little Rock, Little Rock, AR 72204, USA.

Acta Pharmaceutica Sinica. B
|September 30, 2021
PubMed

Insights

Pyroptosis is inflammatory cell death that defends against microbes but can cause disease. Gasdermin D (GsdmD) cleavage initiates pyroptosis, making it a target for treating inflammatory conditions.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Pyroptosis is a highly inflammatory form of programmed cell death crucial for host defense against microbial infections.
  • Dysregulated pyroptosis contributes to inflammatory diseases such as sepsis and autoimmune disorders.
  • Two main pathways, canonical and noncanonical, initiate pyroptosis in response to different molecular patterns.

Purpose of the Study:

  • To review the critical role of gasdermin D (GsdmD) in executing pyroptosis.
  • To explore the involvement of GsdmD in various inflammatory diseases.
  • To highlight GsdmD as a therapeutic target for managing inflammatory conditions.

Main Methods:

  • Review of existing literature on pyroptosis and GsdmD.
  • Analysis of canonical and noncanonical pyroptosis pathways.
  • Examination of GsdmD cleavage and pore formation mechanisms.

Main Results:

  • Gasdermin D (GsdmD) is the essential effector protein in pyroptosis, mediating membrane pore formation.
  • Cleavage of GsdmD by specific caspases (caspase 1, 4/5/11) triggers the release of pro-inflammatory cytokines like IL-1β and IL-18.
  • GsdmD-mediated pore formation leads to significant cellular and tissue inflammation.

Conclusions:

  • Gasdermin D (GsdmD) is central to pyroptosis execution and its pathological consequences.
  • Targeting GsdmD presents a promising therapeutic strategy for inflammatory diseases.
  • Understanding GsdmD's function is key to developing novel treatments for sepsis and autoimmune disorders.
Keywords:
7DG, 7-desacetoxy-6,7-dehydrogeduninADRA2B, α-2B adrenergic receptorAIM, absent in melanomaASC, associated speck-like proteinAc-FLTD-CMK, acetyl-FLTD-chloromethylketoneBMDM, bone marrow-derived macrophagesCARD, caspase activationCD, Crohn’s diseaseCTM, Chinese traditional medicineCTSG, cathepsin GCaspaseDAMP, damage-associated molecular patternDFNA5, deafness autosomal dominant 5DFNB59, deafness autosomal recessive type 59DKD, diabetic kidney diseaseDMF, dimethyl fumarateDamage-associated molecular patterns (DAMPs)ELANE, neutrophil expressed elastaseESCRT, endosomal sorting complexes required for transportFADD, FAS-associated death domainFDA, U.S. Food and Drug AdministrationFIIND, function to find domainFMF, familial Mediterranean feverGI, gastrointestinalGPX, glutathione peroxidaseGasderminGsdmA/B/C/D/E, gasdermin A/B/C/D/EHAMP, homeostasis altering molecular patternHIN, hematopoietic expression, interferon-inducible nature, and nuclear localizationHIV, human immunodeficiency virusHMGB1, high mobility group protein B1IBD, inflammatory bowel diseaseIFN, interferonITPR1, inositol 1,4,5-trisphosphate receptor type 1InflammasomeInflammationLPS, lipopolysaccharideLRR, leucine-rich repeatMAP3K7, mitogen-activated protein kinase kinase kinase 7MCC950, N-[[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino]carbonyl]-4-(1-hydroxy-1-methylethyl)-2-furansulfonamideNAIP, NLR family apoptosis inhibitory proteinNBD, nucleotide-binding domainNEK7, NIMA-related kinase 7NET, neutrophil extracellular trapNIK, NF-κB inducing kinaseNLR, NOD-like receptorNLRP, NLR family pyrin domain containingNSAID, non-steroidal anti-inflammatory drugNSCLC, non-small cell lung cancerNSP, neutrophil specific serine proteasePAMP, pathogen-associated molecular patternPKA, protein kinase APKN1/2, protein kinase1/2PKR, protein kinase-RPRR, pattern recognition receptorsPYD, pyrin domainPathogen-associated molecular patterns (PAMPs)PyroptosisROS, reactive oxygen speciesSTING, stimulator of interferon genesSepsisTLR, Toll-like receptorUC, ulcerative colitiscAMP, cyclic adenosine monophosphatecGAS, cyclic GMP–AMP synthasemtDNA, mitochondrial DNA

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