Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases

Cell Rep. 2021 Apr 13;35(2):108998. doi: 10.1016/j.celrep.2021.108998.

Abstract

Cellular inflammasome activation causes caspase-1 cleavage of the pore-forming protein gasdermin D (GSDMD) with subsequent pyroptotic cell death and cytokine release. Here, we clarify the ambiguous role of the related family member gasdermin E (GSDME) in this process. Inflammasome stimulation in GSDMD-deficient cells led to apoptotic caspase cleavage of GSDME. Endogenous GSDME activation permitted sublytic, continuous interleukin-1β (IL-1β) release and membrane leakage, even in GSDMD-sufficient cells, whereas ectopic expression led to pyroptosis with GSDME oligomerization and complete liberation of IL-1β akin to GSDMD pyroptosis. We find that NLRP3 and NLRP1 inflammasomes ultimately rely concurrently on both gasdermins for IL-1β processing and release separately from their ability to induce cell lysis. Our study thus identifies GSDME as a conduit for IL-1β release independent of its ability to cause cell death.

Keywords: GSDMD; GSDME; IL-1; cell death; gasdermin D; gasdermin E; gasdermins; inflammasome; interleukin-1; pore-forming proteins.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology
  • Caspase 1 / genetics
  • Caspase 1 / immunology
  • Caspase 3 / genetics
  • Caspase 3 / immunology
  • Cell Line, Transformed
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • Humans
  • Inflammasomes / genetics*
  • Inflammasomes / immunology
  • Interleukin-1beta / genetics*
  • Interleukin-1beta / immunology
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology
  • Phosphate-Binding Proteins / deficiency
  • Phosphate-Binding Proteins / genetics*
  • Phosphate-Binding Proteins / immunology
  • Pore Forming Cytotoxic Proteins / deficiency
  • Pore Forming Cytotoxic Proteins / genetics*
  • Pore Forming Cytotoxic Proteins / immunology
  • Pyroptosis / drug effects
  • Pyroptosis / genetics*
  • Pyroptosis / immunology
  • Salmonella typhimurium / chemistry
  • Salmonella typhimurium / pathogenicity
  • Signal Transduction
  • THP-1 Cells

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Gsdmd protein, mouse
  • Gsdme protein, mouse
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • NALP1 protein, mouse
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Phosphate-Binding Proteins
  • Pore Forming Cytotoxic Proteins
  • Casp3 protein, mouse
  • Caspase 3
  • Casp1 protein, mouse
  • Caspase 1