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Mechanism of membrane pore formation by human gasdermin-D

Estefania Mulvihill1, Lorenzo Sborgi2, Stefania A Mari1

  • 1Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zurich, Basel, Switzerland.

The EMBO Journal
|June 15, 2018
PubMed

Insights

Gasdermin-D N-terminal domain inserts into cell membranes and forms pores. Atomic force microscopy reveals its assembly into arc, slit, and ring shapes, independent of caspase cleavage, providing a pore formation model.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Protein-lipid interactions

Background:

  • Gasdermin-D (GSDMD) mediates pyroptosis by forming membrane pores.
  • The precise mechanisms of GSDMD N-terminal domain (GSDMDNterm) membrane insertion and pore assembly remain unclear.
  • Understanding GSDMD function is crucial for studying inflammatory cell death pathways.

Purpose of the Study:

  • To elucidate the molecular mechanisms of GSDMDNterm membrane insertion, oligomerization, and pore formation.
  • To investigate the role of lipid composition in GSDMDNterm membrane interactions.
  • To develop a mechanistic model for GSDMD-mediated pore assembly.

Main Methods:

  • High-resolution atomic force microscopy (AFM) to visualize GSDMDNterm-membrane interactions.
  • Time-lapse AFM to capture dynamic assembly processes.
  • Analysis of GSDMDNterm behavior across various lipid compositions.

Main Results:

  • GSDMDNterm inserts into diverse lipid membranes, with phosphatidylinositide (PI(4,5)P2) promoting and cholesterol inhibiting insertion.
  • GSDMDNterm assembles into arc-, slit-, and ring-shaped oligomers, all capable of forming transmembrane pores.
  • Pore formation is independent of specific inflammatory caspase cleavage (caspase-1, -4, or -5).
  • Dynamic AFM studies show a sequential assembly from arc to slit to ring oligomers.

Conclusions:

  • GSDMDNterm membrane insertion and pore formation involve a stepwise oligomerization process.
  • Lipid composition significantly influences GSDMDNterm membrane binding and insertion.
  • A conserved mechanism of transmembrane pore assembly likely applies to the entire gasdermin family.
Keywords:
cell deathgasdermin‐D pore assemblyinflammationtime‐lapse high‐resolution atomic force microscopytransmission electron microscopy

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