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Human polymorphisms in GSDMD alter the inflammatory response.

Joseph K Rathkey1, Tsan S Xiao1, Derek W Abbott1

  • 1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.

The Journal of Biological Chemistry
|January 29, 2020
PubMed
Summary
This summary is machine-generated.

Genetic variations in gasdermin D (GSDMD) impact pyroptosis, a key inflammatory cell death. Some GSDMD polymorphisms alter its function, converting inflammatory cell death to silent apoptosis.

Keywords:
SNPcell deathgenetic polymorphismgeneticsinflammasomeinflammation

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Area of Science:

  • Immunology
  • Genetics
  • Cell Biology

Background:

  • Innate immune genes show high genetic variation.
  • Phenotypic consequences of this variation are poorly understood.
  • Gasdermin D (GSDMD) is a key effector protein in pyroptosis.

Purpose of the Study:

  • Investigate functional consequences of GSDMD genetic variation.
  • Analyze how polymorphisms affect GSDMD function and pyroptosis.

Main Methods:

  • Studied single nucleotide polymorphisms (SNPs) in GSDMD.
  • Assessed effects on protein function, caspase cleavage, oligomerization, and pore formation.
  • Examined cell death mechanisms downstream of inflammasome activation.

Main Results:

  • SNPs affecting posttranslational modification sites did not alter GSDMD function.
  • Polymorphisms disrupting structurally important sites significantly altered GSDMD function.
  • Altered functions included conserved pyroptosis, inhibited caspase cleavage, and disrupted oligomerization/pore formation.
  • Loss-of-function GSDMD polymorphisms shifted inflammatory pyroptosis to silent apoptotic cell death.

Conclusions:

  • Human genetic variation in GSDMD can modulate pyroptotic cell death.
  • Polymorphisms can alter inflammatory cell death pathways.
  • GSDMD functional variation impacts inflammatory responses.