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Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells

Zhiwei Zhou1,2, Huabin He3,2, Kun Wang2

  • 1Research Unit of Pyroptosis and Immunity, Chinese Academy of Medical Sciences and National Institute of Biological Sciences, Beijing, Beijing 102206, China.

Science (New York, N.Y.)
|April 18, 2020
PubMed

Insights

Cytotoxic lymphocytes kill GSDMB-positive cells via pyroptosis, a programmed cell death. Lymphocyte granzyme A cleaves GSDMB, initiating this inflammatory cell death and promoting antitumor immunity.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Cytotoxic lymphocyte immunity is crucial for eliminating infected or cancerous cells.
  • Granzymes are key mediators of lymphocyte-induced cell death, primarily through apoptosis.
  • The precise mechanisms of granzyme-mediated cell killing are still under investigation.

Purpose of the Study:

  • To investigate the role of granzymes in inducing pyroptosis, a distinct form of programmed cell death.
  • To elucidate the mechanism by which cytotoxic lymphocytes kill gasdermin B (GSDMB)-positive cells.
  • To explore the potential of GSDMB-mediated pyroptosis in cancer immunotherapy.

Main Methods:

  • Investigated the interaction between lymphocyte-derived granzyme A (GZMA) and gasdermin B (GSDMB).
  • Utilized cell-based assays to assess pyroptosis induction in GSDMB-expressing cells upon GZMA treatment.
  • Examined the effect of Interferon-gamma (IFN-γ) on GSDMB expression and pyroptosis.
  • Assessed the therapeutic potential of GZMA-cleavable GSDMB in a mouse cancer model.

Main Results:

  • Cytotoxic lymphocytes, including natural killer cells and cytotoxic T lymphocytes, induce pyroptosis in GSDMB-positive cells.
  • Cleavage of GSDMB by GZMA triggers its pore-forming activity, leading to pyroptosis.
  • IFN-γ enhances GSDMB expression, sensitizing cells to GZMA-induced pyroptosis.
  • GSDMB expression is notable in digestive tract epithelia and associated tumors.
  • Engineered GSDMB in mouse cancer cells promoted tumor clearance, indicating therapeutic potential.

Conclusions:

  • Gasdermin B-mediated pyroptosis is a novel mechanism employed by cytotoxic lymphocytes for target cell elimination.
  • GZMA-mediated cleavage of GSDMB is the critical step initiating this inflammatory cell death pathway.
  • This finding expands our understanding of lymphocyte-mediated cytotoxicity and suggests pyroptosis as a target for enhancing antitumor immunity.

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