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A Colorimetric Assay that Specifically Measures Granzyme B Proteolytic Activity: Hydrolysis of Boc-Ala-Ala-Asp-S-Bzl
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A Colorimetric Assay that Specifically Measures Granzyme B Proteolytic Activity: Hydrolysis of Boc-Ala-Ala-Asp-S-Bzl

Published on: November 28, 2014

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Granzyme B-activated p53 interacts with Bcl-2 to promote cytotoxic lymphocyte-mediated apoptosis

Thouraya Ben Safta1, Linda Ziani1, Loetitia Favre1

  • 1U753 INSERM, 94805 Villejuif, France; Gustave Roussy Cancer Campus, 94805 Villejuif, France; University Paris Sud, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France; and.

Journal of Immunology (Baltimore, Md. : 1950)
|November 19, 2014
PubMed

Insights

Cytotoxic T lymphocyte (CTL) and Natural Killer (NK) cell-mediated apoptosis involves Granzyme B (GzmB). This study reveals that p53 protein interacts with Bcl-2 on mitochondria, enhancing GzmB-induced cell death.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Granzyme B (GzmB) is crucial for cytotoxic T lymphocyte (CTL) and Natural Killer (NK) cell-mediated apoptosis of infected cells and tumors.
  • GzmB induces apoptosis by cleaving Bid, promoting mitochondrial outer membrane permeabilization via Bax.
  • Previous work indicated GzmB induces p53 accumulation, suggesting a role in apoptosis.

Purpose of the Study:

  • To elucidate the role of p53 in GzmB-induced apoptosis.
  • To investigate the interaction between p53 and Bcl-2 in the context of GzmB signaling.
  • To determine the impact of p53-Bcl-2 interaction on CTL/NK-mediated cell death.

Main Methods:

  • Mitochondrial localization and Bcl-2 interaction of GzmB-activated p53 were assessed.
  • The effect of blocking p53-Bcl-2 interaction on GzmB-induced apoptosis markers was evaluated.
  • Target cell sensitivity to GzmB and CTL/NK-mediated killing was measured.

Main Results:

  • GzmB-activated p53 accumulates on target cell mitochondria and interacts with Bcl-2.
  • This interaction disrupts Bcl-2's inhibition of Bax and truncated Bid, promoting mitochondrial permeabilization.
  • Inhibition of the p53-Bcl-2 interaction reduced GzmB-induced apoptosis, cytochrome c release, and caspase activation.

Conclusions:

  • p53 acts as a novel mediator in the GzmB apoptotic pathway.
  • The p53-Bcl-2 interaction is essential for GzmB-mediated mitochondrial permeabilization.
  • p53 plays a significant role in CTL/NK cell-induced apoptosis, offering a potential therapeutic target.

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