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Published on: October 28, 2022
Delivering the kiss of death: progress on understanding how perforin works
Matthew E Pipkin1, Judy Lieberman
1CBR Institute for Biomedical Research, Harvard Medical School, Boston MA 02115, USA.
Abstract:
Killer lymphocytes release perforin and granzymes from cytotoxic granules into the immunological synapse to destroy target cells as a critical mechanism in the defense against viruses and cancer. Perforin, a Ca(2+)-dependent pore-forming protein that multimerizes in membranes, delivers granzymes into the target cell cytosol. The original model for perforin (acting by forming a cell membrane channel through which granzymes pass) does not fit the experimental data. Recently, an alternative model has been proposed that involves active target cell collaboration with perforin to deliver granzymes and direct the target cell to an apoptotic, rather than necrotic, death.
Insights
Killer lymphocytes use perforin and granzymes to eliminate virus-infected and cancerous cells. A new model suggests target cells actively collaborate with perforin for granzyme delivery and controlled cell death.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Cytotoxic lymphocytes are crucial for immune defense against viral infections and cancer.
- Perforin and granzymes are key cytotoxic granule components released by killer lymphocytes.
- The established model of perforin function as a simple membrane channel is insufficient to explain experimental observations.
Purpose of the Study:
- To re-evaluate the mechanism of perforin-mediated cytotoxicity.
- To propose and investigate an alternative model for perforin function in target cell destruction.
Main Methods:
- Analysis of existing experimental data on perforin-granzyme interactions.
- Development of a new mechanistic model for perforin action.
- Comparison of the proposed model with experimental outcomes.
Main Results:
- The classical pore-formation model does not fully align with experimental data.
- An alternative model proposes active target cell involvement in granzyme delivery.
- This revised model explains the induction of apoptosis rather than necrosis.
Conclusions:
- Perforin-mediated cytotoxicity involves a more complex mechanism than previously thought.
- Target cells play an active role in facilitating granzyme entry.
- This collaboration leads to targeted apoptosis, a crucial process in immune surveillance.
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