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Granzyme B-induced and Caspase 3-dependent Cleavage of Gelsolin by Mouse Cytotoxic T Cells Modifies Cytoskeleton Dynamics

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Martin,  Praxedis
Emeritus Group: Cellular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Pardo,  Julián
Max Planck Society;

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Schill,  Natalie
Metchnikoff Laboratory, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Jöckel,  Lars
Max Planck Society;

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Simon,  Markus M.
Metchnikoff Laboratory, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Martin, P., Pardo, J., Schill, N., Jöckel, L., Berg, M., Froehlich, C. J., et al. (2010). Granzyme B-induced and Caspase 3-dependent Cleavage of Gelsolin by Mouse Cytotoxic T Cells Modifies Cytoskeleton Dynamics. The Journal of Biological Chemistry, 285, 18918-18927.


Cite as: https://hdl.handle.net/11858/00-001M-0000-002B-8E8A-4
Abstract
Granule-associated perforin and granzymes (gzms) are key effector molecules of cytotoxic T lymphocytes (Tc cells) and natural killer cells and play a critical role in the control of intracellular pathogens and cancer. Based on the notion that many gzms, including A, B, C, K, H, and M exhibit cytotoxic activity in vitro, all gzms are believed to serve a similar function in vivo. However, more recent evidence supports the concept that gzms are not unidimensional but, rather, possess non-cytotoxic potential, including stimulation of pro-inflammatory cytokines and anti-viral activities. The present study shows that isolated mouse gzmB cleaves the actin-severing mouse protein, cytoplasmic gelsolin (c-gelsolin) in vitro. However, when delivered to intact target cells by ex vivo immune Tc cells, gzmB mediates c-gelsolin proteolysis via activation of caspases 3/7. The NH(2)-terminal c-gelsolin fragment generated by either gzmB or caspase 3 in vitro constitutively severs actin filaments without destroying the target cells. The observation that gzmB secreted by Tc cells initiates a caspase cascade that disintegrates the actin cytoskeleton in target cells suggests that this intracellular process may contribute to anti-viral host defense.