Granzyme B-induced and caspase 3-dependent cleavage of gelsolin by mouse cytotoxic T cells modifies cytoskeleton dynamics.
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.
Martin
Praxedis
P
Metschnikoff Laboratory, Max-Planck-Institute of Immunobiology, 79108 Freiburg, Germany.
Pardo
Julián
J
Schill
Natalie
N
Jöckel
Lars
L
Berg
Matthias
M
Froelich
Christopher J
CJ
Wallich
Reinhard
R
Simon
Markus M
MM
D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D053148:Caspase 3 / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D018260:Gelsolin / Q000737:chemistry* / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism*; D008217:Lymphocytic choriomeningitis virus / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D014158:Transcription, Genetic
D018260:Gelsolin; D012333:RNA, Messenger; D053804:Granzymes; D053148:Caspase 3
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