NK Cell Protease Granzyme M Targets α-Tubulin and Disorganizes the Microtubule Network
| Autor: | Pieter J.A. de Koning, Roel Broekhuizen, Razi Quadir, Niels Bovenschen, J. Alain Kummer, Christopher J. Froelich, J. Mirjam A. Damen, Monique Slijper |
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| Rok vydání: | 2008 |
| Předmět: |
Cytotoxicity
Immunologic Proteases Immunology macromolecular substances Microtubules Granzymes Substrate Specificity Jurkat Cells Ezrin Tubulin Microtubule Humans Immunology and Allergy Cytoskeleton Caspase Cell Death biology Perforin Molecular biology Cell biology Killer Cells Natural Cytoskeletal Proteins Caspases biology.protein Granzyme M HeLa Cells Signal Transduction |
| Zdroj: | The Journal of Immunology. 180:8184-8191 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.180.12.8184 |
| Popis: | Serine protease granzyme M (GrM) is highly expressed in the cytolytic granules of NK cells, which eliminate virus-infected cells and tumor cells. The molecular mechanisms by which GrM induces cell death, however, remain poorly understood. In this study we used a proteomic approach to scan the native proteome of human tumor cells for intracellular substrates of GrM. Among other findings, this approach revealed several components of the cytoskeleton. GrM directly and efficiently cleaved the actin-plasma membrane linker ezrin and the microtubule component α-tubulin by using purified proteins, tumor cell lysates, and tumor cells undergoing cell death induced by perforin and GrM. These cleavage events occurred independently of caspases or other cysteine proteases. Kinetically, α-tubulin was more efficiently cleaved by GrM as compared with ezrin. Direct α-tubulin proteolysis by GrM is complex and occurs at multiple cleavage sites, one of them being Leu at position 269. GrM disturbed tubulin polymerization dynamics in vitro and induced microtubule network disorganization in tumor cells in vivo. We conclude that GrM targets major components of the cytoskeleton that likely contribute to NK cell-induced cell death. |
| Databáze: | OpenAIRE |
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