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https://hdl.handle.net/2440/8953
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Type: | Journal article |
Title: | Interleukin-1β-converting enzyme-like protease cleaves DNA-dependent protein kinase in cytotoxic T cell killing |
Other Titles: | Interleukin-1beta-converting enzyme-like protease cleaves DNA-dependent protein kinase in cytotoxic T cell killing |
Author: | Song, Q. Burrows, S. Smith, G. Lees-Miller, S. Kumar, S. Chan, D. Trapani, J. Alnemri, E. Litwack, G. Lu, H. Moss, D. Jackson, S. Lavin, M. |
Citation: | Journal of Experimental Medicine, 1996; 184(2):619-626 |
Publisher: | ROCKEFELLER UNIV PRESS |
Issue Date: | 1996 |
ISSN: | 0022-1007 1540-9538 |
Statement of Responsibility: | By Qizhong Song, Scott R. Burrows, Graeme Smith, Susan P. Lees-Miller, Sharad Kumar, Doug W. Chan, Joseph A. Trapani, Emad Alnemri, Gerald Litwack, Hong Lu, Denis J. Moss, Stephen Jackson, and Martin F. Lavin |
Abstract: | Cytotoxic T cells (CTL) represent the major defense mechanism against the spread of virus infection. It is believed that the pore-forming protein, perforin, facilitates the entry of a series of serine proteases (particularly granzyme B) into the target cell which ultimately leads to DNA fragmentation and apoptosis. We demonstrate here that during CTL-mediated cytolysis the catalytic subunit of DNA- dependent protein kinase (DNA-PKcs), an enzyme implicated in the repair of double strand breaks in DNA, is specifically cleaved by an interleukin (IL)-1 beta-converting enzyme (ICE)-like protease. A serine protease inhibitor, 3,4-dichloroisocoumarin (DCl), which is known to block granzyme B activity, inhibited CTL-induced apoptosis and prevented the degradation of DNA-PKcs in cells but failed to prevent the degradation of purified DNA-PKcs by CTL extracts. However, Tyr-Val- Ala-Asp-CH2Cl (YVAD-CMK) and other cysteine protease inhibitors prevented the degradation of purified DNA-PKcs by CTL extracts. Furthermore, incubation of DNA-PKcs with granzyme B did not produce the same cleavage pattern observed in cells undergoing apoptosis and when this substrate was incubated with either CTL extracts or the ICE-like protease, CPP32. Sequence analysis revealed that the cleavage site in DNA-PKcs during CTL killing was the same as that when this substrate was exposed to CPP32. This study demonstrates for the first time that the cleavage of DNA-PKcs in this intact cell system is exclusively due to an ICE-like protease. |
Keywords: | T-Lymphocytes, Cytotoxic Cells, Cultured Humans Cysteine Endopeptidases Caspases Metalloendopeptidases Serine Endopeptidases Peptides Peptide Fragments DNA-Binding Proteins Nuclear Proteins Signal Transduction Apoptosis Cytotoxicity, Immunologic Amino Acid Sequence Hydrolysis Time Factors Molecular Sequence Data DNA-Activated Protein Kinase Granzymes Caspase 3 Protein Serine-Threonine Kinases |
Description: | Copyright © 1996 by Rockefeller University Press |
DOI: | 10.1084/jem.184.2.619 |
Published version: | http://jem.rupress.org/cgi/content/abstract/184/2/619 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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