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Blood, 1 May 2006, Vol. 107, No. 9, pp. 3665-3668. Prepublished online as a Blood First Edition Paper on January 12, 2006; DOI 10.1182/blood-2005-03-1140. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 2005-03-1140v1 107/9/3665    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Meade, J. L. Articles by Cook, G. P. Search for Related Content PubMed PubMed Citation Articles by Meade, J. L. Articles by Cook, G. P. Related Collections Immunobiology Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Brief report A family with Papillon-Lefèvre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity Josephine L. Meade, Erika A. de Wynter, Peter Brett, Saghira Malik Sharif, C. Geoffrey Woods, Alexander F. Markham, and Graham P. Cook From the Leeds Institute of Molecular Medicine and the Department of Clinical Genetics, University of Leeds, St James's University Hospital, Leeds, United Kingdom; the Eastman Dental Institute, University College, London, United Kingdom; and Cancer Research UK, London, United Kingdom. Activation of granzyme B, a key cytolytic effector molecule of natural killer (NK) cells, requires removal of an N-terminal pro-domain. In mice, cathepsin C is required for granzyme processing and normal NK cell cytolytic function, whereas in patients with Papillon-Lefèvre syndrome (PLS), loss-of-function mutations in cathepsin C do not affect lymphokine activated killer (LAK) cell function. Here we demonstrate that resting PLS NK cells do have a cytolytic defect and fail to induce the caspase cascade in target cells. NK cells from these patients contain inactive granzyme B, indicating that cathepsin C is required for granzyme B activation in unstimulated human NK cells. However, in vitro activation of PLS NK cells with interleukin-2 restores cytolytic function and granzyme B activity by a cathepsin C-independent mechanism. This is the first documented example of a human mutation affecting granzyme B activity and highlights the importance of cathepsin C in human NK cell function. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Methot, D. Guay, J. Rubin, D. Ethier, K. Ortega, S. Wong, D. Normandin, C. Beaulieu, T. J. Reddy, D. Riendeau, et al. In Vivo Inhibition of Serine Protease Processing Requires a High Fractional Inhibition of Cathepsin C Mol. Pharmacol., June 1, 2008; 73(6): 1857 - 1865. [Abstract] [Full Text] [PDF] Y. M. El-Sherbiny, J. L. Meade, T. D. Holmes, D. McGonagle, S. L. Mackie, A. W. Morgan, G. Cook, S. Feyler, S. J. Richards, F. E. Davies, et al. The Requirement for DNAM-1, NKG2D, and NKp46 in the Natural Killer Cell-Mediated Killing of Myeloma Cells Cancer Res., September 15, 2007; 67(18): 8444 - 8449. [Abstract] [Full Text] [PDF] T. M. Casey, J. L. Meade, and E. W. Hewitt Organelle Proteomics: Identification of the Exocytic Machinery Associated with the Natural Killer Cell Secretory Lysosome Mol. Cell. Proteomics, May 1, 2007; 6(5): 767 - 780. [Abstract] [Full Text] [PDF] V. R. Sutton, N. J. Waterhouse, K. A. Browne, K. Sedelies, A. Ciccone, D. Anthony, A. Koskinen, A. Mullbacher, and J. A. Trapani Residual active granzyme B in cathepsin C-null lymphocytes is sufficient for perforin-dependent target cell apoptosis J. Cell Biol., February 12, 2007; 176(4): 425 - 433. [Abstract] [Full Text] [PDF]

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