A cardinal role for cathepsin d in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

Bewley, M. A., Marriott, H. M., Tulone, C., Francis, S. E., Mitchell, T. J., Read, R. C., Chain, B., Kroemer, G., Whyte, M. K. B. and Dockrell, D. H. (2011) A cardinal role for cathepsin d in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci. PLoS pathogens, 7 (1). Article no. e1001262. ISSN 1553-7374

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Abstract

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D(-/-) hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function.

Item Type:	Article
Copyright, Publisher and Additional Information:	© 2011 Bewley et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield)
Depositing User:	Miss Anthea Tucker
Date Deposited:	29 Mar 2012 09:40
Last Modified:	08 Feb 2013 17:37
Published Version:	http://dx.doi.org/10.1371/journal.ppat.1001262
Status:	Published
Publisher:	Public Library of Science
Refereed:	Yes
Identification Number:	10.1371/journal.ppat.1001262
Related URLs:	PubMed URL
URI:	http://eprints.whiterose.ac.uk/id/eprint/43793

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