| A cardinal role for cathepsin d in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci. | |
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MedLine Citation:
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PMID: 21298030 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Martin A Bewley; Helen M Marriott; Calogero Tulone; Sheila E Francis; Timothy J Mitchell; Robert C Read; Benny Chain; Guido Kroemer; Moira K B Whyte; David H Dockrell |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-01-27 |
Journal Detail:
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Title: PLoS pathogens Volume: 7 ISSN: 1553-7374 ISO Abbreviation: PLoS Pathog. Publication Date: 2011 |
Date Detail:
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Created Date: 2011-02-07 Completed Date: 2011-05-05 Revised Date: 2011-07-25 |
Medline Journal Info:
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Nlm Unique ID: 101238921 Medline TA: PLoS Pathog Country: United States |
Other Details:
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Languages: eng Pagination: e1001262 Citation Subset: IM |
Affiliation:
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Medical School, University of Sheffield, Sheffield, United Kingdom. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* Bone Marrow Cells Bone Marrow Transplantation Cathepsin D / deficiency, genetics, metabolism* Cell Line, Tumor Cytosol / enzymology, microbiology Female Host-Pathogen Interactions Humans Intracellular Membranes / enzymology, microbiology Macrophages / enzymology*, immunology, microbiology Mice Mice, Inbred C57BL Mice, Knockout Phagosomes / enzymology, microbiology Streptococcus pneumoniae / pathogenicity, physiology* |
| Grant Support | |
ID/Acronym/Agency:
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076945//Wellcome Trust; BB/D005469/1//Biotechnology and Biological Sciences Research Council; //Medical Research Council |
| Chemical | |
Reg. No./Substance:
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EC 3.4.23.5/Cathepsin D |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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