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.
journal_name
PLoS Pathogjournal_title
PLoS pathogensauthors
Bewley MA,Marriott HM,Tulone C,Francis SE,Mitchell TJ,Read RC,Chain B,Kroemer G,Whyte MK,Dockrell DHdoi
10.1371/journal.ppat.1001262subject
Has Abstractpub_date
2011-01-27 00:00:00pages
e1001262issue
1eissn
1553-7366issn
1553-7374journal_volume
7pub_type
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