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

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.

Pubmed ID: 21298030

Authors

  • Bewley MA
  • Marriott HM
  • Tulone C
  • Francis SE
  • Mitchell TJ
  • Read RC
  • Chain B
  • Kroemer G
  • Whyte MK
  • Dockrell DH

Journal

PLoS pathogens

Publication Data

February 7, 2011

Associated Grants

  • Agency: Wellcome Trust, Id: 076945
  • Agency: Biotechnology and Biological Sciences Research Council, Id: BB/D005469/1
  • Agency: Medical Research Council, Id:

Mesh Terms

  • Animals
  • Apoptosis
  • Bone Marrow Cells
  • Bone Marrow Transplantation
  • Cathepsin D
  • Cell Line, Tumor
  • Cytosol
  • Female
  • Host-Pathogen Interactions
  • Humans
  • Intracellular Membranes
  • Macrophages
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phagosomes
  • Streptococcus pneumoniae