A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci

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 Dockrell

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1001262
Number of pages17
JournalPLoS Pathogens
Volume7
Issue number1
DOIs
Publication statusPublished - 27 Jan 2011

Keywords

  • LYSOSOMAL MEMBRANE PERMEABILIZATION
  • BONE-MARROW-TRANSPLANTATION
  • HUMAN ALVEOLAR MACROPHAGES
  • CELL-DEATH
  • STREPTOCOCCUS-PNEUMONIAE
  • NEUTROPHIL RECRUITMENT
  • PULMONARY INFECTION
  • OXIDATIVE STRESS
  • NITRIC-OXIDE
  • MCL-1

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