Edinburgh Research Explorer

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

Research output: Contribution to journalArticle

Related Edinburgh Organisations

Open Access permissions

Open

Documents

  • Download as Adobe PDF

    Rights statement: Copyright: © 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.

    Final published version, 909 KB, PDF document

    Licence: Creative Commons: Attribution (CC-BY)

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001262
Original languageEnglish
Article number1001262
Number of pages17
JournalPlos Pathogens
Volume7
Issue number1
DOIs
Publication statusPublished - 27 Jan 2011

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.

    Research areas

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

Download statistics

No data available

ID: 17165439