PLoS Pathogens | |
A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci | |
Moira K. B. Whyte1  Calogero Tulone2  Benny Chain2  Guido Kroemer3  Timothy J. Mitchell4  Martin A. Bewley5  Sheila E. Francis5  Robert C. Read5  Helen M. Marriott5  David H. Dockrell6  | |
[1] Centre de Recherche des Cordeliers, Paris, France;Division of Infection and Immunity, University College London, London, United Kingdom;INSERM U848, Metabolomics Platform, Institut Gustave Roussy, Villejuif, France;Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom;Medical School, University of Sheffield, Sheffield, United Kingdom;Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France | |
关键词: Apoptosis; Macrophages; Cell differentiation; Lysosomes; Neutrophils; Alveolar macrophages; Mitochondria; Bone marrow transplantation; | |
DOI : 10.1371/journal.ppat.1001262 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
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.
【 授权许可】
CC BY
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
RO201902014807936ZK.pdf | 915KB | download |