PLoS Pathog 2011,
PMID: 21298030
Bewley, Martin A; Marriott, Helen M; Tulone, Calogero; Francis, Sheila E; Mitchell, Timothy J; Read, Robert C; Chain, Benny; Kroemer, Guido; Whyte, Moira K B; Dockrell, David H
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.
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Text Mining Data
Mule → cathepsin D: "
As a
result of
cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase
Mule and expression declined
"
Mcl-1 → cathepsin D: "
As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined
"
Manually curated Databases
-
IRef Biogrid Interaction:
HSPA4
—
MCL1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
HSPA4
—
HUWE1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
HUWE1
—
MCL1
(physical association, affinity chromatography technology)
In total, 3 gene pairs are associated to this article in curated databases