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

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

Blog Article

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, Famil-E 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 Automotive 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.