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

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. © 2011 bewley et al.