title: A cardinal role for cathepsin d in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci.
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.
authors.affiliation: Medical School, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Bewley
authors.forename: Helen M
authors.initials: HM
authors.lastname: Marriott
authors.forename: Calogero
authors.initials: C
authors.lastname: Tulone
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Francis
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Robert C
authors.initials: RC
authors.lastname: Read
authors.forename: Benny
authors.initials: B
authors.lastname: Chain
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
authors.forename: David H
authors.initials: DH
authors.lastname: Dockrell
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D002402:Cathepsin D / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000201:enzymology / Q000382:microbiology; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D007425:Intracellular Membranes / Q000201:enzymology / Q000382:microbiology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010588:Phagosomes / Q000201:enzymology / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000472:pathogenicity / Q000502:physiology*
chemical_list: D002402:Cathepsin D