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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
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.
1553-7366
e1001262
Bewley, Martin A.
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Marriott, Helen M.
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Tulone, Calogero
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Francis, Sheila E.
95fa0ffb-4ed9-4d07-8b2a-d3ebff07499e
Mitchell, Timothy J.
56ddfd4d-d6f7-4250-8864-17f156904f95
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Chain, Benny
c83e3462-a8af-446b-9533-3bf440d0a6a3
Kroemer, Guido
b8513b5d-ef12-460c-b8c5-7c8eb08f9f26
Whyte, Moira K.B.
7c8b9870-17db-4359-ac5c-57ba9197ed82
Dockrell, David H.
a068c9bf-35b8-4c10-8f91-58639cfeca0b
Bewley, Martin A.
1412f184-67e0-4fe7-8692-db253d411471
Marriott, Helen M.
34ca8904-d637-4081-b34c-12be45ecef9f
Tulone, Calogero
610d59c8-c094-4a33-b1be-c8ba5323ac9c
Francis, Sheila E.
95fa0ffb-4ed9-4d07-8b2a-d3ebff07499e
Mitchell, Timothy J.
56ddfd4d-d6f7-4250-8864-17f156904f95
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Chain, Benny
c83e3462-a8af-446b-9533-3bf440d0a6a3
Kroemer, Guido
b8513b5d-ef12-460c-b8c5-7c8eb08f9f26
Whyte, Moira K.B.
7c8b9870-17db-4359-ac5c-57ba9197ed82
Dockrell, David H.
a068c9bf-35b8-4c10-8f91-58639cfeca0b

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. and Dockrell, David H. (2011) A cardinal role for cathepsin d in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci. PLOS Pathogens, 7 (1), e1001262. (doi:10.1371/journal.ppat.1001262).

Record type: Article

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.

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Published date: January 2011
Organisations: Clinical & Experimental Sciences

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Local EPrints ID: 346760
URI: http://eprints.soton.ac.uk/id/eprint/346760
ISSN: 1553-7366
PURE UUID: 4991d826-1fe1-4f91-aac8-44a5324028f9
ORCID for Robert C. Read: ORCID iD orcid.org/0000-0002-4297-6728

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Date deposited: 09 Jan 2013 11:37
Last modified: 15 Mar 2024 03:42

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Contributors

Author: Martin A. Bewley
Author: Helen M. Marriott
Author: Calogero Tulone
Author: Sheila E. Francis
Author: Timothy J. Mitchell
Author: Robert C. Read ORCID iD
Author: Benny Chain
Author: Guido Kroemer
Author: Moira K.B. Whyte
Author: David H. Dockrell

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