The University of Southampton
University of Southampton Institutional Repository

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.
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.
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.

Other
fetchObject.action_uri=info_doi%2F10.1371%2Fjournal.ppat.1001262&representation=PDF - Version of Record
Available under License Other.
Download (937kB)

More information

Published date: January 2011
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 346760
URI: https://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

Catalogue record

Date deposited: 09 Jan 2013 11:37
Last modified: 29 Oct 2019 01:40

Export record

Altmetrics

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

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×