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First published online 24 July 2007
doi: 10.1242/jcs.006221

Journal of Cell Science 120, 2796-2806 (2007)
Published by The Company of Biologists 2007
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Research Article

Lipoamide dehydrogenase mediates retention of coronin-1 on BCG vacuoles, leading to arrest in phagosome maturation

Ala-Eddine Deghmane1, Hafid Soualhine1, Horacio Bach1, Khalid Sendide2, Saotomo Itoh3, Andrea Tam1, Sanaa Noubir1, Amina Talal1, Raymond Lo4, Satoshi Toyoshima3, Yossef Av-Gay1 and Zakaria Hmama1,*

1 Division of Infectious Diseases, Department of Medicine, University of British Columbia and Vancouver Costal Health Institute, Vancouver, British Columbia, V5Z 3J5, Canada
2 School of Science and Engineering, Al Akhawayn University, PO Box 104, HII Ave, Ifrane 53 000, Morocco
3 Department of Biochemisty, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
4 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada

* Author for correspondence (e-mail: hmama{at}interchange.ubc.ca)

Accepted 4 June 2007

Mycobacterium tuberculosis evades the innate antimicrobial defenses of macrophages by inhibiting the maturation of its phagosome to a bactericidal phagolysosome. Despite intense studies of the mycobacterial phagosome, the mechanism of mycobacterial persistence dependent on prolonged phagosomal retention of the coat protein coronin-1 is still unclear. The present study demonstrated that several mycobacterial proteins traffic intracellularly in M. bovis BCG-infected cells and that one of them, with an apparent subunit size of Mr 50,000, actively retains coronin-1 on the phagosomal membrane. This protein was initially termed coronin-interacting protein (CIP)50 and was shown to be also expressed by M. tuberculosis but not by the non-pathogenic species M. smegmatis. Cell-free system experiments using a GST-coronin-1 construct showed that binding of CIP50 to coronin-1 required cholesterol. Thereafter, mass spectrometry sequencing identified mycobacterial lipoamide dehydrogenase C (LpdC) as a coronin-1 binding protein. M. smegmatis over-expressing Mtb LpdC protein acquired the capacity to maintain coronin-1 on the phagosomal membrane and this prolonged its survival within the macrophage. Importantly, IFN{gamma}-induced phagolysosome fusion in cells infected with BCG resulted in the dissociation of the LpdC-coronin-1 complex by a mechanism dependent, at least in part, on IFN{gamma}-induced LRG-47 expression. These findings provide further support for the relevance of the LpdC-coronin-1 interaction in phagosome maturation arrest.

Key words: Macrophage, Phagosome biogenesis, Mycobacterium tuberculosis, Mycobacterium smegmatis, IFN{gamma}, LRG-47






© The Company of Biologists Ltd 2007