Document Detail

Mycobacterium's arrest of phagosome maturation in macrophages requires Rab5 activity and accessibility to iron.
MedLine Citation:
PMID:  12925769     Owner:  NLM     Status:  MEDLINE    
Many mycobacteria are intramacrophage pathogens that reside within nonacidified phagosomes that fuse with early endosomes but do not mature to phagolysosomes. The mechanism by which mycobacteria block this maturation process remains elusive. To gain insight into whether fusion with early endosomes is required for mycobacteria-mediated inhibition of phagosome maturation, we investigated how perturbing the GTPase cycles of Rab5 and Rab7, GTPases that regulate early and late endosome fusion, respectively, would affect phagosome maturation. Retroviral transduction of the constitutively activated forms of both GTPases into primary murine macrophages had no effect on Mycobacterium avium retention in an early endosomal compartment. Interestingly, expression of dominant negative Rab5, Rab5(S34N), but not dominant negative Rab7, resulted in a significant increase in colocalization of M. avium with markers of late endosomes/lysosomes and increased mycobacterial killing. This colocalization was specific to mycobacteria since Rab5(S34N) expressing cells showed diminished trafficking of endocytic tracers to lysosomes. We further demonstrated that maturation of M. avium phagosomes was halted in Rab5(S34N) expressing macrophages supplemented with exogenous iron. These findings suggest that fusion with early endosomes is required for mycobacterial retention in early phagosomal compartments and that an inadequate supply of iron is one factor in mycobacteria's inability to prevent the normal maturation process in Rab5(S34N)-expressing macrophages.
Victoria A Kelley; Jeffrey S Schorey
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2003-05-18
Journal Detail:
Title:  Molecular biology of the cell     Volume:  14     ISSN:  1059-1524     ISO Abbreviation:  Mol. Biol. Cell     Publication Date:  2003 Aug 
Date Detail:
Created Date:  2003-08-19     Completed Date:  2004-05-25     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  9201390     Medline TA:  Mol Biol Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3366-77     Citation Subset:  IM    
Department of Biological Sciences, Center of Tropical Disease Research and Training, University of Notre Dame, Notre Dame, Indiana 46556, USA.
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MeSH Terms
Bone Marrow Cells / metabolism*,  microbiology
Cells, Cultured
Cloning, Molecular
Endosomes / metabolism,  microbiology
Iron / metabolism*
Macrophages / cytology*,  metabolism,  microbiology
Mice, Inbred BALB C
Mutation / genetics
Mycobacterium avium / metabolism*
Phagosomes / metabolism*,  microbiology
Transport Vesicles
rab GTP-Binding Proteins / genetics,  metabolism*
rab5 GTP-Binding Proteins / genetics,  metabolism*
Reg. No./Substance:
7439-89-6/Iron; EC 3.6.1.-/rab GTP-Binding Proteins; EC GTP-Binding Proteins

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