Document Detail

ESX-1 secreted virulence factors are recognized by multiple cytosolic AAA ATPases in pathogenic mycobacteria.
MedLine Citation:
PMID:  19682254     Owner:  NLM     Status:  MEDLINE    
The ESX-1 secretion system of Mycobacterium tuberculosis delivers bacterial virulence factors to host cells during infection. The most abundant factor, the ESAT-6/CFP-10 dimer, is targeted for secretion via a C-terminal signal sequence on CFP-10 that is recognized by the cytosolic ATPase, Rv3871. However, the selection determinants for other ESX-1 substrates appear to be more complex. Some substrates, such as ESAT-6, are secreted despite lacking signal sequences. Furthermore, all substrates require targeting of the other ESX-1 secreted proteins, a distinguishing feature of this system. How ESX-1 substrates are selected and the basis for co-dependent secretion is unknown. Here we show that the EspC substrate interacts with Rv3868, a cytosolic AAA ATPase, through its C-terminus. Swapping the C-termini of EspC and CFP-10 revealed that these signals are functionally distinct, suggesting that the proteins are targeted via interactions with different ATPases. Surprisingly, biochemical purification experiments demonstrate that these substrates and ATPases form multi-protein complexes inside the cell and identified a new secreted substrate. By interfering with this protein interaction network, we have partially uncoupled co-dependent substrate secretion. Our results suggest that proper functioning of the ESX-1 pathway requires the interaction of multiple ESX-1 substrates and components prior to their secretion. Ultimately, understanding the details of ESX-1 targeting may allow for engineering of better vaccines to prevent tuberculosis.
Patricia A DiGiuseppe Champion; Matthew M Champion; Paolo Manzanillo; Jeffery S Cox
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-08-04
Journal Detail:
Title:  Molecular microbiology     Volume:  73     ISSN:  1365-2958     ISO Abbreviation:  Mol. Microbiol.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-08-27     Completed Date:  2009-12-03     Revised Date:  2014-09-10    
Medline Journal Info:
Nlm Unique ID:  8712028     Medline TA:  Mol Microbiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  950-62     Citation Subset:  IM    
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MeSH Terms
Adenosine Triphosphatases / metabolism*
Amino Acid Sequence
Antigens, Bacterial / metabolism
Bacterial Proteins / metabolism*
Models, Biological
Molecular Sequence Data
Mycobacterium tuberculosis / metabolism*
Protein Multimerization
Protein Transport
Virulence Factors / metabolism*
Grant Support
Reg. No./Substance:
0/Antigens, Bacterial; 0/Bacterial Proteins; 0/CFP-10 protein, Mycobacterium tuberculosis; 0/ESAT-6 protein, Mycobacterium tuberculosis; 0/Virulence Factors; EC 3.6.1.-/Adenosine Triphosphatases

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