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Title: Nonredundant functions of Mycobacterium tuberculosis chaperones promote survival under stress
Abstract

Bacterial chaperones ClpB and DnaK, homologs of the respective eukaryotic heat shock proteins Hsp104 and Hsp70, are essential in the reactivation of toxic protein aggregates that occur during translation or periods of stress. In the pathogenMycobacterium tuberculosis(Mtb), the protective effect of chaperones extends to survival in the presence of host stresses, such as protein‐damaging oxidants. However, we lack a full understanding of the interplay of Hsps and other stress response genes in mycobacteria. Here, we employ genome‐wide transposon mutagenesis to identify the genes that supportclpBfunction in Mtb. In addition to validating the role of ClpB in Mtb's response to oxidants, we show that HtpG, a homolog of Hsp90, plays a distinct role from ClpB in the proteotoxic stress response. While loss of neitherclpBnorhtpGis lethal to the cell, loss of both through genetic depletion or small molecule inhibition impairs recovery after exposure to host‐like stresses, especially reactive nitrogen species. Moreover, defects in cells lackingclpBcan be complemented by overexpression of other chaperones, demonstrating that Mtb's stress response network depends upon finely tuned chaperone expression levels. These results suggest that inhibition of multiple chaperones could work in concert with host immunity to disable Mtb.

 
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NSF-PAR ID:
10453917
Author(s) / Creator(s):
 ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  
Publisher / Repository:
Wiley-Blackwell
Date Published:
Journal Name:
Molecular Microbiology
Volume:
115
Issue:
2
ISSN:
0950-382X
Page Range / eLocation ID:
p. 272-289
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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