Nonredundant functions of Mycobacterium tuberculosis chaperones promote survival under stress

Alexa Harnagel, Landys Lopez Quezada, Sae Woong Park, Catherine Baranowski, Karen Kieser, Xiuju Jiang, Julia Roberts, Julien Vaubourgeix, Amy Yang, Brock Nelson, Allison Fay, Eric Rubin, Sabine Ehrt, Carl Nathan, Tania J. Lupoli

Research output: Contribution to journalArticlepeer-review


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 pathogen Mycobacterium 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 support clpB function 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 neither clpB nor htpG is 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 lacking clpB can 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.

Original languageEnglish (US)
Pages (from-to)272-289
Number of pages18
JournalMolecular Microbiology
Issue number2
StatePublished - Feb 2021


  • ClpB
  • Mycobacterium tuberculosis
  • chaperone
  • heat shock protein
  • oxidant
  • proteostasis

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology


Dive into the research topics of 'Nonredundant functions of Mycobacterium tuberculosis chaperones promote survival under stress'. Together they form a unique fingerprint.

Cite this