Reconstitution of a Mycobacterium tuberculosis proteostasis network highlights essential cofactor interactions with chaperone DnaK

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Abstract
Significance: The proteostasis pathway may be a source of new drug targets in Mycobacterium tuberculosis (Mtb). The conserved protein chaperone DnaK is essential in Mycobacterium smegmatis and predicted to be essential in Mtb. DnaK is regulated by cofactors, J proteins and nucleotide exchange factor GrpE. In contrast to most bacterial pathogens, Mtb has two J proteins, DnaJ1 and DnaJ2. Here, we characterize in vitro activities of Mtb DnaK, DnaJ1, DnaJ2, and GrpE, the disaggregase ClpB, and the small heat shock protein Hsp20, in reactivation of a protein aggregate. We found that DnaJ1 and DnaJ2 are individually dispensable, but collectively essential and mutations in a conserved motif of each result in cellular loss of function. These findings will help in identifying and characterizing inhibitors of Mtb’s proteostasis network.
Funding Information
  • HHS | NIH | National Institute of Allergy and Infectious Diseases (U19 AI111143-01)
  • HHS | NIH | National Cancer Institute (P30CA008748)
  • HHS | NIH | National Cancer Institute (T32 CA009149)
  • Bill and Melinda Gates Foundation (none)
  • Hearst Foundations (none)
  • Helen Hay Whitney Foundation (none)
  • Simons Foundation (none)

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