ClpXP-mediated Degradation of the TAC Antitoxin is Neutralized by the SecB-like Chaperone in Mycobacterium tuberculosis

J Mol Biol. 2021 Mar 5;433(5):166815. doi: 10.1016/j.jmb.2021.166815. Epub 2021 Jan 13.


Bacterial toxin-antitoxin (TA) systems are composed of a deleterious toxin and its antagonistic antitoxin. They are widespread in bacterial genomes and mobile genetic elements, and their functions remain largely unknown. Some TA systems, known as TAC modules, include a cognate SecB-like chaperone that assists the antitoxin in toxin inhibition. Here, we have investigated the involvement of proteases in the activation cycle of the TAC system of the human pathogen Mycobacterium tuberculosis. We show that the deletion of endogenous AAA+ proteases significantly bypasses the need for a dedicated chaperone and identify the mycobacterial ClpXP1P2 complex as the main protease involved in TAC antitoxin degradation. In addition, we show that the ClpXP1P2 degron is located at the extreme C-terminal end of the chaperone addiction (ChAD) region of the antitoxin, demonstrating that ChAD functions as a hub for both chaperone binding and recognition by proteases.

Keywords: ClpC1; ClpX; HigB1-HigA1; SecB; Toxin-antitoxin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics*
  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Cloning, Molecular
  • Endopeptidase Clp / genetics*
  • Endopeptidase Clp / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Escherichia coli Proteins / genetics*
  • Escherichia coli Proteins / metabolism
  • Gene Expression
  • Gene Expression Regulation, Bacterial*
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • Genome, Bacterial
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / metabolism
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proteolysis
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Toxin-Antitoxin Systems / genetics*


  • Bacterial Proteins
  • Escherichia coli Proteins
  • HigA protein, E coli
  • HigB protein, E coli
  • Molecular Chaperones
  • Protein Isoforms
  • Recombinant Proteins
  • SecB protein, Bacteria
  • ClpP protease, E coli
  • Endopeptidase Clp
  • ClpX protein, E coli
  • ATPases Associated with Diverse Cellular Activities