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

Control of Toxin-Antitoxin Systems by Proteases in Mycobacterium Tuberculosis

“…shown to be the recognition sequence of HigA1 by ClpX in M. tuberculosis (Texier et al, 2021). Noticeably, the Rv2017 antitoxin contains a ClpX-like degron with two hydrophobic residues located at its extreme C-terminal part (Ala-Ile), suggesting that it could also be recognized by ClpX.…”

“…It is striking that when we applied similar search for disordered C-terminal ends, we found that more than 60% of the antitoxins of M. tuberculosis possess this type of C-terminal region, thus suggesting that disordered C-terminal ends could indeed contribute to recognition by proteases. Note that a table presenting the C-terminal ends of all known M. tuberculosis antitoxins can be found in Texier and colleagues (Texier et al, 2021). The HigA1 antitoxin possesses a typical C-terminal ClpX degron with two crucial hydrophobic last residues Val-Ala that were recently FIGURE 1 | Proteolytic regulation and recognition of Toxin-Antitoxin systems in M. tuberculosis.…”

“…Depletion of clpP1P2, clpP2 or clpC1 (Raju et al, 2014;Lunge et al, 2020): orange dots mean protein stabilization and grey dots mean no detectable protein changes. In vitro degradation assays (Ziemski et al, 2020;Texier et al, 2021): orange dots mean degradation. Pupylation: orange dots mean pupylated under routine culture conditions (Festa et al, 2010), red dots mean pupylated by reconstituted system in E. coli and/or in vitro (Chi et al, 2018).…”

“…Note that VapC20 or RelE1 toxin form stable complexes with their cognate antitoxin in which the antitoxin is protected from degradation, further raising questions about how the toxin could be freed from the antitoxin in order to be activated (see above comments). Interestingly, the HigA1 degron has been the only ClpXdependent recognition sequence identified so far for a mycobacterial antitoxin (Texier et al, 2021). HigA1 is part of the tripartite toxin-antitoxin-chaperone (TAC) system of M. tuberculosis that includes a cognate SecB-like chaperone (SecB TA ).…”

“…This suggests that these antitoxins could also be recognized by M. tuberculosis ClpX. In addition, five poorly conserved VapB antitoxins (VapB19, VapB23, VapB28, VapB30 and VapB34) share a highly similar extreme C-terminus, with hydrophobic residues following an arginine (Arg-Gly-Leu-Pro-Ala-Pro, Arg-Gly-Leu-Pro-Ala or Arg-Leu-Gly-Leu-Ala motifs), suggesting that these antitoxins could share similar degrons (Texier et al, 2021).…”