Monday, 18th November, 2024
Xue Han will present their research on the study of the molecular mechanisms and the cellular targets of M. tuberculosis RelE-like toxins.
Abstract :
The bacterium Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis (TB), is a major public health problem. More than 10 million people continue to be infected with TB each year (Global Tuberculosis Report 2023). The increasing occurrence of multi-drug resistant and extensively drug-resistant M. tuberculosis strains has greatly heightened the need for the development of new drugs and new treatment strategies. Remarkably, about 4% of the M. tuberculosis genes encode for stress-responsive toxin-antitoxin (TA) systems (i.e., over 88 chromosomal two-component TAs are found in H37Rv strain). Such an unusually high number of TAs largely exceeds the number of TAs found in other mycobacteria. Although their function is poorly understood, toxins of toxin-antitoxin systems potentially represent stress activable intracellular weapons that could play key roles in the physiology or virulence of M. tuberculosis.
In this thesis we have investigated the toxic mechanism of two highly deleterious toxins of M. tuberculosis TA systems, which likely belong to a large family of toxic Rel ribonucleases that use diverse mechanisms to control growth of the pathogen. We show that both Rel toxins of M. tuberculosis function as RNase that efficiently inhibit translation by specifically targeting the 30S small ribosomal subunit, both in vivo and in vitro. In addition, we solved the structures of both toxins in complex with their cognate antitoxins, which allow the identification of residues essential for catalysis or for toxin inhibition. The impact of such discoveries on the physiology and virulence of M. tuberculosis is discussed.