Ribosomal RNA cleavage by the previously unidentified RelS–RelI toxin–antitoxin system controls growth of…

Abstract

Toxin–antitoxin (TA) systems use diverse strategies to control bacterial growth and represent attractive therapeutic targets to fight pathogens. Mycobacterium tuberculosis, the bacterium responsible for human tuberculosis, encodes one of the largest repertoires of TA systems. Here, we applied a bioinformatic pipeline to predict candidate TA systems in mycobacterial genomes and identified Rv2663–Rv2664 (RelS–RelI) as a previously undetected system in M. tuberculosis. We show that the RelS toxin is highly toxic and is inhibited by a unique antitoxin, RelI. The 1.70 Å X-ray crystallographic structure of RelS:RelI shows an unprecedented heterooctameric quaternary TA complex formed by paired tetramers. In each tetramer, RelS toxins are held at each end of a RelI antitoxin dimer. RelI binds across the putative catalytic center of RelS, resulting in occlusion of essential putative target-binding residues. Investigation of the toxic mechanism revealed that RelS is an atypical RelE/ParE-like RNase toxin that inhibits translation by targeting the 30S ribosomal subunit, specifically cleaving the 16S ribosomal RNA between positions C1520 and U1521, a unique site within the anti-Shine–Dalgarno (anti-SD) core region. This work further highlights the anti-SD region as a hot spot for RNase toxins and extends the arsenal of TA systems harnessed by this major pathogen.

Fragment-based drug discovery strategy reveals an unprecedented allosteric binding site in Mycobacterium tuberculosis DNA gyrase
Sabrina Tami Shiroma, Nicolas de Oliveira Rossini, Jillian F Armenia +5
European Journal of Medicinal Chemistry29 Sep 2026Peer-reviewedPublisher termsFull textStructural biology MicrobiologyHAL
X-ray crystallographic fragment screening reveals novel and conformationally dynamic ligand-binding sites in Mycobacterium tuberculosis FtsZ
K. R. Meeks, E. O. Lazo, D. F. Kreitler
bioRxiv1 Sep 2026PreprintCC0Full textBiophysicsbioRxiv
Mycobacterium tuberculosis gene expression dynamics in host environments with single-cell resolution
Beren Aylan, Laure Botella, Pierre Santucci +5
Cell Reports Methods5 Oct 2026Peer-reviewedCC BY 4.0Full textProteomics & metabolomics MicrobiologyHAL
ESX-5 paralog deletions in Mycobacterium tuberculosis alter macrophage cytokine signaling and bacterial heavy metal response
Austin M. Haynes, Sara B. Cohen, Venkata Aparajita Pesaladinne +4
iScience29 Oct 2026Peer-reviewedCC BY-NC-ND 4.0Full textMolecular biology & gene regulation ImmunologyCell PressCrossrefEurope PMC
Advancing Tuberculosis Antigen Detection by Selecting Sandwich-Compatible Aptamers Against the Mycobacterium tuberculosis ESAT-6/CFP-10 Heterodimer Using Library-Immobilized Strategies.
Shaira Jane Acosta, M Carmen Bermudo Redondo, Lucie Mužíková Čechová +3
ACS infectious diseases1 Oct 2026Peer-reviewedCC BYFull textMolecular biology & gene regulationEurope PMC

Cite

BibTeX RIS

BibTeX

@article{han2026ribosomal,
  title = {{Ribosomal RNA cleavage by the previously unidentified RelS–RelI toxin–antitoxin system controls growth of Mycobacterium tuberculosis}},
  author = {Xue Han and Tom J Arrowsmith and Svetlana Karamycheva and Xibing Xu and Michèle Coddeville and Carine Pagès and Bertille Voisin and Claude Gutierrez and Olivier Neyrolles and Kira S Makarova and Tim R Blower and Pierre Genevaux},
  journal = {Nucleic Acids Research},
  year = {2026},
  month = jul,
  doi = {10.1093/nar/gkag571},
  url = {https://hal.science/hal-05772568v1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Ribosomal RNA cleavage by the previously unidentified RelS–RelI toxin–antitoxin system controls growth of Mycobacterium tuberculosis
AU  - Xue Han
AU  - Tom J Arrowsmith
AU  - Svetlana Karamycheva
AU  - Xibing Xu
AU  - Michèle Coddeville
AU  - Carine Pagès
AU  - Bertille Voisin
AU  - Claude Gutierrez
AU  - Olivier Neyrolles
AU  - Kira S Makarova
AU  - Tim R Blower
AU  - Pierre Genevaux
PY  - 2026
DA  - 2026/07/08
JO  - Nucleic Acids Research
DO  - 10.1093/nar/gkag571
UR  - https://hal.science/hal-05772568v1
AB  - Toxin–antitoxin (TA) systems use diverse strategies to control bacterial growth and represent attractive therapeutic targets to fight pathogens. Mycobacterium tuberculosis, the bacterium responsible for human tuberculosis, encodes one of the largest repertoires of TA systems. Here, we applied a bioinformatic pipeline to predict candidate TA systems in mycobacterial genomes and identified Rv2663–Rv2664 (RelS–RelI) as a previously undetected system in M. tuberculosis. We show that the RelS toxin is highly toxic and is inhibited by a unique antitoxin, RelI. The 1.70 Å X-ray crystallographic structure of RelS:RelI shows an unprecedented heterooctameric quaternary TA complex formed by paired tetramers. In each tetramer, RelS toxins are held at each end of a RelI antitoxin dimer. RelI binds across the putative catalytic center of RelS, resulting in occlusion of essential putative target-binding residues. Investigation of the toxic mechanism revealed that RelS is an atypical RelE/ParE-like RNase toxin that inhibits translation by targeting the 30S ribosomal subunit, specifically cleaving the 16S ribosomal RNA between positions C1520 and U1521, a unique site within the anti-Shine–Dalgarno (anti-SD) core region. This work further highlights the anti-SD region as a hot spot for RNase toxins and extends the arsenal of TA systems harnessed by this major pathogen.
SN  - 0305-1048
SN  - 1362-4962
ER  -

Abstract

Related

Cite