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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\u2013Rv2664 (RelS\u2013RelI) 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 \u00c5 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\u2013Dalgarno (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.<\/jats:p>","DOI":"10.1093\/nar\/gkag571","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T11:51:25Z","timestamp":1781869885000},"source":"Crossref","is-referenced-by-count":0,"title":["Ribosomal RNA cleavage by the previously unidentified RelS\u2013RelI toxin\u2013antitoxin system controls growth of\n                    <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1093","volume":"54","author":[{"given":"Xue","family":"Han","sequence":"first","affiliation":[{"name":"Laboratoire de Microbiologie et G\u00e9n\u00e9tique Mol\u00e9culaires, Centre de Biologie Int\u00e9grative, Universit\u00e9 de Toulouse, CNRS , Toulouse 31062 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom J","family":"Arrowsmith","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Durham University , Stockton Road, Durham DH1 3LE ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9653-8910","authenticated-orcid":false,"given":"Svetlana","family":"Karamycheva","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Library of Medicine, National Institutes of Health , 8600 Rockville Pike, Bethesda, MD 20894 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xibing","family":"Xu","sequence":"additional","affiliation":[{"name":"Laboratoire de Microbiologie et G\u00e9n\u00e9tique Mol\u00e9culaires, Centre de Biologie Int\u00e9grative, Universit\u00e9 de Toulouse, CNRS , Toulouse 31062 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mich\u00e8le","family":"Coddeville","sequence":"additional","affiliation":[{"name":"Laboratoire de Microbiologie et G\u00e9n\u00e9tique 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