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Cancer cells employ various mechanisms to inactivate cellular tumor suppressors, including epigenetic silencing and mutagenesis. Less understood are the mechanisms by which cancer cells inactivate tumor suppressors post-translationally. Here, we uncovered a previously undescribed post-translational mechanism by which cancer cells inactivate the potent mitochondrial tumor suppressor LACTB in breast cancers. We discovered that the substrate of LACTB can be LACTB itself; LACTB possesses autoproteolytic activity, which is important for modulating its tumor suppressor activity. We demonstrate that cancer cells exploit this feature of LACTB to induce LACTB\u2019s self-degradation. This is mechanistically realized through upregulation of mitochondrial MRPS34 protein, which, through interaction with LACTB, is a positive regulator of LACTB\u2019s autoproteolytic activity and a negative regulator of LACTB. This study provides insights into how cancer cells fine-tune the expression and activity of tumor suppressors to promote tumorigenesis.<\/jats:p>","DOI":"10.1038\/s44319-026-00936-9","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T14:22:49Z","timestamp":1790432569000},"page":"6342-6365","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The role of autoproteolysis and mitoribosomal proteins in the regulation of the mitochondrial LACTB tumor suppressor"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1542-7408","authenticated-orcid":false,"given":"Sara","family":"Escudeiro-Lopes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2932-0756","authenticated-orcid":false,"given":"Juan M","family":"Gonzalez-Morena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alzbeta","family":"Baudysova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Svoboda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Marasek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Rodriguez-Gomez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Ferreira Mendes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4619-8895","authenticated-orcid":false,"given":"Chung Weng","family":"Phang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7643-5033","authenticated-orcid":false,"given":"Sravan","family":"Kumar Miryala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5422-4136","authenticated-orcid":false,"given":"Pavel","family":"Jakoube","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Kovarova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3152-1701","authenticated-orcid":false,"given":"Susana","family":"Machado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiong","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3374-6266","authenticated-orcid":false,"given":"Zuzana","family":"Keckesova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"936_CR1","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1126\/science.aaa1193","volume":"348","author":"A Amunts","year":"2015","unstructured":"Amunts A, Brown A, Toots J, Scheres SHW, Ramakrishnan V (2015) The structure of the human mitochondrial ribosome. 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