T cell toxicity induced by tigecycline binding to the mitochondrial ribosome
Abstract Tetracyclines are essential bacterial protein synthesis inhibitors under continual development to combat antibiotic resistance yet suffer from unwanted side effects. Mitoribosomes - responsible for generating oxidative phosphorylation (OXPHOS) subunits - share structural similarities with b...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59388-9 |
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| author | Qiuya Shao Anas Khawaja Minh Duc Nguyen Vivek Singh Jingdian Zhang Yong Liu Joel Nordin Monika Adori C. Axel Innis Xaquin Castro Dopico Joanna Rorbach |
| author_facet | Qiuya Shao Anas Khawaja Minh Duc Nguyen Vivek Singh Jingdian Zhang Yong Liu Joel Nordin Monika Adori C. Axel Innis Xaquin Castro Dopico Joanna Rorbach |
| author_sort | Qiuya Shao |
| collection | DOAJ |
| description | Abstract Tetracyclines are essential bacterial protein synthesis inhibitors under continual development to combat antibiotic resistance yet suffer from unwanted side effects. Mitoribosomes - responsible for generating oxidative phosphorylation (OXPHOS) subunits - share structural similarities with bacterial machinery and may suffer from cross-reactivity. Since lymphocytes rely upon OXPHOS upregulation to establish immunity, we set out to assess the impact of ribosome-targeting antibiotics on human T cells. We find tigecycline, a third-generation tetracycline, to be the most cytotoxic compound tested. In vitro, 5–10 μM tigecycline inhibits mitochondrial but not cytosolic translation, mitochondrial complex I, III and IV expression, and curtails the activation and expansion of unique T cell subsets. By cryo-EM, we find tigecycline to occupy three sites on T cell mitoribosomes. In addition to the conserved A-site found in bacteria, tigecycline also attaches to the peptidyl transferase center of the large subunit. Furthermore, a third, distinct binding site on the large subunit, aligns with helices analogous to those in bacteria, albeit lacking methylation in humans. The data provide a mechanism to explain part of the anti-inflammatory effects of these drugs and inform antibiotic design. |
| format | Article |
| id | doaj-art-e532be8fc8144233af66616996fe94f8 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e532be8fc8144233af66616996fe94f82025-08-20T02:10:54ZengNature PortfolioNature Communications2041-17232025-05-0116111310.1038/s41467-025-59388-9T cell toxicity induced by tigecycline binding to the mitochondrial ribosomeQiuya Shao0Anas Khawaja1Minh Duc Nguyen2Vivek Singh3Jingdian Zhang4Yong Liu5Joel Nordin6Monika Adori7C. Axel Innis8Xaquin Castro Dopico9Joanna Rorbach10Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Laboratory Medicine, Karolinska InstitutetDepartment of Laboratory Medicine, Karolinska InstitutetDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetARNA Laboratory, Univ. Bordeaux, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche MédicaleDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetAbstract Tetracyclines are essential bacterial protein synthesis inhibitors under continual development to combat antibiotic resistance yet suffer from unwanted side effects. Mitoribosomes - responsible for generating oxidative phosphorylation (OXPHOS) subunits - share structural similarities with bacterial machinery and may suffer from cross-reactivity. Since lymphocytes rely upon OXPHOS upregulation to establish immunity, we set out to assess the impact of ribosome-targeting antibiotics on human T cells. We find tigecycline, a third-generation tetracycline, to be the most cytotoxic compound tested. In vitro, 5–10 μM tigecycline inhibits mitochondrial but not cytosolic translation, mitochondrial complex I, III and IV expression, and curtails the activation and expansion of unique T cell subsets. By cryo-EM, we find tigecycline to occupy three sites on T cell mitoribosomes. In addition to the conserved A-site found in bacteria, tigecycline also attaches to the peptidyl transferase center of the large subunit. Furthermore, a third, distinct binding site on the large subunit, aligns with helices analogous to those in bacteria, albeit lacking methylation in humans. The data provide a mechanism to explain part of the anti-inflammatory effects of these drugs and inform antibiotic design.https://doi.org/10.1038/s41467-025-59388-9 |
| spellingShingle | Qiuya Shao Anas Khawaja Minh Duc Nguyen Vivek Singh Jingdian Zhang Yong Liu Joel Nordin Monika Adori C. Axel Innis Xaquin Castro Dopico Joanna Rorbach T cell toxicity induced by tigecycline binding to the mitochondrial ribosome Nature Communications |
| title | T cell toxicity induced by tigecycline binding to the mitochondrial ribosome |
| title_full | T cell toxicity induced by tigecycline binding to the mitochondrial ribosome |
| title_fullStr | T cell toxicity induced by tigecycline binding to the mitochondrial ribosome |
| title_full_unstemmed | T cell toxicity induced by tigecycline binding to the mitochondrial ribosome |
| title_short | T cell toxicity induced by tigecycline binding to the mitochondrial ribosome |
| title_sort | t cell toxicity induced by tigecycline binding to the mitochondrial ribosome |
| url | https://doi.org/10.1038/s41467-025-59388-9 |
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