The Mycobacterium ulcerans toxin mycolactone causes destructive Sec61-dependent loss of the endothelial glycocalyx and vessel basement membrane to drive skin necrosis
The drivers of tissue necrosis in Mycobacterium ulcerans infection (Buruli ulcer disease) have historically been ascribed solely to the directly cytotoxic action of the diffusible exotoxin, mycolactone. However, its role in the clinically evident vascular component of disease aetiology remains poorl...
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eLife Sciences Publications Ltd
2025-02-01
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| Online Access: | https://elifesciences.org/articles/86931 |
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| author | Louise Tzung-Harn Hsieh Belinda S Hall Jane Newcombe Tom A Mendum Sonia Santana Varela Yagnesh Umrania Michael J Deery Wei Q Shi Josué Diaz-Delgado Francisco J Salguero Rachel E Simmonds |
| author_facet | Louise Tzung-Harn Hsieh Belinda S Hall Jane Newcombe Tom A Mendum Sonia Santana Varela Yagnesh Umrania Michael J Deery Wei Q Shi Josué Diaz-Delgado Francisco J Salguero Rachel E Simmonds |
| author_sort | Louise Tzung-Harn Hsieh |
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| description | The drivers of tissue necrosis in Mycobacterium ulcerans infection (Buruli ulcer disease) have historically been ascribed solely to the directly cytotoxic action of the diffusible exotoxin, mycolactone. However, its role in the clinically evident vascular component of disease aetiology remains poorly explained. We have now dissected mycolactone’s effects on human primary vascular endothelial cells in vitro. We show that mycolactone-induced changes in endothelial morphology, adhesion, migration, and permeability are dependent on its action at the Sec61 translocon. Unbiased quantitative proteomics identified a profound effect on proteoglycans, driven by rapid loss of type II transmembrane proteins of the Golgi, including enzymes required for glycosaminoglycan (GAG) synthesis, combined with a reduction in the core proteins themselves. Loss of the glycocalyx is likely to be of particular mechanistic importance, since knockdown of galactosyltransferase II (beta-1,3-galactotransferase 6; B3GALT6), the GAG linker-building enzyme, phenocopied the permeability and phenotypic changes induced by mycolactone. Additionally, mycolactone depleted many secreted basement membrane components and microvascular basement membranes were disrupted in vivo during M. ulcerans infection in the mouse model. Remarkably, exogenous addition of laminin-511 reduced endothelial cell rounding, restored cell attachment and reversed the defective migration caused by mycolactone. Hence supplementing mycolactone-depleted extracellular matrix may be a future therapeutic avenue, to improve wound healing rates. |
| format | Article |
| id | doaj-art-388f76adfa9248c2bcaa2558ddbbf50d |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-388f76adfa9248c2bcaa2558ddbbf50d2025-02-06T15:47:33ZengeLife Sciences Publications LtdeLife2050-084X2025-02-011210.7554/eLife.86931The Mycobacterium ulcerans toxin mycolactone causes destructive Sec61-dependent loss of the endothelial glycocalyx and vessel basement membrane to drive skin necrosisLouise Tzung-Harn Hsieh0https://orcid.org/0000-0002-9499-889XBelinda S Hall1https://orcid.org/0000-0002-3753-1978Jane Newcombe2Tom A Mendum3Sonia Santana Varela4Yagnesh Umrania5Michael J Deery6Wei Q Shi7Josué Diaz-Delgado8Francisco J Salguero9Rachel E Simmonds10https://orcid.org/0000-0003-4843-8266Discipline of Microbes, Infection & Immunity, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United KingdomDiscipline of Microbes, Infection & Immunity, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United KingdomDiscipline of Microbes, Infection & Immunity, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United KingdomDiscipline of Microbes, Infection & Immunity, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United KingdomDiscipline of Microbes, Infection & Immunity, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United KingdomCambridge Centre for Proteomics, University of Cambridge, Cambridge, United KingdomCambridge Centre for Proteomics, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, Ball State University, Muncie, United StatesTexas A&M Veterinary Medical Diagnostic Laboratory, College Station, United StatesUnited Kingdom Health Security Agency, UKHSA-Porton Down, Salisbury, United KingdomDiscipline of Microbes, Infection & Immunity, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United KingdomThe drivers of tissue necrosis in Mycobacterium ulcerans infection (Buruli ulcer disease) have historically been ascribed solely to the directly cytotoxic action of the diffusible exotoxin, mycolactone. However, its role in the clinically evident vascular component of disease aetiology remains poorly explained. We have now dissected mycolactone’s effects on human primary vascular endothelial cells in vitro. We show that mycolactone-induced changes in endothelial morphology, adhesion, migration, and permeability are dependent on its action at the Sec61 translocon. Unbiased quantitative proteomics identified a profound effect on proteoglycans, driven by rapid loss of type II transmembrane proteins of the Golgi, including enzymes required for glycosaminoglycan (GAG) synthesis, combined with a reduction in the core proteins themselves. Loss of the glycocalyx is likely to be of particular mechanistic importance, since knockdown of galactosyltransferase II (beta-1,3-galactotransferase 6; B3GALT6), the GAG linker-building enzyme, phenocopied the permeability and phenotypic changes induced by mycolactone. Additionally, mycolactone depleted many secreted basement membrane components and microvascular basement membranes were disrupted in vivo during M. ulcerans infection in the mouse model. Remarkably, exogenous addition of laminin-511 reduced endothelial cell rounding, restored cell attachment and reversed the defective migration caused by mycolactone. Hence supplementing mycolactone-depleted extracellular matrix may be a future therapeutic avenue, to improve wound healing rates.https://elifesciences.org/articles/86931mycobacterium ulceransmycolactoneSec61endotheliumbasement membranemicrovasculature |
| spellingShingle | Louise Tzung-Harn Hsieh Belinda S Hall Jane Newcombe Tom A Mendum Sonia Santana Varela Yagnesh Umrania Michael J Deery Wei Q Shi Josué Diaz-Delgado Francisco J Salguero Rachel E Simmonds The Mycobacterium ulcerans toxin mycolactone causes destructive Sec61-dependent loss of the endothelial glycocalyx and vessel basement membrane to drive skin necrosis eLife mycobacterium ulcerans mycolactone Sec61 endothelium basement membrane microvasculature |
| title | The Mycobacterium ulcerans toxin mycolactone causes destructive Sec61-dependent loss of the endothelial glycocalyx and vessel basement membrane to drive skin necrosis |
| title_full | The Mycobacterium ulcerans toxin mycolactone causes destructive Sec61-dependent loss of the endothelial glycocalyx and vessel basement membrane to drive skin necrosis |
| title_fullStr | The Mycobacterium ulcerans toxin mycolactone causes destructive Sec61-dependent loss of the endothelial glycocalyx and vessel basement membrane to drive skin necrosis |
| title_full_unstemmed | The Mycobacterium ulcerans toxin mycolactone causes destructive Sec61-dependent loss of the endothelial glycocalyx and vessel basement membrane to drive skin necrosis |
| title_short | The Mycobacterium ulcerans toxin mycolactone causes destructive Sec61-dependent loss of the endothelial glycocalyx and vessel basement membrane to drive skin necrosis |
| title_sort | mycobacterium ulcerans toxin mycolactone causes destructive sec61 dependent loss of the endothelial glycocalyx and vessel basement membrane to drive skin necrosis |
| topic | mycobacterium ulcerans mycolactone Sec61 endothelium basement membrane microvasculature |
| url | https://elifesciences.org/articles/86931 |
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