
마이콜락톤은 Sec61 트랜스로콘을 차단하여 당질층과 기저막을 구성하는 단백질 생성을 억제함으로써 혈관 내피 세포 기능 장애를 유발하고  Mycobacterium ulcerans 감염의 병인에 중요한 역할을 한다.


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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 primary vascular endothelial cells in vitro and in vivo . 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 . 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.

### Competing Interest Statement

The authors have declared no competing interest.

Mycolactone causes destructive Sec61-dependent loss of the endothelial glycocalyx and vessel basement membrane: a new indirect mechanism driving tissue necrosis in Mycobacterium ulcerans infection

마이콜락톤-내피세포-당질층-및-기저막의-sec61-의존성-손실-유발-mycobacterium-ulcerans-감염에서-조직-괴사를-유발하는-새로운-간접적-메커니즘


마이콜락톤, 내피세포 당질층 및 기저막의 Sec61 의존성 손실 유발:  Mycobacterium ulcerans 감염에서 조직 괴사를 유발하는 새로운 간접적 메커니즘


title_rewrite


Mycolactone, the toxin produced by Mycobacterium ulcerans, causes Buruli ulcer disease by inhibiting Sec61, leading to the depletion of proteins crucial for endothelial glycocalyx and basement membrane integrity, ultimately contributing to tissue necrosis.


mycolactone-disrupts-endothelial-glycocalyx-and-basement-membrane-integrity-a-novel-mechanism-of-tissue-necrosis-in-buruli-ulcer-disease


Mycolactone Disrupts Endothelial Glycocalyx and Basement Membrane Integrity: A Novel Mechanism of Tissue Necrosis in Buruli Ulcer Disease
