PXD037489-1

PXD037489 is an original dataset announced via ProteomeXchange.

Title	Mycolactone causes catastrophic Sec61-dependent loss of the endothelial glycocalyx and basement membrane: a new indirect mechanism driving tissue necrosis in Mycobacterium ulcerans infection
Description	The drivers of tissue necrosis in Mycobacterium ulcerans infection (Buruli ulcer disease) have historically been ascribed solely to the cytotoxic action of the diffusible endotoxin, mycolactone. However, clinical evidence supporting a strong vascular contribution to disease aetiology has, until recently, been under-explored. We have now dissected mycolactone’s effects on primary vascular endothelial cells in vitro and in vivo. We show that mycolactone’s effect on 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 both by a rapid loss of type II transmembrane proteins of the Golgi, including enzymes required for glycosaminoglycan (GAG) synthesis and 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 cell rounding, restored cell attachment and reversed the defective migration caused by mycolactone suggesting that this might be a viable therapeutic avenue in the future.
HostingRepository	PRIDE
AnnounceDate	2025-01-14
AnnouncementXML	Submission_2025-01-14_06:46:46.910.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yagnesh Umrania
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-10-17 01:28:02	ID requested
⏵ 1	2025-01-14 06:46:47	announced
2	2025-01-16 02:54:44	announced	2025-01-16: Updated project metadata.

10.7554/ELIFE.86931.2;

submitter keyword: Sec61 translocon.,tissue necrosis,proteomics,Buruli ulcer disease,mycolactone

Rachel Simmonds
contact affiliation	Dept of Microbial Sciences, School of Bioscience and Medicine, University of Surrey
contact email	rachel.simmonds@surrey.ac.uk
lab head
Yagnesh Umrania
contact affiliation	University of Cambridge
contact email	yu206@cam.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD037489
     1. Label: PRIDE project
     2. Name: Mycolactone causes catastrophic Sec61-dependent loss of the endothelial glycocalyx and basement membrane: a new indirect mechanism driving tissue necrosis in Mycobacterium ulcerans infection