Browsing by Author "Jan, Hau-Ming"

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Cholesteryl alpha-D-glucoside 6-acyltransferase enhances the adhesion of Helicobacter pylori to gastric epithelium
(2020-03-13)
Jan, Hau-Ming
;
Chen, Yi-Chi
;
Yang, Tsai-Chen
;
Ong, Lih-Lih
;
Chang, Chia-Chen
Helicobacter pylori, the most common etiologic agent of gastric diseases including gastric cancer, is auxotrophic for cholesterol and has to hijack it from gastric epithelia. Upon uptake, the bacteria convert cholesterol to cholesteryl 6 '-O-acyl-alpha-D-glucopyranoside (CAG) to promote lipid raft clustering in the host cell membranes. However, how CAG appears in the host to exert the pathogenesis still remains ambiguous. Herein we identified hp0499 to be the gene of cholesteryl alpha-D-glucopyranoside acyltransferase (CGAT). Together with cholesteryl glucosyltransferase (catalyzing the prior step), CGAT is secreted via outer membrane vesicles to the host cells for direct synthesis of CAG. This significantly enhances lipid rafts clustering, gathers adhesion molecules (including Lewis antigens and integrins alpha 5, beta 1), and promotes more bacterial adhesion. Furthermore, the clinically used drug amiodarone was shown as a potent inhibitor of CGAT to effectively reduce the bacterial adhesion, indicating that CGAT is a potential target of therapeutic intervention. Jan et al. identify cholesteryl alpha-D- glucopyranoside acyltransferase as a key enzyme in Helicobacter pylori's synthesis of cholesteryl 6'-O-acyl-alpha-D-glucopyranoside, which promotes bacterial adhesion. This study provides insights into the H. pylori-induced pathogenesis and therapeutic strategies against it.
Metabolic labelling of cholesteryl glucosides in Helicobacter pylori reveals how the uptake of human lipids enhances bacterial virulence
(2016-01-01)
Jan, Hau-Ming
;
Chen, Yi-Chi
;
Shih, Yu-Yin
;
Huang, Yu-Chen
;
Tu, Zhijay
Helicobacter pylori infects approximately half of the human population and is the main cause of various gastric diseases. This pathogen is auxotrophic for cholesterol, which it converts upon uptake to various cholesteryl alpha-glucoside derivatives, including cholesteryl 6'-acyl and 6'-phosphatidyl alpha-glucosides (CAGs and CPGs). Owing to a lack of sensitive analytical methods, it is not known if CAGs and CPGs play distinct physiological roles or how the acyl chain component affects function. Herein we established a metabolite-labelling method for characterising these derivatives qualitatively and quantitatively with a femtomolar detection limit. The development generated an MS/MS database of CGds, allowing for profiling of all the cholesterol-derived metabolites. The subsequent analysis led to the unprecedented information that these bacteria acquire phospholipids from the membrane of epithelial cells for CAG biosynthesis. The resulting increase in longer or/and unsaturated CAG acyl chains helps to promote lipid raft formation and thus delivery of the virulence factor CagA into the host cell, supporting the idea that the host/pathogen interplay enhances bacterial virulence. These findings demonstrate an important connection between the chain length of CAGs and the bacterial pathogenicity.