Infecting more than half of the world’s population, Helicobacter pylori not only represents the most common etiological agent of gastric diseases (including gastric carcinoma and gastric mucosa-associated lymphoid tissue lymphoma), but is also a leading cause of cancer-related deaths. H. pylori is auxotrophic for cholesterol. It assimilates cholesterol into its membrane by taking up cholesterol from epithelial cells of the stomach. Upon uptake, the bacterial cells modify the cholesterol by a-glucosylation. Specifically, the bacterial glucosyltransferase catalyzes the transfer of glucose to the 3-hydroxyl group of cholesterol, yielding cholesteryl a-D-glucopyranoside (CG). There is a subsequent modification occurring at O6’ of glucose in CG; the attachment of an acyl group results in cholesteryl 6’-O-acyl-a-D-glucopyranoside (CAG).
In this article (Commun Biol. 2020 Mar 13;3(1):120), we identify hp0499 as the gene corresponding to cholesteryl a-D-glucopyranoside 6’-acyltransferase (CGAT) and share an extensive characterization of the recombinant protein. The enzyme is located in the outer membrane of H. pylori, secreted extracellularly in the form of outer membrane vesicles (OMVs), and thus delivered to host cells to directly produce CAGs. Our results thus demonstrate a previously undocumented host–microbe interplay. Upon the uptake of cholesterol, the bacteria convert it to CAGs that significantly gather adhesion molecules (including integrins a5, b1 and Lewis antigens) on the membrane of host cells, and thus enhance bacterial adhesion. Leveraging the outer membrane vesicles is also a clever and efficient way to deliver the two bacterial enzymes (including the acyltransferase and the enzyme catalyzing the prior step) to the host cells. CAGs are critical to enhance the lipid-raft clustering in the host membranes, thereby promoting further bacterial adhesion.
Finally, we found amiodazone (an antiarrhythmic medication used in clinic to treat and prevent irregular heartbeats) to be a potent CGAT inhibitor, effectively blockading the H. pylori adhesion. This result indicated that CGAT is a potential target of therapeutic intervention.
Article title: “Cholesteryl α-D-glucoside 6-acyltransferase enhances the adhesion of Helicobacter pylori to gastric epithelium”
Article link: https://doi.org/10.1038/s42003-020-0855-y
Authors: Jan HM, Chen YC, Yang TC, Ong LL, Chang CC, Muthusamy S, Abera AB, Wu MS, Gervay-Hague J, Mong KT*, Lin CH*