MUC1 limits Helicobacter pylori infection both by steric hindrance and by acting as a releasable decoy.
The bacterium Helicobacter pylori can cause peptic ulcer disease, gastric adenocarcinoma and MALT lymphoma. The cell-surface mucin MUC1 is a large glycoprotein which is highly expressed on the mucosal surface and limits the density of H. pylori in a murine infection model. We now demonstrate that by using the BabA and SabA adhesins, H. pylori bind MUC1 isolated from human gastric cells and MUC1 shed into gastric juice. Both H. pylori carrying these adhesins, and beads coated with MUC1 antibodies, induced shedding of MUC1 from MKN7 human gastric epithelial cells, and shed MUC1 was found bound to H. pylori. Shedding of MUC1 from non-infected cells was not mediated by the known MUC1 sheddases ADAM17 and MMP-14. However, knockdown of MMP-14 partially affected MUC1 release early in infection, whereas ADAM17 had no effect. Thus, it is likely that shedding is mediated both by proteases and by disassociation of the non-covalent interaction between the alpha- and beta-subunits. H. pylori bound more readily to MUC1 depleted cells even when the bacteria lacked the BabA and SabA adhesins, showing that MUC1 inhibits attachment even when bacteria cannot bind to the mucin. Bacteria lacking both the BabA and SabA adhesins caused less apoptosis in MKN7 cells than wild-type bacteria, having a greater effect than deletion of the CagA pathogenicity gene. Deficiency of MUC1/Muc1 resulted in increased epithelial cell apoptosis, both in MKN7 cells in vitro, and in H. pylori infected mice. Thus, MUC1 protects the epithelium from non-MUC1 binding bacteria by inhibiting adhesion to the cell surface by steric hindrance, and from MUC1-binding bacteria by acting as a releasable decoy.
Lindén
Sara K
SK
Mucosal Diseases Program, Mater Medical Research Institute, Mater Health Services, South Brisbane, Queensland, Australia. sara.linden@gu.se
Sheng
Yong H
YH
Every
Alison L
AL
Miles
Kim M
KM
Skoog
Emma C
EC
Florin
Timothy H J
TH
Sutton
Philip
P
McGuckin
Michael A
MA
D000818:Animals; D001422:Bacterial Adhesion / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D005753:Gastric Mucosa / Q000382:microbiology; D006031:Glycosylation; D016481:Helicobacter Infections / Q000517:prevention & control*; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D051379:Mice; D018396:Mucin-1 / Q000502:physiology*; D011485:Protein Binding; D021122:Protein Subunits; D013270:Stomach / Q000382:microbiology / Q000502:physiology
C060192:MUC1 protein, human; D018396:Mucin-1; D021122:Protein Subunits