Gliadin peptide P31-43 interferes with Hrs localization to endocytic vesicles

Gliadin peptide P31-43 induces Epidermal Growth Factor Receptor (EGFR) dependent proliferation and actinmodifications in cultured cell lines and in enterocytes from celiac disease (CD) patients. These effects aremediated by delayed degradation of the EGFR in endocytic vesicles. We investigated the molecular mechanismsunderlying the effects of gliadin peptides on trafficking of endocytic vesicles responsible for EGFR degradation.P31-43 peptide entered CaCo-2 cells and localized in early endosomes, maturation to late endosomes of P31-43 containing vesicles was delayed. A sequence similarity search revealed that P31-43 is similar to a region ofHrs (HGF-regulated tyrosine kinase substrate) needed for its correct localization to the endocytic vesicles. P31-43 interfering with Hrs localization to early endosomes induced delay of endocytic maturation and increase ofrecycling pathway markers, transferrin receptor and LAMP, on cells surface. In the celiac enterocytes P31-43 isdelayed in early endocytic vesicles. In conclusion P31-43 delays vesicle trafficking by interfering with Hrsmediatedmaturation to late endosomes, and promotes the recycling pathway in cells and intestinal biopsies.Consequently, in P31-43-treated cells and biopsies, EGFR activation is extended and more transferrin receptorreaches the surface. This may explain the role played by gliadin peptides in CD.