Abstract
Helicobacter pylori (H. pylori) expresses the serine protease and chaperone High temperature requirement A (HtrA) that is involved in periplasmic unfolded protein stress response. Additionally, H. pylori-secreted HtrA directly cleaves the human cell adhesion molecule E-cadherin leading to a local disruption of intercellular adhesions during pathogenesis. HtrA-mediated E-cadherin cleavage has been observed in response to a broad range of pathogens, implying that it is a prevalent mechanism in humans. However, less is known whether E-cadherin orthologues serve as substrates for bacterial HtrA. Here, we compared HtrA-mediated cleavage of human E-cadherin with murine, canine, and simian E-cadherin in vitro and during bacterial infection. We found that HtrA targeted mouse and dog E-cadherin equally well, whereas macaque E-cadherin was less fragmented in vitro. We stably re-expressed orthologous E-cadherin (Cdh1) in a CRISPR/Cas9-mediated cdh1 knockout cell line to investigate E-cadherin shedding upon infection using H. pylori wildtype, an isogenic htrA deletion mutant, or complemented mutants as bacterial paradigms. In Western blot analyses and super-resolution microscopy, we demonstrated that H. pylori efficiently cleaved E-cadherin orthologues in an HtrA-dependent manner. These data extend previous knowledge to HtrA-mediated E-cadherin release in mammals, which may shed new light on bacterial infections in non-human organisms.
Highlights
Publisher’s Note: MDPI stays neutralCadherins are key players in cell adhesion, regulation of tissue organization and morphogenesis [1]
Using Homo sapiens (Hs). pylori High temperature requirement A (HtrA) as a prime example for active HtrA proteases, we investigated the hypothesis that cleavage of E-cadherin from other species represents a gateway for bacterial pathogens in non-human organisms
In this study it was shown that HtrA targets Cdh1 orthologues from Macaca fascicularis, Canis lupus familiaris, and Mus muculus to a similar extent as human Cdh1
Summary
Cadherins are key players in cell adhesion, regulation of tissue organization and morphogenesis [1]. E-cadherin represents a crucially important molecule in the establishment of intercellular adhesions and functions as a tumor suppressor. The domain structure of E-cadherin is characterized by an extracellular domain (EC), a transmembrane (TM) domain, and an intracellular domain (IC). The extracellular domain contains five tandemly repeated sequences (EC1-5). Calcium ions bind to negatively charged motifs located between the EC repeats to provide the adhesive properties of E-cadherin. The IC domain of E-cadherin recruits cytoplasmic signaling proteins, including β-catenin and p120-catenin, which control the strength and integrity of the adhesion complex and regulate downstream signaling transduction pathways implicated in the actin cytoskeleton reorganization and cancer-associated gene transcription [4,5]
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