Identification of Desmoglein-2 as a novel target of Helicobacter pylori HtrA in epithelial cells.
ADAM10 Protein
/ genetics
ADAM17 Protein
/ genetics
Bacterial Proteins
/ genetics
Desmoglein 2
/ genetics
Ephrin-B2
/ genetics
Epithelial Cells
/ microbiology
Helicobacter Infections
/ genetics
Helicobacter pylori
/ genetics
Host-Pathogen Interactions
/ genetics
Humans
Neuropilin-1
/ genetics
Proteomics
/ methods
Semaphorins
/ genetics
Serine Proteases
/ genetics
Desmoglein-2
E-cadherin
Helicobacter pylori
HtrA
Protease
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
06 11 2021
06 11 2021
Historique:
received:
09
09
2021
accepted:
14
09
2021
entrez:
7
11
2021
pubmed:
8
11
2021
medline:
25
2
2022
Statut:
epublish
Résumé
High temperature requirement A (HtrA) is an active serine protease secreted by the group-I carcinogen Helicobacter pylori (H. pylori). The human cell adhesion protein and tumor suppressor E-cadherin (hCdh1) expressed on the surface of gastric epithelial cells was identified as the first HtrA substrate. HtrA-mediated hCdh1 cleavage and subsequent disruption of intercellular adhesions are considered as important steps in H. pylori pathogenesis. In this study, we performed a proteomic profiling of H. pylori HtrA (HpHtrA) to decipher the complex mechanism of H. pylori interference with the epithelial barrier integrity. Using a proteomic approach we identified human desmoglein-2 (hDsg2), neuropilin-1, ephrin-B2, and semaphorin-4D as novel extracellular HpHtrA substrates and confirmed the well characterized target hCdh1. HpHtrA-mediated hDsg2 cleavage was further analyzed by in vitro cleavage assays using recombinant proteins. In infection experiments, we demonstrated hDsg2 shedding from H. pylori-colonized MKN28 and NCI-N87 cells independently of pathogen-induced matrix-metalloproteases or ADAM10 and ADAM17. Characterizing the substrate specificity of HpHtrA revealed efficient hDsg2 cleavage underlining the importance of HpHtrA in opening intercellular junctions. Video Abstract.
Sections du résumé
BACKGROUND
High temperature requirement A (HtrA) is an active serine protease secreted by the group-I carcinogen Helicobacter pylori (H. pylori). The human cell adhesion protein and tumor suppressor E-cadherin (hCdh1) expressed on the surface of gastric epithelial cells was identified as the first HtrA substrate. HtrA-mediated hCdh1 cleavage and subsequent disruption of intercellular adhesions are considered as important steps in H. pylori pathogenesis. In this study, we performed a proteomic profiling of H. pylori HtrA (HpHtrA) to decipher the complex mechanism of H. pylori interference with the epithelial barrier integrity.
RESULTS
Using a proteomic approach we identified human desmoglein-2 (hDsg2), neuropilin-1, ephrin-B2, and semaphorin-4D as novel extracellular HpHtrA substrates and confirmed the well characterized target hCdh1. HpHtrA-mediated hDsg2 cleavage was further analyzed by in vitro cleavage assays using recombinant proteins. In infection experiments, we demonstrated hDsg2 shedding from H. pylori-colonized MKN28 and NCI-N87 cells independently of pathogen-induced matrix-metalloproteases or ADAM10 and ADAM17.
CONCLUSIONS
Characterizing the substrate specificity of HpHtrA revealed efficient hDsg2 cleavage underlining the importance of HpHtrA in opening intercellular junctions. Video Abstract.
Identifiants
pubmed: 34742300
doi: 10.1186/s12964-021-00788-x
pii: 10.1186/s12964-021-00788-x
pmc: PMC8571890
doi:
Substances chimiques
Bacterial Proteins
0
Desmoglein 2
0
EFNB2 protein, human
0
Ephrin-B2
0
Semaphorins
0
Neuropilin-1
144713-63-3
HtrA protein, H pylori
EC 3.4.-
Serine Proteases
EC 3.4.-
ADAM10 Protein
EC 3.4.24.81
ADAM17 Protein
EC 3.4.24.86
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
108Subventions
Organisme : Austrian Science Fund FWF
ID : P 31507
Pays : Austria
Informations de copyright
© 2021. The Author(s).
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