Abstract
Tight junctions help prevent the passage of digestive enzymes and microorganisms through the space between adjacent epithelial cells lining. However, Helicobacter pylori encoded virulence factors negatively regulate these tight junctions and contribute to dysfunction of gastric mucosa. Here, we have predicted the regulation of important tight junction proteins, such as Zonula occludens-1, Claudin-2 and Connexin32 in the presence of pathogenic proteins. Molecular events such as post translational modifications and crosstalk between phosphorylation, O-glycosylation, palmitoylation and methylation are explored which may compromise the integrity of these tight junction proteins. Furthermore, the signaling pathways disrupted by dysregulated kinases, proteins and post-translational modifications are reviewed to design an abstracted computational model showing the situation-dependent dynamic behaviors of these biological processes and entities. A qualitative hybrid Petri Net model is therefore constructed showing the altered host pathways in the presence of virulence factor cytotoxin-associated gene A, leading to the disruption of tight junction proteins. The model is qualitative logic-based, which does not depend on any kinetic parameter and quantitative data and depends on knowledge derived from experiments. The designed model provides insights into the tight junction disruption and disease progression. Model is then verified by the available experimental data, nevertheless formal in vitro experimentation is a promising way to ensure its validation. The major findings propose that H. pylori activated kinases are responsible to trigger specific post translational modifications within tight junction proteins, at specific sites. These modifications may favor alterations in gastric barrier and provide a route to bacterial invasion into host cells.
Highlights
Organized intercellular tight junctions (TJ) are crucial structural components of the intact epithelium architecture and provide protection against intruding pathogens
We propose a probabilistic model to predict a pathway induced by H. pylori infection to stimulate post translational modifications (PTMs) within TJ proteins and resultant altered behavior
CLDN2 and CX32 have four trans-membrane domains and two extracellular loops along with cytosolic N- and C-terminals (Figure 4) The adapter protein ZO1 binds with TJ proteins at cytoplasmic side and is targeted by various transcription factors to modulate cell growth and permeability
Summary
Organized intercellular tight junctions (TJ) are crucial structural components of the intact epithelium architecture and provide protection against intruding pathogens. Disruption of these epithelial barriers is an important hallmark of Helicobacter pylori-dependent inflammation and neoplastic tissue transformation (Wessler and Backert, 2008). H. pylori actively interferes the host cells and exerts an astounding set of strategies to manipulate these epithelial cell-to-cell junctions. This negative interaction between the pathogen and host results into major consequences such as altered cell polarity, migration and invasive growth as well as pro-inflammatory and proliferative responses (Ashida et al, 2012)
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