Wnt/β-Catenin Signaling as a Molecular Target by Pathogenic Bacteria

Abstract

The Wnt/β-catenin signaling pathway is crucial to regulate cell proliferation and polarity, cell determination, and tissue homeostasis. The activation of Wnt/β-catenin signaling is based on the interaction between Wnt glycoproteins and seven transmembrane receptors—Frizzled (Fzd). This binding promotes recruitment of the scaffolding protein Disheveled (Dvl), which results in the phosphorylation of the co-receptor LRP5/6. The resultant molecular complex Wnt–Fzd–LRP5/6-Dvl forms a structural region for Axin interaction that disrupts Axin-mediated phosphorylation/degradation of the transcriptional co-activator β-catenin, thereby allowing it to stabilize and accumulate in the nucleus where it activates the expression of Wnt-dependent genes. Due to the prominent physiological function, the Wnt/β-catenin signaling must be strictly controlled because its dysregulation, which is caused by different stimuli, may lead to alterations in cell proliferation, apoptosis, and inflammation-associated cancer. The virulence factors from pathogenic bacteria such as Salmonella enterica sv Typhimurium, Helicobacter pylori, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Citrobacter rodentium, Clostridium difficile, Bacteroides fragilis, Escherichia coli, Haemophilus parasuis, Lawsonia intracellularis, Shigella dysenteriae, and Staphylococcus epidermidis employ a variety of molecular strategies to alter the appropriate functioning of diverse signaling pathways. Among these, Wnt/β-catenin has recently emerged as an important target of several virulence factors produced by bacteria. The mechanisms used by these factors to interfere with the activity of Wnt/β-catenin is diverse and include the repression of Wnt inhibitors' expression by the epigenetic modification of histones, blocking Wnt–Fzd ligand binding, activation or inhibition of β-catenin nuclear translocation, down- or up-regulation of Wnt family members, and inhibition of Axin-1 expression that promotes β-catenin activity. Such a variety of mechanisms illustrate an evolutionary co-adaptation of eukaryotic molecular signaling to a battery of soluble or structural components synthesized by pathogenic bacteria. This review gathers the recent efforts to elucidate the mechanistic details through which bacterial virulence factors modulate Wnt/β-catenin signaling and its physiological consequences concerning the inflammatory response and cancer.

A gene co-association network regulating gut microbial communities in a Duroc pig population

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Sanguinarine suppresses migration and metastasis in colorectal carcinoma associated with the inversion of EMT through the Wnt/β‐catenin signaling

“…The Wnt family is constituted by a group of cysteine‐rich glycoproteins that can initiate varied signaling cascades such as the planar cell polarity pathway, the canonical pathway, and the Wnt/Ca 2+ pathway 4 . Typically, initiation and progression of CRC are closely associated with deregulation of the canonical Wnt/β‐catenin pathway.…”

Systematic evaluation, verification and comparison of tuberculosis‐related non‐coding RNA diagnostic panels

“…GO analysis and KEGG analysis demonstrated that most ncRNAs in included panels involved into Wnt signalling pathway, oxidative stress and immune cell activation and differentiation, which were closely related to the pathogenesis of TB 55‐57 . MiR‐150‐5p was selected by 3/13 miRNA panels which targeted different populations and used different sample types.…”

“…54 GO analysis and KEGG analysis demonstrated that most ncRNAs in included panels involved into Wnt signalling pathway, oxidative stress and immune cell activation and differentiation, which were closely related to the pathogenesis of TB. [55][56][57] MiR-150-5p was selected by 3/13 miRNA panels which targeted wide application ranges, especially in limited-resource regions. [66][67][68] Benefiting from the rapid development of these technologies, Large-scale prospective validation in diverse populations is a necessary step for the entry of these panels into the clinic.…”