Abstract
The intestinal epithelium consists of a single cell layer, which is a critical selectively permeable barrier to both absorb nutrients and avoid the entry of potentially harmful entities, including microorganisms. Epithelial cells are held together by the apical junctional complexes, consisting of adherens junctions, and tight junctions (TJs), and by underlying desmosomes. TJs lay in the apical domain of epithelial cells and are mainly composed by transmembrane proteins such as occludin, claudins, JAMs, and tricellulin, that are associated with the cytoplasmic plaque formed by proteins from the MAGUK family, such as ZO-1/2/3, connecting TJ to the actin cytoskeleton, and cingulin and paracingulin connecting TJ to the microtubule network. Extracellular bacteria such as EPEC and EHEC living in the intestinal lumen inject effectors proteins directly from the bacterial cytoplasm to the host cell cytoplasm, where they play a relevant role in the manipulation of the eukaryotic cell functions by modifying or blocking cell signaling pathways. TJ integrity depends on various cell functions such as actin cytoskeleton, microtubule network for vesicular trafficking, membrane integrity, inflammation, and cell survival. EPEC and EHEC effectors target most of these functions. Effectors encoded inside or outside of locus of enterocyte effacement (LEE) disrupt the TJ strands. EPEC and EHEC exploit the TJ dynamics to open this structure, for causing diarrhea. EPEC and EHEC secrete effectors that mimic host proteins to manipulate the signaling pathways, including those related to TJ dynamics. In this review, we focus on the known mechanisms exploited by EPEC and EHEC effectors for causing TJ disruption.
Highlights
The intestinal epithelium is the largest mucosal surfaces of the body, covering about 400 m2 of surface area with a single layer of cells organized into crypts and villi
When cells are infected with EPEC wild type, the E. coli secreted protein F (EspF) and mitochondrial associated protein (Map) activity result in the removal of proteins from tight junctions (TJs), while NleA blocks the delivery of newly synthesized TJ proteins by the inhibition of COPII
The TJ structure is a large protein complex, the major types are the claudins and the occludins. These are associated with different peripheral membrane proteins, such as zonulae occludens (ZO)-1 located on the intracellular side of plasma membrane, which anchor the strands to the actin component of the cytoskeleton
Summary
The intestinal epithelium is the largest mucosal surfaces of the body, covering about 400 m2 of surface area with a single layer of cells organized into crypts and villi. Alterations of mucosal barrier function are increasingly linked to a broad spectrum of pathologies, such as nonalcoholic fatty liver disease (Miele et al, 2009), type 1 diabetes (Bosi et al, 2006) and chronic intestinal inflammation (Pastorelli et al, 2013) Through all these protein complexes, the TJs are found in the most apical part of the epithelial cells restricting, among other factors, the entry of most of the microorganisms living or colonizing the intestinal mucosa. Manipulation of TJs is not exclusive of viruses, fungi or parasites, pathogenic bacteria produce virulence factors for targeting the TJs. For example, Helicobacter pylori injects, through the type 4 secretion system, the CagA protein into the cytoplasm of gastric epithelial cells. We will focus on the molecular strategies used by EPEC and EHEC to disrupt the TJs
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