Abstract
The intestinal epithelium not only provides a vital physical barrier between the host and environment but is also required for uptake of nutrients and the induction of tolerance against commensals. Deregulation of any of these functions leads to several disease states including chronic infection, inflammatory bowel disease, and cancer. Here, we describe a novel role for the complement regulator CD46 in the regulation of intestinal epithelial cell (IEC) barrier function. We found that CD46 directly interacts in IECs with the cytoplasmic kinase SPAK and with transmembrane E-cadherin, both proteins necessary for epithelial cell junction and barrier formation. Further, CD46 activation on Caco-2 cells induced rapid and significant decrease in transepithelial resistance with concomitant increase in paracellular permeability. Importantly, though CD46 activation of IEC layers allowed for increased transgression of pathogenic E. coli, it also increased epithelial cell proliferation and accelerated wound repair. These data suggest a previously unappreciated role for CD46 in the maintenance of epithelial cell barrier integrity as well as barrier repair. However, this role for CD46 as “gate keeper” of the epithelium could also provide reason as to why so many pathogens bind to CD46 as such event would facilitate infection.
Highlights
The surface covered by the epithelium of the human intestinal mucosa is estimated to be 300 m2
Though we observed that the SPS1-related kinase (SPAK)/CD46 interaction is required for CD46-driven IL-10 production in T cells, SPAK was initially discovered as a stress-induced key regulator of ion co-transporters (Delpire and Gagnon, 2008), systemic fluid homeostasis (San-Cristobal et al, 2009) and regulator of intestinal epithelial cell (IEC) layer integrity (Yan et al, 2007)
In addition to SPAK, we identified α-E-catenin and the intracellular portion of E-cadherin as CD46-interacting proteins in the same yeast-two-hybrid screen. α-E-catenin and E-cadherin are key constituents of the E-cadherin/catenin network forming the adherence junction (AJ) that are vitally required for normal cell/cell interactions and epithelial cell layer maintenance (Vermeulen et al, 1999; Van Aken et al, 2001; Kobielak and Fuchs, 2004; Yamada et al, 2005)
Summary
The surface covered by the epithelium of the human intestinal mucosa is estimated to be 300 m2. Deregulation or dysfunction of proteins involved in TJ and/or AJ formation or function disrupt the normal epithelial barrier integrity leading to activation of intestinal immunity and exposure of internal tissues to commensal or pathogenic microorganisms (Sansonetti, 2004). This can cumulate in chronic inflammation and barrier dysfunction which is characteristic of inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis (Hugot et al, 2001; Ogura et al, 2001). Mutations in E-cadherin, α-E-catenin, or occludins as well the deregulation of their expression profiles are implicated in various steps of intestinal cancer development (Vermeulen et al, 1999; Kobielak and Fuchs, 2004)
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