SLC26A3 (DRA) prevents TNF-alpha-induced barrier dysfunction and dextran sulfate sodium-induced acute colitis

Abstract

SLC26A3 encodes a Cl/HCO ion transporter that is also known as downregulated in adenoma (DRA) and is involved in HCO/mucus formation. The role of DRA in the epithelial barrier has not been previously established. In this study, we investigated the in vivo and in vitro mechanisms of DRA in the colon epithelial barrier. Immunofluorescence (IF) and co-immunoprecipitation (co-IP) studies reveal that DRA binds directly to tight junction (TJ) proteins and affects the expression of TJ proteins in polarized Caco-2BBe cells. Similarly, DRA colocalizes with ZO-1 in the intestinal epithelium. Knockdown or overexpression of DRA leads to alterations in TJ proteins and epithelial permeability. In addition, TNF-α treatment downregulates DRA by activating NF-кB and subsequently affecting intestinal epithelial barrier integrity. Furthermore, overexpression of DRA partly reverses the TNF-α-induced damage by stabilizing TJ proteins. Neutralization of TNF-α in dextran sulfate sodium (DSS)-induced colitis mice demonstrates improved the outcomes, and the therapeutic effect of the TNF-α neutralizing mAb is mediated in part by the preservation of DRA expression. These data suggest that DRA may be one of the therapeutic targets of TNF-α. Moreover, DRA delivered by adenovirus vector significantly prevents the exacerbation of colitis and improves epithelial barrier function by promoting the recovery of TJ proteins in DSS-treated mice. In conclusion, DRA plays a role in protecting the epithelial barrier and may be a therapeutic target in gut homeostasis.

Functional characterization of SLC26A3 c.392C>G (p.P131R) mutation in intestinal barrier function using CRISPR/CAS9-created cell models

“…We have also demonstrated that this mutation caused increased ubiquitination mediated degradation of SLC26A3, leading to decreased protein levels of SLC26A3. Our findings, along with other reports [27], demonstrated that SLC26A3 overexpression enhances intestinal epithelial cell barrier function and may explain why SNP rs386833481 mutation caused increased intestinal epithelial cell permeability. Our study is the first to supply the evidence that SLC26A3 SNP rs386833481 (c.392C>G; p.P131R) is a likely causative mutation for diarrhea and has also provided a molecular mechanism underlying this observation.…”

Adaptation to inflammatory acidity through neutrophil-derived adenosine regulation of SLC26A3

“…Mutations resulting in loss of SLC26A3 expression are associated with congenital chloride diarrhea (CLD) 42 . In addition to being associated with CLD, SLC26A3 is dysregulated in intestinal inflammation 43,44 and DSS colitis severity is increased in SLC26A3 −/− mice 34,45 . Both in vivo and in vitro SLC26A3 dysregulation has been associated with decreased bicarbonate secretion and chloride absorption, but not chloride secretion 46,47 .…”

A guide to plasma membrane solute carrier proteins

“…However, its specific role in relation to cancer development is not clear [326]. In healthy gut cells, this transporter has been found to interact with tight junction proteins and play a role in protecting the epithelial barrier, suggesting that this transporter may play a role in cellular growth or motility [312,327].…”