abstract
- Autophagy is an intracellular degradation pathway and is considered to be an essential cell survival mechanism. Defects in autophagy are implicated in many pathological processes including inflammatory bowel disease (IBD). Among the innate defense mechanisms of intestinal mucosa, defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in causation and progression of IBD by allowing increased antigenic permeation. The crosstalk between autophagy and TJ barrier has not yet been described. In this study we present a novel finding that autophagy enhances TJ barrier function in Caco-2 intestinal epithelial cells. Nutrient starvation-induced autophagy significantly increased transepithelial electrical resistance and reduced the ratio of sodium/chloride paracellular permeability. Nutrient starvation reduced paracellular permeability of small sized urea but not larger molecules. The role of autophagy in modulation of paracellular permeability was confirmed by pharmacological induction as well as pharmacological and genetic inhibition of autophagy. Consistent with the autophagy-induced reduction in paracellular permeability, a marked decrease in the level of cation selective, pore forming TJ protein claudin-2 was observed after cell starvation. Starvation reduced membrane presence of claudin-2 and increased its cytoplasmic, lysosomal localization. Thus, our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of TJ protein claudin-2.Copyright © 2015, The American Society for Biochemistry and Molecular Biology.