title: Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation.
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. Among the innate defense mechanisms of intestinal mucosa, a defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in the causation and progression of inflammatory bowel disease by allowing increased antigenic permeation. The cross-talk between autophagy and the TJ barrier has not yet been described. In this study, we present the 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 the paracellular permeability of small-sized urea but not larger molecules. The role of autophagy in the 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 the cation-selective, pore-forming TJ protein claudin-2 was observed after cell starvation. Starvation reduced the membrane presence of claudin-2 and increased its cytoplasmic, lysosomal localization. Therefore, our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of the TJ protein claudin-2.
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Prashant K
authors.initials: PK
authors.lastname: Nighot
authors.affiliation: Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131 and.
authors.forename: Chien-An Andy
authors.initials: CA
authors.lastname: Hu
authors.affiliation: From the Departments of Internal Medicine and the Veterans Affairs Medical Center, Albuquerque, New Mexico 87108 TMa@salud.unm.edu.
authors.forename: Thomas Y
authors.initials: TY
authors.lastname: Ma
mesh_terms: D001343:Autophagy; D018938:Caco-2 Cells; D062446:Claudin-2 / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism; D010539:Permeability; D059748:Proteolysis; D019108:Tight Junctions / Q000378:metabolism*
chemical_list: D062446:Claudin-2
keywords: Autophagy; Claudin-2; Epithelial Cell; Intestinal Epithelium; Protein Degradation; Tight Junction