title: Actin-interacting protein 1 controls assembly and permeability of intestinal epithelial apical junctions.
abstract: Adherens junctions (AJs) and tight junctions (TJs) are crucial regulators of the integrity and restitution of the intestinal epithelial barrier. The structure and function of epithelial junctions depend on their association with the cortical actin cytoskeleton that, in polarized epithelial cells, is represented by a prominent perijunctional actomyosin belt. The assembly and stability of the perijunctional cytoskeleton is controlled by constant turnover (disassembly and reassembly) of actin filaments. Actin-interacting protein (Aip) 1 is an emerging regulator of the actin cytoskeleton, playing a critical role in filament disassembly. In this study, we examined the roles of Aip1 in regulating the structure and remodeling of AJs and TJs in human intestinal epithelium. Aip1 was enriched at apical junctions in polarized human intestinal epithelial cells and normal mouse colonic mucosa. Knockdown of Aip1 by RNA interference increased the paracellular permeability of epithelial cell monolayers, decreased recruitment of AJ/TJ proteins to steady-state intercellular contacts, and attenuated junctional reassembly in a calcium-switch model. The observed defects of AJ/TJ structure and functions were accompanied by abnormal organization and dynamics of the perijunctional F-actin cytoskeleton. Moreover, loss of Aip1 impaired the apico-basal polarity of intestinal epithelial cell monolayers and inhibited formation of polarized epithelial cysts in 3-D Matrigel. Our findings demonstrate a previously unanticipated role of Aip1 in regulating the structure and remodeling of intestinal epithelial junctions and early steps of epithelial morphogenesis.
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia;
authors: Susana
authors: http://orcid.org/0000-0003-0614-1990
authors: S
authors: Lechuga
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia;
authors: Somesh
authors: S
authors: Baranwal
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia; Virginia Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia aivanov2@vcu.edu.
authors: Andrei I
authors: AI
authors: Ivanov
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism / Q000473:pathology; D000205:Actomyosin / Q000378:metabolism; D022005:Adherens Junctions / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D018938:Caco-2 Cells; D016764:Cell Polarity; D003560:Cysts / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009024:Morphogenesis; D010539:Permeability; D034622:RNA Interference; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
chemical_list: D008840:Microfilament Proteins; C118067:WDR1 protein, human; C115237:actin interacting protein 1; D000205:Actomyosin
keywords: actin cytoskeleton; actin turnover; adherens junctions; epithelial barrier; tight junctions