Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms

Susana Lechuga1, Andrei I. Ivanov1,2,3
1Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA
2Virginia Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
3Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA

Tài liệu tham khảo

Madara, 1998, Regulation of the movement of solutes across tight junctions, Annu. Rev. Physiol., 60, 143, 10.1146/annurev.physiol.60.1.143 McGuckin, 2009, Intestinal barrier dysfunction in inflammatory bowel diseases, Inflamm. Bowel Dis., 15, 100, 10.1002/ibd.20539 Bischoff, 2014, Intestinal permeability--a new target for disease prevention and therapy, BMC Gastroenterol., 14, 189, 10.1186/s12876-014-0189-7 Turner, 2009, Intestinal mucosal barrier function in health and disease, Nat. Rev. Immunol., 9, 799, 10.1038/nri2653 Barmeyer, 2015, Claudin-related intestinal diseases, Semin. Cell Dev. Biol., 42, 30, 10.1016/j.semcdb.2015.05.006 Halpern, 2015, The role of intestinal epithelial barrier function in the development of NEC, Tissue Barriers, 3, e1000707, 10.1080/21688370.2014.1000707 Brandl, 2015, Is intestinal inflammation linking dysbiosis to gut barrier dysfunction during liver disease?, Expert Rev. Gastroenterol. Hepatol., 9, 1069, 10.1586/17474124.2015.1057122 Winer, 2016, The intestinal immune system in obesity and insulin resistance, Cell Metab., 23, 413, 10.1016/j.cmet.2016.01.003 Luissint, 2016, Inflammation and the intestinal barrier: leukocyte-epithelial cell interactions, Cell Junction Remodel. Mucosal Repair Gastroenterol., 151, 616 Onyiah, 2016, Cytokine responses and epithelial function in the intestinal mucosa, Cell. Mol. Life Sci., 73, 4203, 10.1007/s00018-016-2289-8 Blander, 2016, Death in the intestinal epithelium-basic biology and implications for inflammatory bowel disease, FEBS J., 283, 2720, 10.1111/febs.13771 Cornick, 2015, Roles and regulation of the mucus barrier in the gut, Tissue Barriers, 3, e982426, 10.4161/21688370.2014.982426 Farquhar, 1963, Junctional complexes in various epithelia, J. Cell Biol., 17, 375, 10.1083/jcb.17.2.375 Hartsock, 2008, Adherens and tight junctions: structure, function and connections to the actin cytoskeleton, Biochim. Biophys. Acta, 1778, 660, 10.1016/j.bbamem.2007.07.012 Ivanov, 2013, Dynamics and regulation of epithelial adherens junctions: recent discoveries and controversies, Int. Rev. Cell Mol. Biol., 303, 27, 10.1016/B978-0-12-407697-6.00002-7 Gumbiner, 2005, Regulation of cadherin-mediated adhesion in morphogenesis, Nat. Rev. Mol. Cell Biol., 6, 622, 10.1038/nrm1699 Hardy, 2002, Transient P-cadherin expression in radiation proctitis; a model of mucosal injury and repair, J. Pathol., 197, 194, 10.1002/path.1092 Rikitake, 2012, The role of nectins in different types of cell-cell adhesion, J. Cell Sci., 125, 3713, 10.1242/jcs.099572 Tanaka-Okamoto, 2011, Involvement of afadin in barrier function and homeostasis of mouse intestinal epithelia, J. Cell Sci., 124, 2231, 10.1242/jcs.081000 Anderson, 2009, Physiology and function of the tight junction, Cold Spring Harb. Perspect. Biol., 1, a002584, 10.1101/cshperspect.a002584 Furuse, 2010, Molecular basis of the core structure of tight junctions, Cold Spring Harb. Perspect. Biol., 2, a002907, 10.1101/cshperspect.a002907 Ivanov, 2012, Structure and regulation of intestinal epithelial tight junctions: current concepts and unanswered questions, Adv. Exp. Med. Biol., 763, 132, 10.1007/978-1-4614-4711-5_6 Capaldo, 2015, Claudin switching: physiological plasticity of the tight junction, Semin. Cell Dev. Biol., 42, 22, 10.1016/j.semcdb.2015.04.003 Lu, 2013, Claudins in intestines: distribution and functional significance in health and diseases, Tissue Barriers, 1, e24978, 10.4161/tisb.24978 Barmeyer, 2017, Active and passive involvement of claudins in the pathophysiology of intestinal inflammatory diseases, Pflugers Arch., 469, 15, 10.1007/s00424-016-1914-6 Van Itallie, 2014, Architecture of tight junctions and principles of molecular composition, Semin. Cell Dev. Biol., 36, 157, 10.1016/j.semcdb.2014.08.011 Raleigh, 2010, Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions, Mol. Biol. Cell, 21, 1200, 10.1091/mbc.e09-08-0734 Furuse, 2014, Molecular organization of tricellular tight junctions, Tissue Barriers, 2, e28960, 10.4161/tisb.28960 Zihni, 2014, Signalling at tight junctions during epithelial differentiation and microbial pathogenesis, J. Cell Sci., 127, 3401, 10.1242/jcs.145029 Luissint, 2014, JAM-related proteins in mucosal homeostasis and inflammation, Semin. Immunopathol., 36, 211, 10.1007/s00281-014-0421-0 Gonzalez-Mariscal, 2008, Crosstalk of tight junction components with signaling pathways, Biochim. Biophys. Acta, 1778, 729, 10.1016/j.bbamem.2007.08.018 Ivanov, 2010, Tumor suppressor scribble regulates assembly of tight junctions in the intestinal epithelium, Am. J. Pathol., 176, 134, 10.2353/ajpath.2010.090220 Umeda, 2006, ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation, Cell, 126, 741, 10.1016/j.cell.2006.06.043 Pastorelli, 2013, Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics, Front. Immunol., 4, 280, 10.3389/fimmu.2013.00280 Shen, 2011, Tight junction pore and leak pathways: a dynamic duo, Annu. Rev. Physiol., 73, 283, 10.1146/annurev-physiol-012110-142150 Das, 2012, Comparative tight junction protein expressions in colonic Crohn's disease, ulcerative colitis, and tuberculosis: a new perspective, Virchows Arch., 460, 261, 10.1007/s00428-012-1195-1 Goswami, 2014, Are alterations of tight junctions at molecular and ultrastructural level different in duodenal biopsies of patients with celiac disease and Crohn's disease?, Virchows Arch., 465, 521, 10.1007/s00428-014-1651-1 Landy, 2014, Innate immune factors in the development and maintenance of pouchitis, Inflamm. Bowel Dis., 20, 1942, 10.1097/MIB.0000000000000182 Zeissig, 2007, Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn's disease, Gut, 56, 61, 10.1136/gut.2006.094375 Jankowski, 1998, Alterations in classical cadherins associated with progression in ulcerative and Crohn's colitis, Lab. Investig., 78, 1155 Kosovac, 2010, Association of the NOD2 genotype with bacterial translocation via altered cell-cell contacts in Crohn's disease patients, Inflamm. Bowel Dis., 16, 1311, 10.1002/ibd.21223 Perry, 1999, Reduced cadherin/catenin complex expression in celiac disease can be reproduced in vitro by cytokine stimulation, Lab. Investig., 79, 1489 Wilcz-Villega, 2014, Reduced E-cadherin expression is associated with abdominal pain and symptom duration in a study of alternating and diarrhea predominant IBS, Neurogastroenterol. Motil., 26, 316, 10.1111/nmo.12262 Zhang, 2015, Expressions of E-cadherin, p120ctn, beta-catenin and NF-kappaB in ulcerative colitis, J. Huazhong Univ. Sci. Technol. Med. Sci., 35, 368, 10.1007/s11596-015-1439-9 U.I.G. Consortium, 2009, Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region, Nat. Genet., 41, 1330, 10.1038/ng.483 Muise, 2009, Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn's disease, Gut, 58, 1121, 10.1136/gut.2008.175117 Vieira, 2015, P-cadherin and the journey to cancer metastasis, Mol. Cancer, 14, 178, 10.1186/s12943-015-0448-4 Gassler, 2001, Inflammatory bowel disease is associated with changes of enterocytic junctions, Am. J. Physiol. Gastrointest. Liver Physiol., 281, G216, 10.1152/ajpgi.2001.281.1.G216 Koch, 2012, The life and death of epithelia during inflammation: lessons learned from the gut, Annu. Rev. Pathol., 7, 35, 10.1146/annurev-pathol-011811-120905 Hermiston, 1995, Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin, Science, 270, 1203, 10.1126/science.270.5239.1203 Schneider, 2010, A key role for E-cadherin in intestinal homeostasis and Paneth cell maturation, PLoS One, 5, e14325, 10.1371/journal.pone.0014325 Smalley-Freed, 2010, p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice, J. Clin. Invest., 120, 1824, 10.1172/JCI41414 Fevr, 2007, Wnt/beta-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells, Mol. Cell. Biol., 27, 7551, 10.1128/MCB.01034-07 Naydenov, 2013, Novel mechanism of cytokine-induced disruption of epithelial barriers: Janus kinase and protein kinase D-dependent downregulation of junction protein expression, Tissue Barriers, 1, e25231, 10.4161/tisb.25231 Muise, 2007, Protein-tyrosine phosphatase sigma is associated with ulcerative colitis, Curr. Biol., 17, 1212, 10.1016/j.cub.2007.06.013 Ciccocioppo, 2006, Altered expression, localization, and phosphorylation of epithelial junctional proteins in celiac disease, Am. J. Clin. Pathol., 125, 502, 10.1309/DTYRA91G8R0KTM8M Capaldo, 2009, Cytokine regulation of tight junctions, Biochim. Biophys. Acta, 1788, 864, 10.1016/j.bbamem.2008.08.027 Azarschab, 2002, Epigenetic control of the E-cadherin gene (CDH1) by CpG methylation in colectomy samples of patients with ulcerative colitis, Genes Chromosom. Cancer, 35, 121, 10.1002/gcc.10101 Wheeler, 2001, Hypermethylation of the promoter region of the E-cadherin gene (CDH1) in sporadic and ulcerative colitis associated colorectal cancer, Gut, 48, 367, 10.1136/gut.48.3.367 Silvera, 2009, Essential role for eIF4GI overexpression in the pathogenesis of inflammatory breast cancer, Nat. Cell Biol., 11, 903, 10.1038/ncb1900 Hu, 2007, Translational inhibition of colonic epithelial heat shock proteins by IFN-gamma and TNF-alpha in intestinal inflammation, Gastroenterology, 133, 1893, 10.1053/j.gastro.2007.09.026 Elmi, 2016, Campylobacter jejuni outer membrane vesicle-associated proteolytic activity promotes bacterial invasion by mediating cleavage of intestinal epithelial cell E-cadherin and occludin, Cell. Microbiol., 18, 561, 10.1111/cmi.12534 Wu, 2007, Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and gamma-secretase-dependent E-cadherin cleavage, J. Cell Sci., 120, 1944, 10.1242/jcs.03455 Boxio, 2016, Neutrophil elastase cleaves epithelial cadherin in acutely injured lung epithelium, Respir. Res., 17, 129, 10.1186/s12931-016-0449-x Butin-Israeli, 2016, Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration, FASEB J., 30, 4007, 10.1096/fj.201600734R Nava, 2013, Cleavage of transmembrane junction proteins and their role in regulating epithelial homeostasis, Tissue Barriers, 1, e24783, 10.4161/tisb.24783 Oshima, 2008, Changes in the expression of claudins in active ulcerative colitis, J. Gastroenterol. Hepatol., 23, S146, 10.1111/j.1440-1746.2008.05405.x Ding, 2012, Inflammation and disruption of the mucosal architecture in claudin-7-deficient mice, Gastroenterology, 142, 305, 10.1053/j.gastro.2011.10.025 Amasheh, 2009, Regulation of mucosal structure and barrier function in rat colon exposed to tumor necrosis factor alpha and interferon gamma in vitro: a novel model for studying the pathomechanisms of inflammatory bowel disease cytokines, Scand. J. Gastroenterol., 44, 1226, 10.1080/00365520903131973 Gerlach, 2015, IL-9 regulates intestinal barrier function in experimental T cell-mediated colitis, Tissue Barriers, 3, e983777, 10.4161/21688370.2014.983777 Haines, 2016, Interleukin-1beta mediates beta-catenin-driven downregulation of claudin-3 and barrier dysfunction in CaCo2 cells, Dig. Dis. Sci., 61, 2252, 10.1007/s10620-016-4145-y Haines, 2016, TNFalpha/IFNgamma mediated intestinal epithelial barrier dysfunction is attenuated by microRNA-93 downregulation of PTK6 in mouse colonic epithelial cells, PLoS One, 11, e0154351, 10.1371/journal.pone.0154351 Wang, 2016, Pro-inflammatory miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in inflammatory bowel disease, Genome Biol., 17, 58, 10.1186/s13059-016-0901-8 Lili, 2016, Claudin-based barrier differentiation in the colonic epithelial crypt niche involves Hopx/Klf4 and Tcf7l2/Hnf4-alpha cascades, Tissue Barriers, 4, e1214038, 10.1080/21688370.2016.1214038 Saeedi, 2015, HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity, Mol. Biol. Cell, 26, 2252, 10.1091/mbc.e14-07-1194 Kalla, 2015, MicroRNAs: new players in IBD, Gut, 64, 504, 10.1136/gutjnl-2014-307891 McKenna, 2010, MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function, Gastroenterology, 139, 1654, 10.1053/j.gastro.2010.07.040 Zhou, 2015, MicroRNA 29 targets nuclear factor-kappaB-repressing factor and Claudin 1 to increase intestinal permeability, Gastroenterology, 148, 158, 10.1053/j.gastro.2014.09.037 Yang, 2014, Posttranscriptional regulation of intestinal epithelial tight junction barrier by RNA-binding proteins and microRNAs, Tissue Barriers, 2, e28320, 10.4161/tisb.28320 Ye, 2011, MicroRNA regulation of intestinal epithelial tight junction permeability, Gastroenterology, 141, 1323, 10.1053/j.gastro.2011.07.005 Luettig, 2015, Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation, Tissue Barriers, 3, e977176, 10.4161/21688370.2014.977176 Weber, 2008, Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation, Lab. Investig., 88, 1110, 10.1038/labinvest.2008.78 Zhang, 2013, Salmonella infection upregulates the leaky protein claudin-2 in intestinal epithelial cells, PLoS One, 8, e58606, 10.1371/journal.pone.0058606 Capaldo, 2014, Proinflammatory cytokine-induced tight junction remodeling through dynamic self-assembly of claudins, Mol. Biol. Cell, 25, 2710, 10.1091/mbc.e14-02-0773 Ahmad, 2014, Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis, Mucosal Immunol., 7, 1340, 10.1038/mi.2014.21 Laukoetter, 2007, JAM-A regulates permeability and inflammation in the intestine in vivo, J. Exp. Med., 204, 3067, 10.1084/jem.20071416 Naydenov, 2016, Nonmuscle myosin IIA regulates intestinal epithelial barrier in vivo and plays a protective role during experimental colitis, Sci. Rep., 6, 24161, 10.1038/srep24161 Nighot, 2015, Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation, J. Biol. Chem., 290, 7234, 10.1074/jbc.M114.597492 Coeffier, 2010, Increased proteasome-mediated degradation of occludin in irritable bowel syndrome, Am. J. Gastroenterol., 105, 1181, 10.1038/ajg.2009.700 Kucharzik, 2001, Neutrophil transmigration in inflammatory bowel disease is associated with differential expression of epithelial intercellular junction proteins, Am. J. Pathol., 159, 2001, 10.1016/S0002-9440(10)63051-9 Schulzke, 2005, Epithelial transport and barrier function in occludin-deficient mice, Biochim. Biophys. Acta, 1669, 34, 10.1016/j.bbamem.2005.01.008 Katsuno, 2008, Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells, Mol. Biol. Cell, 19, 2465, 10.1091/mbc.e07-12-1215 Fasano, 1995, Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro, J. Clin. Invest., 96, 710, 10.1172/JCI118114 Bergmann, 2013, Bifidobacteria stabilize claudins at tight junctions and prevent intestinal barrier dysfunction in mouse necrotizing enterocolitis, Am. J. Pathol., 182, 1595, 10.1016/j.ajpath.2013.01.013 Spindler, 2015, Loss of desmoglein 2 contributes to the pathogenesis of Crohn's disease, Inflamm. Bowel Dis., 21, 2349 Fletcher, 2014, Analysis of occludin trafficking, demonstrating continuous endocytosis, degradation, recycling and biosynthetic secretory trafficking, PLoS One, 9, e111176, 10.1371/journal.pone.0111176 Ivanov, 2004, The epithelium in inflammatory bowel disease: potential role of endocytosis of junctional proteins in barrier disruption, Novartis Found. Symp., 263, 115 Ivanov, 2004, Endocytosis of epithelial apical junctional proteins by a clathrin-mediated pathway into a unique storage compartment, Mol. Biol. Cell, 15, 176, 10.1091/mbc.e03-05-0319 Smyth, 2012, Reduced surface expression of epithelial E-cadherin evoked by interferon-gamma is Fyn kinase-dependent, PLoS One, 7, e38441, 10.1371/journal.pone.0038441 Durer, 2007, TFF3 and EGF induce different migration patterns of intestinal epithelial cells in vitro and trigger increased internalization of E-cadherin, Cell. Physiol. Biochem., 20, 329, 10.1159/000107519 Yang, 2013, Numb modulates the paracellular permeability of intestinal epithelial cells through regulating apical junctional complex assembly and myosin light chain phosphorylation, Exp. Cell Res., 319, 3214, 10.1016/j.yexcr.2013.07.003 Shen, 2005, Actin depolymerization disrupts tight junctions via caveolae-mediated endocytosis, Mol. Biol. Cell, 16, 3919, 10.1091/mbc.e04-12-1089 Bruewer, 2005, Interferon-gamma induces internalization of epithelial tight junction proteins via a macropinocytosis-like process, FASEB J., 19, 923, 10.1096/fj.04-3260com Marchiando, 2010, Caveolin-1-dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo, J. Cell Biol., 189, 111, 10.1083/jcb.200902153 Hopkins, 2003, Constitutive activation of Rho proteins by CNF-1 influences tight junction structure and epithelial barrier function, J. Cell Sci., 116, 725, 10.1242/jcs.00300 Nusrat, 2000, Tight junctions are membrane microdomains, J. Cell Sci., 113, 1771, 10.1242/jcs.113.10.1771 Van Itallie, 2010, Occludin is required for cytokine-induced regulation of tight junction barriers, J. Cell Sci., 123, 2844, 10.1242/jcs.065581 Schwarz, 2007, LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms, Gastroenterology, 132, 2383, 10.1053/j.gastro.2007.02.052 Raikwar, 2010, Nedd4-2 interacts with occludin to inhibit tight junction formation and enhance paracellular conductance in collecting duct epithelia, Am. J. Physiol. Ren. Physiol., 299, F436, 10.1152/ajprenal.00674.2009 Takahashi, 2009, The E3 ubiquitin ligase LNX1p80 promotes the removal of claudins from tight junctions in MDCK cells, J. Cell Sci., 122, 985, 10.1242/jcs.040055 Li, 2015, Changes in the phosphorylation of claudins during the course of experimental colitis, Int. J. Clin. Exp. Pathol., 8, 12225 Twiss, 2013, HGF signaling regulates Claudin-3 dynamics through its C-terminal tyrosine residues, Tissue Barriers, 1, e27425, 10.4161/tisb.27425 Kersting, 2004, Antigen transport and cytoskeletal characteristics of a distinct enterocyte population in inflammatory bowel diseases, Am. J. Pathol., 165, 425, 10.1016/S0002-9440(10)63308-1 Pravda, 2011, Crohn's disease: evidence for involvement of unregulated transcytosis in disease etio-pathogenesis, World J. Gastroenterol., 17, 1416, 10.3748/wjg.v17.i11.1416 Soderholm, 2004, Increased epithelial uptake of protein antigens in the ileum of Crohn's disease mediated by tumour necrosis factor alpha, Gut, 53, 1817, 10.1136/gut.2004.041426 Burgoyne, 2003, Secretory granule exocytosis, Physiol. Rev., 83, 581, 10.1152/physrev.00031.2002 Rodriguez-Feo, 2015, A new role for reticulon-4B/NOGO-B in the intestinal epithelial barrier function and inflammatory bowel disease, Am. J. Physiol. Gastrointest. Liver Physiol., 308, G981, 10.1152/ajpgi.00309.2014 Naydenov, 2012, Loss of soluble N-ethylmaleimide-sensitive factor attachment protein alpha (alphaSNAP) induces epithelial cell apoptosis via down-regulation of Bcl-2 expression and disruption of the Golgi, J. Biol. Chem., 287, 5928, 10.1074/jbc.M111.278358 Naydenov, 2012, A membrane fusion protein alphaSNAP is a novel regulator of epithelial apical junctions, PLoS One, 7, e34320, 10.1371/journal.pone.0034320 Yu, 2015, Par-3 modulates intestinal epithelial barrier function through regulating intracellular trafficking of occludin and myosin light chain phosphorylation, J. Gastroenterol., 50, 1103, 10.1007/s00535-015-1066-z Guichard, 2013, Cholera toxin disrupts barrier function by inhibiting exocyst-mediated trafficking of host proteins to intestinal cell junctions, Cell Host Microbe, 14, 294, 10.1016/j.chom.2013.08.001 Yu, 2014, TLR sorting by Rab11 endosomes maintains intestinal epithelial-microbial homeostasis, EMBO J., 33, 1882, 10.15252/embj.201487888 Yamamura, 2008, The interaction of JRAB/MICAL-L2 with Rab8 and Rab13 coordinates the assembly of tight junctions and adherens junctions, Mol. Biol. Cell, 19, 971, 10.1091/mbc.e07-06-0551 Ohira, 2009, Dislocation of Rab13 and vasodilator-stimulated phosphoprotein in inactive colon epithelium in patients with Crohn's disease, Int. J. Mol. Med., 24, 829 Ivanov, 2010, Cytoskeletal regulation of epithelial barrier function during inflammation, Am. J. Pathol., 177, 512, 10.2353/ajpath.2010.100168 Baranwal, 2012, Nonredundant roles of cytoplasmic beta- and gamma-actin isoforms in regulation of epithelial apical junctions, Mol. Biol. Cell, 23, 3542, 10.1091/mbc.e12-02-0162 Ivanov, 2008, Actin motors that drive formation and disassembly of epithelial apical junctions, Front. Biosci., 13, 6662, 10.2741/3180 Musch, 2006, Roles of ZO-1, occludin, and actin in oxidant-induced barrier disruption, Am. J. Physiol. Gastrointest. Liver Physiol., 290, G222, 10.1152/ajpgi.00301.2005 Utech, 2005, Mechanism of IFN-gamma-induced endocytosis of tight junction proteins: myosin II-dependent vacuolarization of the apical plasma membrane, Mol. Biol. Cell, 16, 5040, 10.1091/mbc.e05-03-0193 Noth, 2011, Increased intestinal permeability and tight junction disruption by altered expression and localization of occludin in a murine graft versus host disease model, BMC Gastroenterol., 11, 109, 10.1186/1471-230X-11-109 Ivanov, 2005, Differential roles for actin polymerization and a myosin II motor in assembly of the epithelial apical junctional complex, Mol. Biol. Cell, 16, 2636, 10.1091/mbc.e05-01-0043 Ivanov, 2004, Role for actin filament turnover and a myosin II motor in cytoskeleton-driven disassembly of the epithelial apical junctional complex, Mol. Biol. Cell, 15, 2639, 10.1091/mbc.e04-02-0163 Lechuga, 2015, Actin-interacting protein 1 controls assembly and permeability of intestinal epithelial apical junctions, Am. J. Physiol. Gastrointest. Liver Physiol., 308, G745, 10.1152/ajpgi.00446.2014 Ono, 2007, Mechanism of depolymerization and severing of actin filaments and its significance in cytoskeletal dynamics, Int. Rev. Cytol., 258, 1, 10.1016/S0074-7696(07)58001-0 Zhou, 2015, The Arp2/3 complex has essential roles in vesicle trafficking and transcytosis in the mammalian small intestine, Mol. Biol. Cell, 26, 1995, 10.1091/mbc.e14-10-1481 Wang, 2016, Actin-depolymerizing factor and cofilin-1 have unique and overlapping functions in regulating intestinal epithelial junctions and mucosal inflammation, Am. J. Pathol., 186, 844, 10.1016/j.ajpath.2015.11.023 Citalan-Madrid, 2017, Cortactin deficiency causes increased RhoA/ROCK1-dependent actomyosin contractility, intestinal epithelial barrier dysfunction, and disproportionately severe DSS-induced colitis, Mucosal Immunol., 10.1038/mi.2016.136 Kim, 2015, Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1beta, J. Exp. Med., 212, 927, 10.1084/jem.20142384 Vicente-Manzanares, 2009, Non-muscle myosin II takes centre stage in cell adhesion and migration, Nat. Rev. Mol. Cell Biol., 10, 778, 10.1038/nrm2786 Heissler, 2015, Four things to know about myosin light chains as reporters for non-muscle myosin-2 dynamics in live cells, Cytoskeleton (Hoboken), 72, 65, 10.1002/cm.21212 Liu, 2016, Mammalian nonmuscle myosin II binds to anionic phospholipids with concomitant dissociation of the regulatory light chain, J. Biol. Chem., 291, 24828, 10.1074/jbc.M116.739185 Ivanov, 2007, A unique role for nonmuscle myosin heavy chain IIA in regulation of epithelial apical junctions, PLoS One, 2, e658, 10.1371/journal.pone.0000658 Citalan-Madrid, 2013, Small GTPases of the Ras superfamily regulate intestinal epithelial homeostasis and barrier function via common and unique mechanisms, Tissue Barriers, 1, e26938, 10.4161/tisb.26938 Zihni, 2015, RhoGTPase signalling at epithelial tight junctions: bridging the GAP between polarity and cancer, Int. J. Biochem. Cell Biol., 64, 120, 10.1016/j.biocel.2015.02.020 Nusrat, 1995, Rho protein regulates tight junctions and perijunctional actin organization in polarized epithelia, Proc. Natl. Acad. Sci. U. S. A., 92, 10629, 10.1073/pnas.92.23.10629 Samarin, 2007, Rho/Rho-associated kinase-II signaling mediates disassembly of epithelial apical junctions, Mol. Biol. Cell, 18, 3429, 10.1091/mbc.e07-04-0315 Schaefer, 2014, Toward understanding RhoGTPase specificity: structure, function and local activation, Small GTPases, 5, 6, 10.4161/21541248.2014.968004 Segain, 2003, Rho kinase blockade prevents inflammation via nuclear factor kappa B inhibition: evidence in Crohn's disease and experimental colitis, Gastroenterology, 124, 1180, 10.1016/S0016-5085(03)00283-X Lopez-Posadas, 2016, Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation, J. Clin. Invest., 126, 611, 10.1172/JCI80997 Hegan, 2016, Mice lacking myosin IXb, an inflammatory bowel disease susceptibility gene, have impaired intestinal barrier function and superficial ulceration in the ileum, Cytoskeleton (Hoboken), 73, 163, 10.1002/cm.21292 Lee, 2016, Arhgap17, a RhoGTPase activating protein, regulates mucosal and epithelial barrier function in the mouse colon, Sci. Rep., 6, 26923, 10.1038/srep26923 Melendez, 2013, Cdc42 coordinates proliferation, polarity, migration, and differentiation of small intestinal epithelial cells in mice, Gastroenterology, 145, 808, 10.1053/j.gastro.2013.06.021 Liu, 2016, DOCK2 confers immunity and intestinal colonization resistance to Citrobacter rodentium infection, Sci. Rep., 6, 27814, 10.1038/srep27814