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dc.contributor.authorGarber, J.J.
dc.contributor.authorMallick, E.M.
dc.contributor.authorScanlon, K.M.
dc.date.accessioned2019-05-21T18:56:22Z
dc.date.available2019-05-21T18:56:22Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85043573767&doi=10.1016%2fj.jcmgh.2017.11.015&partnerID=40&md5=5c773dfcdaa797d770830df788beb13b
dc.identifier.urihttp://hdl.handle.net/10713/9255
dc.description.abstractBackground & Aims: Neural Wiskott-Aldrich Syndrome protein (N-WASP) is a key regulator of the actin cytoskeleton in epithelial tissues and is poised to mediate cytoskeletal-dependent aspects of apical junction complex (AJC) homeostasis. Attaching-and-effacing (AE) pathogens disrupt this homeostasis through translocation of the effector molecule early secreted antigenic target-6 (ESX)-1 secretion-associated protein F (EspF). Although the mechanisms underlying AJC disruption by EspF are unknown, EspF contains putative binding sites for N-WASP and the endocytic regulator sorting nexin 9 (SNX9). We hypothesized that N-WASP regulates AJC integrity and AE pathogens use EspF to induce junction disassembly through an N-WASP-and SNX9-dependent pathway. Methods: We analyzed mice with intestine-specific N-WASP deletion and generated cell lines with N-WASP and SNX9 depletion for dynamic functional assays. We generated EPEC and Citrobacter rodentium strains complemented with EspF bearing point mutations abolishing N-WASP and SNX9 binding to investigate the requirement for these interactions. Results: Mice lacking N-WASP in the intestinal epithelium showed spontaneously increased permeability, abnormal AJC morphology, and mislocalization of occludin. N-WASP depletion in epithelial cell lines led to impaired assembly and disassembly of tight junctions in response to changes in extracellular calcium. Cells lacking N-WASP or SNX9 supported actin pedestals and type III secretion, but were resistant to EPEC-induced AJC disassembly and loss of transepithelial resistance. We found that during in vivo infection with AE pathogens, EspF must bind both N-WASP and SNX9 to disrupt AJCs and induce intestinal barrier dysfunction. Conclusions: Overall, these studies show that N-WASP critically regulates AJC homeostasis, and the AE pathogen effector EspF specifically exploits both N-WASP and SNX9 to disrupt intestinal barrier integrity during infection. Copyright 2018 The Authorsen_US
dc.description.urihttps://dx.doi.org/10.1016/j.jcmgh.2017.11.015en_US
dc.language.isoen_USen_US
dc.publisherElsevier Incen_US
dc.relation.ispartofCellular and Molecular Gastroenterology and Hepatology
dc.subjectCytoskeletonen_US
dc.subjectEspFen_US
dc.subjectJunction Regulationen_US
dc.subjectN-WASPen_US
dc.titleAttaching-and-Effacing Pathogens Exploit Junction Regulatory Activities of N-WASP and SNX9 to Disrupt the Intestinal Barrieren_US
dc.typeArticleen_US
dc.identifier.doi10.1016/j.jcmgh.2017.11.015


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