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The mechanism(s) by which CT inhibits NHE3 is partially understood, although no drug therapy has been successful at reversing this inhibition. We now describe that CT phosphorylates an amino acid in the PDZ domain of SNX27, which inhibits SNX27-mediated trafficking of NHE3 from the early endosomes to the plasma membrane (PM), and contributes to reduced basal NHE3 activity through a mechanism that involves reduced PM expression and reduced endocytic recycling. Importantly, mutagenesis studies (Ser to Asp) showed that the effect of this phosphorylation of SNX27 phenocopies the effects seen upon loss of SNX27 function, affecting PM trafficking of cargo proteins that bind SNX27\u2013retromer. Additionally, CT destabilizes retromer function by decreasing the amount of core retromer proteins. These effects of CT can be partially rescued by enhancing retromer stability by using \u2018pharmacological chaperones\u2019. Moreover, pharmacological chaperones can be used to increase basal and cholera toxin-inhibited NHE3 activity and fluid absorption by intestinal epithelial cells.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/jcs.218610","type":"journal-article","created":{"date-parts":[[2018,7,20]],"date-time":"2018-07-20T13:35:22Z","timestamp":1532093722000},"source":"Crossref","is-referenced-by-count":24,"title":["Cholera toxin inhibits SNX27-retromer-mediated delivery of cargo proteins to the plasma membrane"],"prefix":"10.1242","volume":"131","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0796-2619","authenticated-orcid":false,"given":"Varsha","family":"Singh","sequence":"first","affiliation":[{"name":"School of Medicine, Johns Hopkins University 1 Departments of Medicine and Physiology , , Baltimore, MD 21205 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianbo","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Medicine, Johns Hopkins University 1 Departments of Medicine and Physiology , , Baltimore, MD 21205 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianyi","family":"Yin","sequence":"additional","affiliation":[{"name":"School of Medicine, Johns Hopkins University 1 Departments of Medicine and Physiology , , Baltimore, MD 21205 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Cole","sequence":"additional","affiliation":[{"name":"School of Medicine, Johns Hopkins University 2 Department of Biological Chemistry , , Baltimore, MD 21205 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Tse","sequence":"additional","affiliation":[{"name":"School of Medicine, Johns Hopkins University 1 Departments of Medicine and Physiology , , Baltimore, MD 21205 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego E.","family":"Berman","sequence":"additional","affiliation":[{"name":"The Taub Institute for Research on Alzheimer's Disease and the Aging Brain 3 , Department of Pathology , , New York, NY 10032 , USA"},{"name":"Columbia University College of Physicians and Surgeons 3 , Department of Pathology , , New York, NY 10032 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott A.","family":"Small","sequence":"additional","affiliation":[{"name":"The Taub Institute for Research on Alzheimer's Disease and the Aging Brain 3 , Department of Pathology , , New York, NY 10032 , USA"},{"name":"Columbia University College of Physicians and Surgeons 3 , Department of Pathology , , New York, NY 10032 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory","family":"Petsko","sequence":"additional","affiliation":[{"name":"Weill Cornell Medical College 4 Helen and Robert Appel Alzheimer's Disease Research Institute and Department of Neurology , , New York, NY 10021, \u2008 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0477-8824","authenticated-orcid":false,"given":"Mark","family":"Donowitz","sequence":"additional","affiliation":[{"name":"School of Medicine, Johns Hopkins University 1 Departments of Medicine and Physiology , , Baltimore, MD 21205 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2018,8,17]]},"reference":[{"key":"2024061317515578700_JCS218610C1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1083\/jcb.200312055","article-title":"Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor","volume":"165","author":"Arighi","year":"2004","journal-title":"J. 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