The Tissue Specific Role of Endosome Associated Protein SNX27 in Colonic Inflammation and Tumorigenesis

SNX27, member of the sorting nexin (SNX) family, carries a unique PDZ domain and mediates recycling of endocytosed transmembrane proteins. SNX27 is critical for neurodevelopment and whole body knockout in mice has been found to be embryonically lethal. Although SNX27 is variably expressed in different tissues, its role specifically in the intestines and the development of intestinal disorders remains to be unexplored. Epithelial barrier integrity, regulated by junction proteins, is critical for the maintenance of intestinal tissue homeostasis. Weakening of the intestinal barrier thus promotes susceptibility towards intestinal disorders, such as IBD and CRC. Many junction proteins carry a PDZ-binding motif, however their interactions with SNX27 and its impact on the intestinal epithelial barrier integrity and pathophysiology of intestinal disorders has not been previously investigated. Reanalysis of publicly available datasets revealed significantly lower SNX27 expression in IBD and CRC patients. We generated novel mouse models of SNX27 conditional deletion from intestinal epithelial cells (SNX27ΔIEC), Paneth cells (SNX27ΔPC), and myeloid cells (SNX27ΔLyz) to investigate the tissue-specific roles of SNX27 in intestinal physiology. We then challenged these mice with DSS-induced colitis and AOM/DSS-induced CRC to study the initiation and progression of intestinal disorders. Loss of intestinal epithelial SNX27 resulted in poor differentiation of secretory Paneth and goblet cells, narrowing of the protective mucin layer, increased epithelial apoptosis, and downregulation of crucial epithelial junction proteins (ꞵ-catenin, E-cadherin, ZO-1, and claudin10). Thus, SNX27ΔIEC mice exhibited poor barrier integrity, leakier guts, increased mucosal inflammation, and greater susceptibility towards chemically induced colitis and CRC. While conditional deletion of SNX27 from Paneth cells also increased sensitivity to DSS, SNX27ΔLyz mice contrastingly exhibited less severity towards colitis and delayed onset of CRC. Not only did SNX27ΔLyz mice develop significantly fewer colonic tumors than SNX27ΔIEC mice, the percentage survival rate was also drastically higher in SNX27ΔLyz vs SNX27ΔIEC mice. Overall, this dissertation investigates the tissue-specific roles of SNX27 in intestinal physiology. Our results indicate a previously unknown role of SNX27 in regulating intestinal tissue homeostasis and responses towards inflammation and tumorigenesis. Thus, a thorough understanding of SNX27-driven mechanisms in IBD and CRC will provide insights into new therapeutic strategies.