Epithelial Rab guanine nucleotide exchange factor 1 (Rabgef1) deficiency increases susceptibility to DSS-induced intestinal inflammation in mice

Rab guanine nucleotide exchange factor (GEF)1 (Rabgef1) is a guanine nucleotide exchange factor for the endocytic GTPase Rab5, and also exhibits E3 ubiquitin ligase activity in vitro. In vivo functions of Rabgef1 remain largely unknown, but Rabgef1 is critical for health, as globally Rabgef1-deficient mice exhibit perinatal mortality and those surviving to adulthood spontaneously develop severe skin inflammation. In the mouse gut, we found that Rabgef1 is highly expressed in intestinal epithelial cells (IECs). We performed conditional deletion of Rabgef1 using the cre-lox system to obtain mice lacking Rabgef1 specifically in IECs (Rabgef1IEC-KO). These mice did not develop spontaneous intestinal abnormalities but showed an increased susceptibility to inflammation in dextran sodium sulfate (DSS)-induced colitis model. Indeed, compared to littermate controls, mice lacking Rabgef1 in IECs exhibited shorter and highly inflamed colons and higher inflammatory scores in histopathological examination of colons, suggesting that Rabgef1 expression regulates IEC function and is critical in limiting DSS induced inflammation and damage. In addition, we also showed that mRNA expression of pro-inflammatory cytokines, such as Il1b and Tnfa, was upregulated in IECs isolated from Rabgef1IEC-KO mice compared to the ones isolated from littermate controls. Taken together, these results suggest that Rabgef1 acts as a regulator of intestinal homeostasis, and that dysregulated Rabgef1 expression could contribute to intestinal barrier dysfunction in inflammatory conditions of the gut.