Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation

• Published in: The Journal of clinical investigation Vol. 126; no. 2; pp. 611 - 626
• Main Authors: López-Posadas, Rocío, Becker, Christoph, Günther, Claudia, Tenzer, Stefan, Amann, Kerstin, Billmeier, Ulrike, Atreya, Raja, Fiorino, Gionata, Vetrano, Stefania, Danese, Silvio, Ekici, Arif B, Wirtz, Stefan, Thonn, Veronika, Watson, Alastair J M, Brakebusch, Cord, Bergö, Martin, Neurath, Markus F, Atreya, Imke
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-02-2016
• Subjects: Alkyl and Aryl Transferases - genetics; Alkyl and Aryl Transferases - metabolism; alpha; Animals; barrier function; Biomedical research; bowel-disease; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Cellular signal transduction; Clinical Medicine; Colorectal diseases; crohns-disease; Cytoskeleton; Design of experiments; Development and progression; Disease; Gastrointestinal diseases; Gene expression; Genetic aspects; Genetic transcription; Health aspects; Homeostasis; Humans; in-vivo; Inflammation; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - metabolism; Inflammatory Bowel Diseases - pathology; Inflammatory Bowel Diseases - therapy; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Klinisk medicin; Medicin och hälsovetenskap; Mice; Mice, Mutant Strains; migration; Pathogenesis; Physiology; Prenylation; Proteins; Research & Experimental Medicine; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - metabolism; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; Signal Transduction; Small intestine; stem-cells; ulcerative-colitis
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/jci80997

Although defects in intestinal barrier function are a key pathogenic factor in patients with inflammatory bowel diseases (IBDs), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we addressed this issue by characterizing the transcriptome of IECs from IBD patients using a genome-wide approach. We observed disease-specific alterations in IECs with markedly impaired Rho-A signaling in active IBD patients. Localization of epithelial Rho-A was shifted to the cytosol in IBDs, and inflammation was associated with suppressed Rho-A activation due to reduced expression of the Rho-A prenylation enzyme geranylgeranyltransferase-I (GGTase-I). Functionally, we found that mice with conditional loss of Rhoa or the gene encoding GGTase-I, Pggt1b, in IECs exhibit spontaneous chronic intestinal inflammation with accumulation of granulocytes and CD4+ T cells. This phenotype was associated with cytoskeleton rearrangement and aberrant cell shedding, ultimately leading to loss of epithelial integrity and subsequent inflammation. These findings uncover deficient prenylation of Rho-A as a key player in the pathogenesis of IBDs. As therapeutic triggering of Rho-A signaling suppressed intestinal inflammation in mice with GGTase-I-deficient IECs, our findings suggest new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients.