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

Lopez-Posadas, Rocio, Becker, Christoph, Gunther, Claudia, Tenzer, Stefan, Amann, Kerstin, Billmeier, Ulrike, Atreya, Raja, Fiorino, Gionata, Vetrano, Stefania, Danese, Silvio, Ekici, Arif B., Wirtz, Stefan, Thonn, Veronika, Watson, Alastair, Brakebusch, Cord, Bergo, Martin, Neurath, Marcus and Atreya, Imke (2016) Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation. Journal of Clinical Investigation, 126 (2). pp. 611-626. ISSN 0021-9738

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Abstract

Although defects in intestinal barrier function are discussed as a key pathogenic factor in patients with inflammatory bowel diseases (IBD), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we performed a novel approach to characterize 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 IBD where Rho-A activation was suppressed due to reduced expression of the Rho-A prenylation enzyme GGTase-I. The functional relevance of this pathway was highlighted by studies in mice with conditional gene targeting in which deletion of RhoA or GGTase-I in IECs caused 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 IBD. As therapeutic triggering of Rho-A signaling suppressed intestinal inflammation in mice with GGTase-I deficient IECs, our findings open new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients.

Item Type: Article
Uncontrolled Keywords: prenylation,intestine,apoptosis,barrier
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 18 Feb 2016 13:00
Last Modified: 08 Oct 2019 13:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/57176
DOI: 10.1172/JCI80997

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