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

Rocío López-Posadas, Christoph Becker, Claudia Günther, Stefan Tenzer, Kerstin Amann, Ulrike Billmeier, Raja Atreya, Gionata Fiorino, Stefania Vetrano, Silvio Danese, Arif B. Ekici, Stefan Wirtz, Veronika Thonn, Alastair J M Watson, Cord Brakebusch, Martin Bergö, Markus F. Neurath, Imke Atreya

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)611-626
Number of pages16
JournalJournal of Clinical Investigation
Volume126
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

ASJC Scopus subject areas

  • Medicine(all)

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    López-Posadas, R., Becker, C., Günther, C., Tenzer, S., Amann, K., Billmeier, U., Atreya, R., Fiorino, G., Vetrano, S., Danese, S., Ekici, A. B., Wirtz, S., Thonn, V., Watson, A. J. M., Brakebusch, C., Bergö, M., Neurath, M. F., & Atreya, I. (2016). Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation. Journal of Clinical Investigation, 126(2), 611-626. https://doi.org/10.1172/JCI80997