Rho-A prenylation—a new key player in IBD pathogenesis?

▸ López-Posadas R, Becker C, Günther C, et al. Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation. J Clin Invest 2016;126:611–26. doi:10.1172/JCI80997

Intestinal epithelial cells (IECs) serve as a barrier against pathogens, toxins and antigens. In vivo studies have revealed that disruption of the IEC layer plays a significant role in the pathogenesis of IBD, but the specific intrinsic mechanisms responsible for barrier function loss remain unclear. Rho GTPases are signalling molecules that take part in cytoskeletal protein arrangement and epithelial cell dynamics. Small GTPase recruitment is achieved by prenylation—a post-translational process involving hydrophobic isoprenoids attaching to the C-terminal CAAX motif of the protein. Rho-A signalling regulation in the intestinal epithelium and the impact it has on gut homeostasis in vivo remain relatively unknown. In the present study, López-Posadas and colleagues characterised the transcriptome of IECs from patients with IBD using a genome-wide approach. The research team used gene expression profiling of IECs from inflamed and uninflamed tissue of patients with IBD. They observed disease-specific changes in IECs and found that Rho-A signalling was impaired in patients with IBD. Interestingly, epithelial Rho-A localised in the cytosol of IECs, and inflammation was associated with suppressed Rho-A activation due to reduced expression of the Rho-A prenylation enzyme GGTase-I. When Rhoa or Pggt1b (the gene encoding GGTase-l) was deleted in murine IECs, the mice displayed spontaneous chronic intestinal inflammation along with cytoskeleton rearrangement and abnormal cell shedding leading to epithelial injury. Taken together, these data reveal that Rho-A dysfunction drives injury in GGTase-l-deficient epithelium and this injury can be reversed upon Rho activation. In summary, this study establishes the importance of functional Rho-A signalling and its regulation via prenylation in epithelial integrity maintenance. Therapeutic triggering of Rho-A signalling reduced intestinal inflammation in mice with GGTase-I–deficient IECs, therefore, suggesting potential treatment …