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Träfflista för sökning "WFRF:(Lopez Posadas R.) srt2:(2016)"

Sökning: WFRF:(Lopez Posadas R.) > (2016)

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  • Lopez-Posadas, R., et al. (författare)
  • Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation
  • 2016
  • Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 126:2, s. 611-626
  • Tidskriftsartikel (refereegranskat)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-l). Functionally, we found that mice with conditional loss of Rhoa or the gene encoding GGTase-1, Pggtlb, 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-l-deficient IECs, our findings suggest new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients.
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