TY - JOUR

T1 - Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation

AU - López-Posadas, Rocío

AU - Becker, Christoph

AU - Günther, Claudia

AU - Tenzer, Stefan

AU - Amann, Kerstin

AU - Billmeier, Ulrike

AU - Atreya, Raja

AU - Fiorino, Gionata

AU - Vetrano, Stefania

AU - Danese, Silvio

AU - Ekici, Arif B

AU - Wirtz, Stefan

AU - Thonn, Veronika

AU - Watson, Alastair J M

AU - Brakebusch, Cord

AU - Bergö, Martin

AU - Neurath, Markus F

AU - Atreya, Imke

PY - 2016/2

Y1 - 2016/2

N2 - 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.

AB - 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.

KW - Alkyl and Aryl Transferases

KW - Animals

KW - CD4-Positive T-Lymphocytes

KW - Humans

KW - Inflammatory Bowel Diseases

KW - Intestinal Mucosa

KW - Mice

KW - Mice, Mutant Strains

KW - Prenylation

KW - Signal Transduction

KW - rho GTP-Binding Proteins

KW - rhoA GTP-Binding Protein

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1172/JCI80997

DO - 10.1172/JCI80997

M3 - Journal article

C2 - 26752649

VL - 126

SP - 611

EP - 626

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 2

ER -