Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation. / López-Posadas, Rocío; Becker, Christoph; Günther, Claudia; Tenzer, Stefan; Amann, Kerstin; Billmeier, Ulrike; Atreya, Raja; Fiorino, Gionata; Vetrano, Stefania; Danese, Silvio; Ekici, Arif B; Wirtz, Stefan; Thonn, Veronika; Watson, Alastair J M; Brakebusch, Cord; Bergö, Martin; Neurath, Markus F; Atreya, Imke.
I: The Journal of Clinical Investigation, Bind 126, Nr. 2, 02.2016, s. 611-26.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 169564179