title: Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation.
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.
authors.forename: Rocío
authors.initials: R
authors.lastname: López-Posadas
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.forename: Claudia
authors.initials: C
authors.lastname: Günther
authors.forename: Stefan
authors.initials: S
authors.lastname: Tenzer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Billmeier
authors.forename: Raja
authors.initials: R
authors.lastname: Atreya
authors.forename: Gionata
authors.initials: G
authors.lastname: Fiorino
authors.forename: Stefania
authors.initials: S
authors.lastname: Vetrano
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.forename: Veronika
authors.initials: V
authors.lastname: Thonn
authors.forename: Alastair J M
authors.initials: AJ
authors.lastname: Watson
authors.forename: Cord
authors.initials: C
authors.lastname: Brakebusch
authors.forename: Martin
authors.initials: M
authors.lastname: Bergö
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.forename: Imke
authors.initials: I
authors.lastname: Atreya
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D054876:Prenylation; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C066737:RHOA protein, human; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein