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

Rocío López-Posadas; Christoph Becker; Claudia Günther; Stefan Tenzer; Kerstin Amann; Ulrike Billmeier; Raja Atreya; Gionata Fiorino; Stefania Vetrano; Silvio Danese; Arif B Ekici; Stefan Wirtz; Veronika Thonn; Alastair J M Watson; Cord Brakebusch; Martin Bergö; Markus F Neurath; Imke Atreya

doi:10.1172/JCI80997

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

Rocío López-Posadas, Christoph Becker, Claudia Günther, Stefan Tenzer, Kerstin Amann, Ulrike Billmeier, Raja Atreya, Gionata Fiorino, Stefania Vetrano, Silvio Danese, Arif B Ekici, Stefan Wirtz, Veronika Thonn, Alastair J M Watson, Cord Brakebusch, Martin Bergö, Markus F Neurath, Imke Atreya

27 Citations (Scopus)

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.

Original language	English
Journal	The Journal of Clinical Investigation
Volume	126
Issue number	2
Pages (from-to)	611-26
Number of pages	16
ISSN	0021-9738
DOIs	https://doi.org/10.1172/JCI80997
Publication status	Published - 1 Feb 2016

Keywords

Alkyl and Aryl Transferases
Animals
CD4-Positive T-Lymphocytes
Humans
Inflammatory Bowel Diseases
Intestinal Mucosa
Mice
Mice, Mutant Strains
Prenylation
Signal Transduction
rho GTP-Binding Proteins
rhoA GTP-Binding Protein
Journal Article
Research Support, Non-U.S. Gov't

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López-Posadas, R., Becker, C., Günther, C., Tenzer, S., Amann, K., Billmeier, U., Atreya, R., Fiorino, G., Vetrano, S., Danese, S., Ekici, A. B., Wirtz, S., Thonn, V., Watson, A. J. M., Brakebusch, C., Bergö, M., Neurath, M. F., & Atreya, I. (2016). Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation. The Journal of Clinical Investigation, 126(2), 611-26. https://doi.org/10.1172/JCI80997

López-Posadas, R, Becker, C, Günther, C, Tenzer, S, Amann, K, Billmeier, U, Atreya, R, Fiorino, G, Vetrano, S, Danese, S, Ekici, AB, Wirtz, S, Thonn, V, Watson, AJM, Brakebusch, C, Bergö, M, Neurath, MF & Atreya, I 2016, 'Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation', The Journal of Clinical Investigation, vol. 126, no. 2, pp. 611-26. https://doi.org/10.1172/JCI80997

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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.",

keywords = "Alkyl and Aryl Transferases, Animals, CD4-Positive T-Lymphocytes, Humans, Inflammatory Bowel Diseases, Intestinal Mucosa, Mice, Mice, Mutant Strains, Prenylation, Signal Transduction, rho GTP-Binding Proteins, rhoA GTP-Binding Protein, Journal Article, Research Support, Non-U.S. Gov't",

author = "Roc{\'i}o L{\'o}pez-Posadas and Christoph Becker and Claudia G{\"u}nther and Stefan Tenzer and Kerstin Amann and Ulrike Billmeier and Raja Atreya and Gionata Fiorino and Stefania Vetrano and Silvio Danese and Ekici, {Arif B} and Stefan Wirtz and Veronika Thonn and Watson, {Alastair J M} and Cord Brakebusch and Martin Berg{\"o} and Neurath, {Markus F} and Imke Atreya",

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doi = "10.1172/JCI80997",

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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 - 2016/2/1

Y1 - 2016/2/1

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

SN - 0021-9738

VL - 126

SP - 611

EP - 626

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 2

ER -

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

Abstract

Keywords

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