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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	The Journal of Clinical Investigation
Vol/bind	126
Udgave nummer	2
Sider (fra-til)	611-26
Antal sider	16
ISSN	0021-9738
DOI	https://doi.org/10.1172/JCI80997
Status	Udgivet - 1 feb. 2016

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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, bind 126, nr. 2, s. 611-26. https://doi.org/10.1172/JCI80997

@article{983ec058ef474c74aacf456be869daab,

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",

year = "2016",

month = feb,

day = "1",

doi = "10.1172/JCI80997",

language = "English",

volume = "126",

pages = "611--26",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

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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 - 2016/2/1

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

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