Original Article
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2014; 20(40): 14855-14864
Published online Oct 28, 2014. doi: 10.3748/wjg.v20.i40.14855
Modulating effects of acyl-CoA synthetase 5-derived mitochondrial Wnt2B palmitoylation on intestinal Wnt activity
Christina Klaus, Ursula Schneider, Christian Hedberg, Anke K Schütz, Jürgen Bernhagen, Herbert Waldmann, Nikolaus Gassler, Elke Kaemmerer
Christina Klaus, Ursula Schneider, Nikolaus Gassler, Elke Kaemmerer, Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany
Christian Hedberg, Herbert Waldmann, Department of Chemical Biology, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany
Anke K Schütz, Jürgen Bernhagen, Department of Biochemistry and Molecular Cell Biology, RWTH Aachen University, 52074 Aachen, Germany
Elke Kaemmerer, Department of Pediatrics, RWTH Aachen University, 52074 Aachen, Germany
Author contributions: Klaus C, Waldmann H and Gassler N designed the research; Klaus C, Schneider U and Kaemmerer E performed the research; Hedberg C, Schütz AK and Bernhagen J contributed new reagents/analytic tools; Klaus C, Waldmann H and Gassler N wrote the paper.
Supported by Deutsche Forschungsgemeinschaft No. DFG GA 785/5-1 and Deutsche Krebshilfe No. GA 109313
Correspondence to: Nikolaus Gassler, Professor, Institute of Pathology, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany. ngassler@ukaachen.de
Telephone: +49-241-8088897 Fax: +49-241-8082439
Received: March 30, 2014
Revised: May 5, 2014
Accepted: June 21, 2014
Published online: October 28, 2014
Abstract

AIM: To investigate the role of acyl-CoA synthetase 5 (ACSL5) activity in Wnt signaling in intestinal surface epithelia.

METHODS: Several cell lines were used to investigate the ACSL5-dependent expression and synthesis of Wnt2B, a mitochondrially expressed protein of the Wnt signaling family. Wnt activity was functionally assessed with a luciferase reporter assay. ACSL5-related biochemical Wnt2B modifications were investigated with a modified acyl-exchange assay. The findings from the cell culture models were verified using an Apcmin/+ mouse model as well as normal and neoplastic diseased human intestinal tissues.

RESULTS: In the presence of ACSL5, Wnt2B was unable to translocate into the nucleus and was enriched in mitochondria, which was paralleled by a significant decrease in Wnt activity. ACSL5-dependent S-palmitoylation of Wnt2B was identified as a molecular reason for mitochondrial Wnt2B accumulation. In cell culture systems, a strong relation of ACSL5 expression, Wnt2B palmitoylation, and degree of malignancy were found. Using normal mucosa, the association of ACSL5 and Wnt2B was seen, but in intestinal neoplasias the mechanism was only rudimentarily observed.

CONCLUSION: ACSL5 mediates antiproliferative activities via Wnt2B palmitoylation with diminished Wnt activity. The molecular pathway is probably relevant for intestinal homeostasis, overwhelmed by other pathways in carcinogenesis.

Keywords: Acyl-CoA synthetases, Wnt signaling, Palmitoylation, Intestinal barrier, Carcinogenesis

Core tip: Acyl-CoA synthetase 5 (ACSL5) plays a key role in fatty acid metabolism. Besides its proapoptotic effects along the crypt-villus-axis ACSL5 also functions as an antiproliferative modifier of Wnt signaling activity. In the presence of ACSL5, Wnt2B was S-palmitoylated and thereby enriched in mitochondria, which was paralleled by a significant decrease in Wnt activity. The molecular pathway is probably of relevance for the homeostasis of the intestinal barrier.