Modulating effects of acyl-CoA synthetase 5-derived mitochondrial Wnt2B palmitoylation on intestinal Wnt activity

• Published in: World journal of gastroenterology : WJG Vol. 20; no. 40; pp. 14855 - 14864
• Main Authors: Klaus, Christina, Schneider, Ursula, Hedberg, Christian, Schütz, Anke K, Bernhagen, Jürgen, Waldmann, Herbert, Gassler, Nikolaus, Kaemmerer, Elke
• Format: Journal Article
• Language: English
• Published: United States Baishideng Publishing Group Inc 28-10-2014
• Subjects: Active Transport, Cell Nucleus; Acyl-CoA; Adenocarcinoma - enzymology; Adenocarcinoma - pathology; Adenoma - enzymology; Adenoma - genetics; Adenoma - pathology; Animals; Caco-2 Cells; Cell Proliferation; Coenzyme A Ligases - genetics; Coenzyme A Ligases - metabolism; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Epithelial Cells - drug effects; Epithelial Cells - enzymology; Epithelial Cells - pathology; Genes, APC; Glycoproteins - metabolism; HCT116 Cells; HT29 Cells; Humans; Intestinal Mucosa - drug effects; Intestinal Mucosa - enzymology; Intestinal Mucosa - pathology; Lipoylation; Mice, Transgenic; Mitochondria - drug effects; Mitochondria - enzymology; Original; Palmitoylation; Propiolactone - analogs & derivatives; Propiolactone - pharmacology; RNA Interference; signaling; synthetases; Transfection; Wnt; Wnt Proteins - metabolism; Wnt Signaling Pathway - drug effects; Wnt3A Protein - pharmacology; Intestinal barrier; Wnt signaling; Acyl-CoA synthetases; Palmitoylation; Carcinogenesis
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v20.i40.14855

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 investigatedwith 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.