title: Modulating effects of acyl-CoA synthetase 5-derived mitochondrial Wnt2B palmitoylation on intestinal Wnt activity.
abstract: OBJECTIVE
  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 Apc(min/+) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Christina Klaus, Ursula Schneider, Nikolaus Gassler, Elke Kaemmerer, Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Klaus
authors.affiliation: Christina Klaus, Ursula Schneider, Nikolaus Gassler, Elke Kaemmerer, Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Schneider
authors.affiliation: Christina Klaus, Ursula Schneider, Nikolaus Gassler, Elke Kaemmerer, Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hedberg
authors.affiliation: Christina Klaus, Ursula Schneider, Nikolaus Gassler, Elke Kaemmerer, Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Anke K
authors.initials: AK
authors.lastname: Schütz
authors.affiliation: Christina Klaus, Ursula Schneider, Nikolaus Gassler, Elke Kaemmerer, Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.affiliation: Christina Klaus, Ursula Schneider, Nikolaus Gassler, Elke Kaemmerer, Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.affiliation: Christina Klaus, Ursula Schneider, Nikolaus Gassler, Elke Kaemmerer, Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.affiliation: Christina Klaus, Ursula Schneider, Nikolaus Gassler, Elke Kaemmerer, Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Kaemmerer
mesh_terms: D021581:Active Transport, Cell Nucleus; D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000818:Animals; D018938:Caco-2 Cells; D049109:Cell Proliferation; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D017491:Genes, APC; D006023:Glycoproteins / Q000378:metabolism*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D054878:Lipoylation; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D011420:Propiolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D034622:RNA Interference; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D060509:Wnt3A Protein / Q000494:pharmacology
chemical_list: D006023:Glycoproteins; C115496:WNT2B protein, human; D051153:Wnt Proteins; C492031:Wnt2b protein, mouse; D060509:Wnt3A Protein; C578782:palmostatin B; D011420:Propiolactone; D003066:Coenzyme A Ligases; C485465:ACSL5 protein, human
keywords: Acyl-CoA synthetases; Carcinogenesis; Intestinal barrier; Palmitoylation; Wnt signaling