Published online Oct 28, 2014. doi: 10.3748/wjg.v20.i40.14855
Revised: May 5, 2014
Accepted: June 21, 2014
Published online: October 28, 2014
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.
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.