Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 16, Pages 6273-6282Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.007268
Keywords
Wnt pathway; signal transduction; fatty acid; Wnt signaling; acyltransferase; posttranslational modification (PTM); fatty acylation; membrane-bound O-acyltransferase (MBOAT); palmitoleation; Porcupine (PORCN); Wntless (WLS)
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Funding
- Welch Foundation [I-1665]
- Cancer Prevention and Research Institute of Texas Grant [RP130212]
- NCI, National Institutes of Health [1R01 CA168761]
- American Cancer Society [RSG-16-090-01-TBG]
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The maintenance of adult animal tissues depends upon highly conserved intercellular signaling molecules that include the secreted WNT proteins. Although it is generally accepted that lipidation of WNTs by the acyltransferase Porcupine (PORCN) and their subsequent recognition by the Wntless (WLS) protein is essential for their cellular secretion, the molecular understanding of this process remains limited. Using structurally diverse fatty acyl donor analogs and mouse embryonic fibroblasts expressing PORCN protein from different metazoan phyla, we demonstrate here that PORCN active-site features, which are conserved across the animal kingdom, enforce cis-9 fatty acylation of WNTs. Aberrant acylation of a WNT with an exogenously supplied trans-9 fatty acid induced the accumulation of WNT-PORCN complexes, suggesting that the fatty acyl species is critical for the extrication of lipidated WNTs from PORCN. Our findings reveal a previously unrecognized fatty acyl-selective checkpoint in the manufacturing of a lipoprotein that forms a basis for WNT signaling sensitivity to trans fats and to PORCN inhibitors in clinical development.
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