Stereoselective fatty acylation is essential for the release of lipidated WNT proteins from the acyltransferase Porcupine (PORCN)

Rubina Tuladhar, Nageswari Yarravarapu, Yuyong Ma, Chengwei Zhang, Jeremiah Herbert, James Kim, Chuo Chen, Lawrence Lum

Research output: Contribution to journalArticle

Abstract

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-Δ9 fatty acylation of WNTs. Aberrant acylation of a WNT with an exogenously supplied trans-Δ9 fatty acid induced the accumulation of WNT-PORCN complexes, suggesting that the fatty acyl species is critical for the extrication of lipidatedWNTsfrom PORCN. Our findings reveal a previously unrecognized fatty acyl-selective checkpoint in the manufacturing of a lipoprotein that forms a basis forWNTsignaling sensitivity to trans fats and to PORCN inhibitors in clinical development.

Original languageEnglish (US)
Pages (from-to)6273-6282
Number of pages10
JournalJournal of Biological Chemistry
Volume294
Issue number16
DOIs
StatePublished - Apr 19 2019

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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