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

By Rubina Tuladhar, Nageswari Yarravarapu, Yuyong Ma, Chengwei Zhang, Jeremiah Herbert, James Kim, Chuo Chen, L. Lum. 2019

15 citations recorded by the source corpus.

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 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.

Subfields: Biochemistry, Molecular Biology

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In Molecular Biology

1. Jonathan Kim
2. O. Clarke
3. G. Parisi
4. F. Mancia
5. Daniela Ross
6. R. Nygaard
7. Jia Yu
8. D. Virshup

Citations in the corpus

• Structural model of PORCN illuminates disease-associated variants and drug binding sites (2021, background): “The structural model thus suggests Asn306 could enforce the use of cisdouble bond-containing fatty acid substrates (Tuladhar et al., 2019).”
• Structural basis of WLS/Evi-mediated Wnt transport and secretion (2020, result): “This observation is in contrast to the high specificity reported for PORCN and the Wnt deacylase NOTUM for 16:1 acyl groups (Kakugawa et al., 2015; Lee et al., 2019; Rios-Esteves and Resh, 2013; Tuladhar et al., 2019).”