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XB-ART-56364
J Biol Chem January 1, 2019; 294 (16): 6273-6282.

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

Tuladhar R , Yarravarapu N , Ma Y , Zhang C , Herbert J , Kim J , Chen C , Lum L .


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 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.

PubMed ID: 30737280
PMC ID: PMC6484125
Article link: J Biol Chem
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ctrl dvl2 fas hap1 hhat myc porcn scd shh tbl1x wls wnt3a wnt7b wnt9b
GO keywords: cell-cell signaling [+]


Article Images: [+] show captions
References [+] :
Abrami, Palmitoylation and ubiquitination regulate exit of the Wnt signaling protein LRP6 from the endoplasmic reticulum. 2008, Pubmed