The role of Evi/Wntless in exporting Wnt proteins

Intercellular communication by Wnt proteins governs many essential processes during development, tissue homeostasis and disease in all metazoans. Many context-dependent effects are initiated in the Wnt-producing cells and depend on the export of lipidated Wnt proteins. Although much focus has been on understanding intracellular Wnt signal transduction, the cellular machinery responsible for Wnt secretion became better understood only recently. After lipid modification by the acyl-transferase Porcupine, Wnt proteins bind their dedicated cargo protein Evi/Wntless for transport and secretion. Evi/Wntless and Porcupine are conserved transmembrane proteins, and their 3D structures were recently determined. In this Review, we summarise studies and structural data highlighting how Wnts are transported from the ER to the plasma membrane, and the role of SNX3-retromer during the recycling of its cargo receptor Evi/Wntless. We also describe the regulation of Wnt export through a post-translational mechanism and review the importance of Wnt secretion for organ development and cancer, and as a future biomarker.