Wnts are lipid-modified signaling glycoproteins present in all metazoans that play key roles in development and homeostasis. Post-translational modifications of Wnts regulate their function. Wnts have a unique post-translational modification, O-linked palmitoleation, that is absolutely required for their function. This Wnt-specific modification occurs during Wnt biosynthesis in the endoplasmic reticulum (ER), catalyzed by the O-acyltransferase Porcupine (PORCN). Palmitoleation is required for Wnt to bind to its transporter Wntless (WLS/Evi) as well as to its receptor Frizzled (FZD). Recent structural studies have illustrated how PORCN recognizes its substrates, and how drugs inhibit this. The abundance of WLS is tightly regulated by intracellular recycling and ubiquitylation-mediated degradation in the ER. The function of Wnt glycosylation is less well understood, and the sites and types of glycosylation are not largely conserved among different Wnts. In polarized tissues, the type of glycans can determine whether the route of trafficking is apical or basolateral. In addition, pairing of the 24 highly conserved cysteines in Wnts to form disulfide bonds is critical in maintaining proper structure and activities. Extracellularly, the amino terminus of a subset of Wnts can be cleaved by a dedicated glycosylphosphatidylinositol (GPI)-anchored metalloprotease TIKI, resulting in the inactivation of these Wnt proteins. Additionally, NOTUM is a secreted extracellular carboxylesterase that removes the palmitoleate moiety from Wnt, antagonizing its activity. In summary, Wnt signaling activity is controlled at multiple layers by post-translational modifications.
Many dietary plants possess high levels of 18-carbon containing lipids from both omega-6 and omega-3 unsaturated fatty acids (e.g., linoleic and alpha-linolenic acid, respectively). These dietary lipids can be metabolized to lipid mediators collectively termed octadecanoids, which can in turn interact with immune cells (e.g., macrophages, eosinophils) to exert a number of potent biological effects. These octadecanoid lipid mediators have been little studied and represent an exciting new area of lipid biochemistry. For further information, see the review in this issue by Quaranta and colleagues (pages 1569–1582). Cover image credit: Emmanuelle Chevallier.
Functional regulation of Wnt protein through post-translational modifications
Jia Yu, David M. Virshup; Functional regulation of Wnt protein through post-translational modifications. Biochem Soc Trans 16 December 2022; 50 (6): 1797–1808. doi: https://doi.org/10.1042/BST20220735
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