Secretion of Wnt Ligands Requires Evi, a Conserved Transmembrane Protein

Abstract

Wnt signaling pathways are important for multiple biological processes during development and disease. Wnt proteins are secreted factors that activate target-gene expression in both a short- and long-range manner. Currently, little is known about how Wnts are released from cells and which factors facilitate their secretion. Here, we identify a conserved multipass transmembrane protein, Evenness interrupted (Evi/Wls), through an RNAi survey for transmembrane proteins involved in Drosophila Wingless (Wg) signaling. During development, evi mutants have patterning defects that phenocopy wg loss-of-function alleles and fail to express Wg target genes. evi's function is evolutionarily conserved as depletion of its human homolog disrupts Wnt signaling in human cells. Epistasis experiments and clonal analysis place evi in the Wg-producing cell. Our results show that Wg is retained by evi mutant cells and suggest that evi is the founding member of a gene family specifically required for Wg/Wnt secretion.

ERAD‐dependent control of the Wnt secretory factor Evi

“…Evi is an essential component of the Wnt secretion machinery (Bänziger et al , 2006; Bartscherer et al , 2006; Goodman et al , 2006), and its protein levels are increased in cancer compared to normal colon tissue (Voloshanenko et al , 2013; Stewart et al , 2015). Since Evi must mediate the secretion of different Wnt proteins, it must be available as soon as any of the Wnt proteins is expressed.…”

“…Nineteen Wnt ligands are produced and subsequently processed in the endoplasmic reticulum (ER) by the attachment of palmitoleic acid to a conserved serine residue by the acyltransferase Porcupine (Porcn) (Kadowaki et al , 1996; Willert et al , 2003; Takada et al , 2006). In the Wnt secretory pathway, this lipid modification is important for the interaction between Wnt proteins and the conserved transmembrane protein Evi (Wls, GPR177), which shuttles lipid‐modified Wnt proteins to the plasma membrane and onto exovesicles (Bänziger et al , 2006; Bartscherer et al , 2006; Goodman et al , 2006; Gross et al , 2012; Herr & Basler, 2012). Evi is then recycled via the retromer complex back to the Golgi and ER (Coudreuse, 2006; Belenkaya et al , 2008; Franch‐Marro et al , 2008; Pan et al , 2008; Port et al , 2008; Yang et al , 2008; Yu et al , 2014).…”

Molecular regulation of kidney development: is the answer blowing in the Wnt?

“…However, recent studies suggest that, in addition to regulating the transcription of the Wnt mRNA, pathway activity may be regulated at the level of ligand secretion. Studies performed on flies and worms have indicated that secretion of Wnts from the producing cells is regulated and that this level of regulation may be conserved in mammals [106][107][108]. Thus, mRNA expression, and even protein expression, do not equate to the production of active, secreted ligand.…”

Tri sélectif et recyclage

“…Une série d'articles publiés entre 2006 et 2008 par des équipes travaillant sur C. elegans, la drosophile et l'homme ont montré que la sécrétion du signal EGL-20/Wingless/ Wnt (différents noms d'un des WNT dans ces organismes respectifs) requiert l'intervention d'une protéine à plusieurs domaines transmembra naires conservée au cours de l'évolution jusqu'à l'homme et appelée Wntless/Evi/ Sprinter chez la drosophile [8][9][10] WNT est une glycolipoprotéine qui agit en qualité de molécule de signalisation dans de nombreux processus biologiques. WNT se distribue de façon graduée autour des cellules adjacentes aux cellules qui le produisent (en vert).…”

“…Dans les épithéliums de drosophile, certaines données suggèrent que WNT serait préférentiellement adressé au pôle apical [20], bien qu'un adressage au pôle basolatéral coexiste [20,21]. Dans les mutants Wntless, on trouve WNT dans toute l'épaisseur de la cellule [9]. Bien que ces résultats puissent indiquer que Wntless pourrait être requise pour la localisation apicale de WNT, ils pourraient tout aussi bien être secondaires à l'accumulation de WNT dans la cellule sécrétrice.…”