WLS Retrograde Transport to the Endoplasmic Reticulum during Wnt Secretion

Yu, Jia; Chia, Joanne; Canning, Claire Ann; Jones, C. Michael; Bard, Frédéric; Virshup, David M.

doi:10.1016/j.devcel.2014.03.016

Cited by 125 publications

(134 citation statements)

References 45 publications

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“…Since Wnt‐induced Evi stabilization takes place in the ER (Fig 3D), a Wnt‐Evi interaction might occur in this compartment, as has been suggested previously (Yu et al , 2014). Porcn is an ER‐resident protein and responsible for Wnt palmitoylation, which is a pre‐requisite for the subsequent binding of Wnt proteins to Evi (Herr & Basler, 2012).…”

Section: Resultssupporting

confidence: 70%

“…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). The levels of both Wnt and Evi proteins are often aberrantly regulated in cancer (Augustin et al , 2012; Voloshanenko et al , 2013; Stewart et al , 2015), which contributes to high Wnt activity during tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

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ERAD‐dependent control of the Wnt secretory factor Evi

et al. 2018

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Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β‐catenin by the ubiquitin‐proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)‐associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP‐dependent manner. Ubiquitination of Evi involves the E2‐conjugating enzyme UBE2J2 and the E3‐ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD‐dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.

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Section: Resultssupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

ERAD‐dependent control of the Wnt secretory factor Evi

et al. 2018

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“…The lipidation of Wnt3a and Wnt11 occurs in the ER, is catalyzed by porcupine and is essential for their exit from the ER. Wntless (Wls), which plays a crucial role in the trafficking of Wnt, recognizes palmitoleic-acid-modified Wnts in the ER and cycles between the plasma membranes and the ER through the Golgi (Port and Basler, 2010;Yu et al, 2014). Wls itself is trafficked to the basolateral membranes and its recycling is not required for the apical sorting of Wnt11 from the transGolgi (Yamamoto et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Basolateral secretion of Wnt5a in polarized epithelial cells is required for apical lumen formation

Yamamoto

Awada

Matsumoto

et al. 2015

Journal of Cell Science

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BSTRACTWnt5a regulates planar cell polarity in epithelial cells, but it remains to be determined whether Wnt5a and its receptors are sorted apically or basolaterally, and how Wnt5a signaling is involved in apical and basolateral polarization. We found that Wnt5a was secreted basolaterally in polarized kidney epithelial cells. The basolateral secretion of Wnt5a required Wntless (Wls), clathrin and adaptor protein 1 (AP-1). Wnt5a receptors were also localized to the basolateral membranes, but their sorting did not require Wls. Wnt5a-induced signaling was stimulated more efficiently at the basolateral side than the apical side of epithelial cells. Knockdown of Wnt5a delayed apical lumen formation of the epithelial cyst, and these phenotypes were rescued by wild-type Wnt5a, but not by a Wnt5a mutant that is secreted apically. Although apoptosis was not required for apical lumen formation in a wild-type cyst, apoptosis was necessary for eliminating luminal cells in a Wnt5a-depleted cyst. These results suggest that Wnt5a and its receptors are sorted to their correct destination by different mechanisms and that the basolateral secretion of Wnt5a is necessary for apical lumen formation in the epithelial cyst.

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“…2D,F). Importantly, a previously reported antibody against endogenous Wls (Coombs et al, 2010;Yu et al, 2014a) was able to co-immunoprecipitate SEC12 with Wls in HeLa cell lysates (Fig. 3A). )…”

Section: -388mentioning

confidence: 96%

“…Sorting of ligand-bound Wls from endosomes to multivesicular bodies (MVBs) has been shown to lead to exosome-mediated export of unsecreted Wnts that remain with Wls (Gross et al, 2012). Recent studies further illustrated the involvement of ARF/ERGIC2 and COPI vesicles in regulating a further retrograde transport of Wls from the Golgi to the ER for new rounds of Wnt transport (Yu et al, 2014a). These studies highlighted a sophisticated regulation of retrograde Wls traffic, which is presumably designed for reusing the transporter for an effective Wnt export.…”

Section: Introductionmentioning

confidence: 99%

A Wntless–SEC12 complex on the ER membrane regulates early Wnt secretory vesicle assembly and mature ligand export

Sun

Zhang

et al. 2017

Journal of Cell Science

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Wntless (Wls) transports Wnt molecules for secretion; however, the cellular mechanism underlying the initial assembly of Wnt secretory vesicles is still not fully defined. Here, we performed proteomic and mutagenic analyses of mammalian Wls, and report a mechanism for formation of early Wnt secretory vesicles on ER membrane. Wls forms a complex with SEC12 (also known as PREB), an ER membrane-localized guanine nucleotide-exchange factor (GEF) activator of the SAR1 (the SAR1A isoform) small GTPase. Compared to palmitoylation-deficient Wnt molecules, binding of mature Wnt to Wls increases Wls-SEC12 interaction and promotes association of Wls with SAR1, the key activator of the COPII machinery. Incorporation of Wls into this exporting ER compartment is affected by Wnt ligand binding and SEC12 binding to Wls, as well as the structural integrity and, potentially, the folding of the cytosolic tail of Wls. In contrast, Wls-SEC12 binding is stable, with the interacting interface biochemically mapped to cytosolic segments of individual proteins. Mutant Wls that fails to communicate with the COPII machinery cannot effectively support Wnt secretion. These data suggest that formation of early Wnt secretory vesicles is carefully regulated to ensure proper export of functional ligands.

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WLS Retrograde Transport to the Endoplasmic Reticulum during Wnt Secretion

Cited by 125 publications

References 45 publications

ERAD‐dependent control of the Wnt secretory factor Evi

ERAD‐dependent control of the Wnt secretory factor Evi

Basolateral secretion of Wnt5a in polarized epithelial cells is required for apical lumen formation

A Wntless–SEC12 complex on the ER membrane regulates early Wnt secretory vesicle assembly and mature ligand export

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