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

Jiaxin Sun, Shiyan Yu, Xiao Zhang, Catherine Capac, Onyedikachi Aligbe, Timothy Daudelin, Edward M. Bonder, Nan Gao

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2159-2171
Number of pages13
JournalJournal of cell science
Volume130
Issue number13
DOIs
StatePublished - Jul 1 2017

All Science Journal Classification (ASJC) codes

  • Cell Biology

Keywords

  • COPII
  • SAR1
  • SEC12
  • Secretion
  • Wls
  • Wnt
  • Wntless

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