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

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          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.

          Abstract

          Summary: WLS and SEC12 form a stable complex on ER membrane that binds to mature Wnt molecules. We find that several independent protein motifs within WLS are essential for the association of this complex with COPII ER-exiting machinery.

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          Author and article information

          Journal
          J Cell Sci
          J. Cell. Sci
          JCS
          joces
          Journal of Cell Science
          The Company of Biologists Ltd
          0021-9533
          1477-9137
          1 July 2017
          1 July 2018
          : 130
          : 13
          : 2159-2171
          Affiliations
          [1 ] Department of Biological Sciences, Rutgers University , Newark, NJ, USA
          [2 ] Rutgers Cancer Institute of New Jersey, Rutgers University , Piscataway, NJ, USA
          Author notes
          [* ]Author for correspondence ( ngao@ 123456rutgers.edu )
          Author information
          http://orcid.org/0000-0003-4264-7438
          Article
          PMC5536887 PMC5536887 5536887 JCS200634
          10.1242/jcs.200634
          5536887
          28515233
          bcc85c5a-a860-4d06-8caf-92014eee8c8e
          © 2017. Published by The Company of Biologists Ltd
          History
          : 12 December 2016
          : 11 May 2017
          Funding
          Funded by: National Institutes of Health, http://dx.doi.org/10.13039/100000002;
          Award ID: DK102934
          Award ID: CA178599
          Funded by: Rutgers University;
          Funded by: National Science Foundation, http://dx.doi.org/10.13039/100000001;
          Award ID: 1353890
          Funded by: American Cancer Society, http://dx.doi.org/10.13039/100000048;
          Award ID: RSG-15-060-01-TBE
          Funded by: Crohn's and Colitis Foundation of America, http://dx.doi.org/10.13039/100001063;
          Award ID: 406794
          Categories
          Research Article

          Wnt,Wntless,Wls,Secretion,SAR1,SEC12,COPII
          Wnt, Wntless, Wls, Secretion, SAR1, SEC12, COPII

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