Gurriarán Rodríguez, UxíaDatzkiw, DavidRadusky, LeandroEsper, MarieJavandoost, EhsanXiao, FanMing, HongFisher, SolomonMarina, AlbertoDe Repentigny, YvesKothary, RashmiAzkargorta, MikelElortza, FélixRojas, Adriana L.Serrano Pubull, Luis, 1982-Hierro, AitorRudnicki, Michael A.Gurriarán Rodríguez, Uxía; Datzkiw, David; Radusky, Leandro; Esper, Marie; Javandoost, Ehsan; Xiao, Fan; Ming, Hong; Fisher, Solomon; Marina, Alberto; De Repentigny, Yves; Kothary, Rashmi; Azkargorta, Mikel; Elortza, Félix; Rojas, Adriana L.; Serrano Pubull, Luis, 1982-; Hierro, Aitor; Rudnicki, Michael A.2025-02-072025-02-072024Gurriaran-Rodriguez U, Datzkiw D, Radusky LG, Esper M, Javandoost E, Xiao F, et al. Identification of the Wnt signal peptide that directs secretion on extracellular vesicles. Sci Adv. 2024 Dec 13;10(50):eado5914. DOI: 10.1126/sciadv.ado59142375-2548http://hdl.handle.net/10230/69518Wnt proteins are hydrophobic glycoproteins that are nevertheless capable of long-range signaling. We found that Wnt7a is secreted long distance on the surface of extracellular vesicles (EVs) following muscle injury. We defined a signal peptide region in Wnts required for secretion on EVs, termed exosome-binding peptide (EBP). Addition of EBP to an unrelated protein directed secretion on EVs. Palmitoylation and the signal peptide were not required for Wnt7a-EV secretion. Coatomer was identified as the EV-binding protein for the EBP. Analysis of cocrystal structures, binding thermodynamics, and mutagenesis found that a dilysine motif mediates EBP binding to coatomer with a conserved function across the Wnt family. We showed that EBP is required for Wnt7a bioactivity when expressed in vivo during regeneration. Overall, our study has elucidated the structural basis and singularity of Wnt secretion on EVs, alternatively to canonical secretion, opening avenues for innovative therapeutic targeting strategies and systemic protein delivery.application/pdfengCopyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). This is an open-access article distributed under the terms of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Glicoproteïnesinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1126/sciadv.ado5914info:eu-repo/semantics/openAccess