EYA Proteins Couple Endosomes With Golgi During Wntless Trafficking

Wnts are secreted ligands that are crucial for development. Retrograde transport of Wntless from endosomes to Golgi is required for efficient Wnt secretion. However, the molecular machineries connecting endosomes to Golgi during Wntless trafficking is unknown. Here, we identified an essential role for EYA proteins during retrograde trafficking of Wntless to Golgi. EYAs (EYA1-4) form a complex and interacts with retromer on early endosomes. Retromer bound EYA complex recruits SCAMP3 to endosomes, which is necessary for docking and fusion of Wntless loaded endosomes to Golgi. Loss of either EYA complex or SCAMP3 leads to defective transport of Wntless to Golgi and failed Wnt secretion. EYA mutations found in patients with sensorineural hearing loss forms dysfunctional EYA-retromer complex that fails to activate Wnt signaling, suggesting an important role of this complex during development. These findings identify EYA complex as a critical mediator of retrograde trafficking of Wntless from endosome to Golgi.<br><br>Funding Information: This work was supported by DBT/Wellcome Trust India Alliance Senior Fellowship grant (IA/S/16/2/502729 to S.M), DBT National Bioscience Award for Career Development (BT/HRD/NBA/39/08/2018-19) and CDFD core funds. H.A.R acknowledges the support of Research Fellowship from Indian Council of Medical Research (ICMR).<br><br>Declaration of Interests: The authors declare no competing financial interests.