B4GALT1 and Wntless collaborate to block LRP5/6 translocation from Golgi to cell surface

After translation, low-density lipoprotein receptor–related protein 5/6, LRP5/6, are transported from ER through Golgi to cell surface, where they serve as the co-receptors of Wnt proteins to elicit the WNT/β-catenin signaling. Here, Golgi-resident β-1, 4-galactosyltransferase B4GALT1 is revealed to interact with LRP5/6, causing the Golgi retention of LRP5/6 and ultimately reducing LRP5/6 on the cell surface. In addition to LRP5/6, B4GALT1 can also bind to the exclusive Wnt transporter Wntless. Interestingly, this interaction does not affect the Wnt secretion but participates in the LRP5/6 Golgi-retention mediated by B4GALT1. On the other hand, the Wnt secretion that occupies Wntless antagonizes the B4GALT1-mediated LRP5/6 retention on the Golgi apparatus. Accordingly, LGK974-targeted uncoupling of the Wnt/Wntless complex is able to enhance LRP5/6 Golgi retention, thereby attenuating LRP5/6 cell surface translocation. Taken together, the surface presentation of LRP5/6 is regulated by the Golgi-resident B4GALT1 as well as the Wnt secretion activity.