A novel flippase dependent mechanism in Wnt secretion

Wnt proteins are secreted signaling molecules that play a central role in development, stem cell maintenance and disease. Previous studies have shown that Wnt proteins require a specialized secretory mechanism to be released from producing cells. Central to this mechanism is the Wnt sorting receptor Wntless, which binds Wnt in the endoplasmic reticulum and transports it to the cell surface for release. Importantly, Wntless needs to be recycled back to maintain efficient Wnt secretion, which is mediated through endocytosis and retromer dependent transport from early endosomes to the Golgi network.

The endosomal retrieval of Wntless requires a novel retromer pathway that depends on the sorting nexin SNX3 instead of SNX-BAR sorting nexins. In the classical retromer pathway, the membrane curvature sensing BAR domains of the SNX-BAR sorting nexins are required for the formation of tubular transport carriers. SNX3 lacks such membrane deforming domains, but vesicular transport carriers are still formed by the SNX3 retromer complex. How such transport vesicles are generated was still unknown.

In this paper, the two groups show that this requires the recruitment of an evolutionarily conserved membrane remodeling complex composed of MON2, DOPEY2 and the lipid flippase ATP9A. Lipid flippases translocate specific lipids between the inner and outer leaflets of the membrane. This creates an asymmetry in lipid composition and induces bending of the membrane. The study concludes that by binding the MON2:DOPEY2:ATP9A complex, the SNX3 retromer harnesses the activity of the lipid flippase ATP9A to induce the membrane deformation that is necessary for Wntless carrier formation.

Shared first authors: Ian McGough, Reinoud de Groot and Adam Jellett.
Shared senior authors: Rik Korswagen and Pete Cullen