TY - JOUR T1 - Feedback control of Wnt signaling based on histidine cluster co-aggregation between Naked/NKD and Axin JF - bioRxiv DO - 10.1101/2020.06.10.144725 SP - 2020.06.10.144725 AU - Melissa Gammons AU - Miha Renko AU - Joshua E. Flack AU - Juliusz Mieszczanek AU - Mariann Bienz Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/06/10/2020.06.10.144725.abstract N2 - Feedback control is a universal feature of cell signaling pathways. Naked/NKD is a widely conserved feedback regulator of Wnt signaling which controls animal development and tissue homeostasis. Naked/NKD destabilizes Dishevelled, which assembles Wnt signalosomes to inhibit the β-catenin destruction complex via recruitment of Axin. Here, we discover that the molecular mechanism underlying Naked/NKD function relies on its assembly into ultrastable decameric core aggregates via its conserved C-terminal histidine cluster (HisC). HisC aggregation is facilitated by Dishevelled and depends on accumulation of Naked/NKD during prolonged Wnt stimulation. Naked/NKD HisC cores co-aggregate with a conserved histidine cluster within Axin, to destabilize it along with Dishevelled, possibly via the autophagy receptor p62 which binds to HisC aggregates. Consistent with this, attenuated Wnt responses are observed in CRISPR-engineered flies and human epithelial cells whose HisC has been deleted. Thus, HisC aggregation by Naked/NKD provides context-dependent feedback control of prolonged Wnt responses.Competing Interest StatementThe authors have declared no competing interest. ER -