Amyloid-Like Assembly During Embryogenesis Activates Herzog, a Novel Prion-Like Phosphatase

Abstract

Prion-like proteins can assume distinct conformational and physical states in the same cell. Sequence analysis suggests prion-like proteins are prevalent in various species, however it remains unclear what functional space they occupy in multicellular organisms. Here, we report a novel prion-like protein, Herzog (CG5830), identified through a multimodal screen in Drosophila melanogaster. Herzog functions as a membrane-associated phosphatase and controls embryonic patterning by acting on components of TGF-β/BMP and FGF/EGF signaling pathways. Remarkably, monomeric Herzog is enzymatically inactive and becomes active upon amyloid-like assembly during gastrulation. The prion-like domain of Herzog is necessary for both its assembly and membrane-targeting. Removal of the prion-like domain impairs activity, while restoring assembly on the membrane using a heterologous prion-like domain and membrane targeting motif can restore phosphatase activity. This study provides a definitive example of a prion-like domain that allows an enzyme to gain essential functionality via amyloid-like assembly to control animal development.