Liquid-liquid phase separation and the formation of amyloid fibrils from DcpS scavenger enzymes

Decapping Scavenger (DcpS) enzyme was initially identified by its ability to hydrolyze the cap structure resulting from mRNA decay. Human DcpS is an established target for acute myeloid leukemia (AML) and hepatic metastasis. Recently, the protein has been linked to neuronal development regulation and implicated in certain developmental neurological disorders. Here we demonstrate for the first time that DcpS of the human and C. elegans nematode origin undergoes misfolding in vitro, leading to the formation of amyloid-like fibrils. Additionally, the DcpS^INS15 insertional mutant linked to the Al-Raqad syndrome exhibited accelerated fibril aggregation kinetics compared to the wild type protein. Importantly, we demonstrate that the DcpS species investigated in this study undergo liquid-liquid phase separation (LLPS), which appears to lead in turn to amyloid formation. We propose that the LLPS phase transition underlies the intricate kinetics (e.g. lack of a clearly-resolved lag phase) of the misfolding process. As the physiological implications of the here-reported propensity of DcpS to lose its biological function through the coupled LLPS-fibrillization transition remain to be elucidated, this work lays the groundwork for further studies on this phenomenon and provides a potential link between DcpS aggregation and disease-associated loss of function.