Aging-Associated Modulation of UFMylation Impairs Proteostasis in C. elegans

The attachment of Post-Translational Modifications (PTMs) to proteins plays key roles in the regulation of the activity and stability of various proteins. Here we utilized the nematode Caenorhabditis elegans to test whether UFMylation, a PTM that was found to be essential for key biological functions, is involved in the regulation of aging and protein homeostasis (proteostasis). Our results indicate that lowering UFMylation extends lifespan and mitigates the toxicity of aggregative proteins that underlie the development of neurodegenerative disorders in humans. Mass spectrometric analysis unveiled that UFMylation of aging-regulating proteins, including components of the nucleolar FIB-1-NOL-56 complex and the germline resident proteins CAR-1 and CGH-1, governs proteostasis across tissues. Functional analyses indicate that the proteostasis-regulating transcription factors DAF-16 and SKN-1 are crucial for the counter proteotoxic effect of reduced UFMylation which is mediated by reduced rate of aggregation and enhanced protein degradation. These insights highlight the important roles of PTMs in the regulation of proteostasis and point at research directions for the development of new therapies for neurodegenerative disorders.