Aging-associated modulation of UFMylation impairs proteostasis in C. elegans.

The attachment of Post-Translational Modifications (PTMs) to proteins regulates their activities and stability. Here we utilized the nematode Caenorhabditis elegans to test whether UFMylation, a PTM which affects key biological functions, regulate aging and protein homeostasis (proteostasis). We find that lowering UFMylation extends lifespan and mitigates the toxicity of aggregation-prone proteins that underlie the development of neurodegenerative disorders in humans. Mass spectrometric analysis suggests that UFMylation of aging-regulating proteins, including of the nucleolar FIB-1-NOL-56 complex and the germline-resident proteins CAR-1 and CGH-1, governs proteostasis, probably across tissues. Functional analyses indicate that the proteostasis-regulating transcription factors DAF-16 and SKN-1 are crucial for the protective effects of reduced UFMylation. Counter-proteotoxic effect of reduced UFMylation are mediated by enhanced nascent protein quality control, reduced protein aggregation, and increased protein degradation by the ubiquitin-proteasome system. These insights highlight the important roles of PTMs in the regulation of proteostasis and point at research directions for the development of therapies for neurodegenerative disorders.