UFMylation is a post-translational modification that conjugates ubiquitin-fold modifier 1 (UFM1) to substrate proteins, regulating fundamental processes including ribosomal homeostasis, the endoplasmic reticulum (ER) stress response and DNA damage repair. While loss-of-function mutations in the UFMylation cascade cause lethality in mammals, they are viable in Caenorhabditis elegans, offering a unique opportunity to investigate its physiological role at the organismal level. We demonstrate that UFM-1 expression progressively increases from larval stages to adulthood, with predominant localization in intestinal cells. Its expression is upregulated during ER stress and autophagy induction, linking it to these pathways. We used CRISPR/Cas9 to create a targeted ufm-1 loss-of-function mutant, which revealed that UFMylation is crucial for lifespan, development and reproduction, with mutants exhibiting increased gonadal dysfunction and sterility. Deletion of ufm-1 enhanced tolerance to various stressors, a resilience potentially arising from a hormetic response to persistent ER stress. Loss of ufm-1 selectively activated the unfolded protein response in the ER but not in mitochondria. Notably, ufm-1 loss exacerbated proteotoxicity in C. elegans muscle-expressed models of protein aggregation, accelerating paralysis and increasing the number and size of amyloid-β, α-synuclein and polyQ aggregates. Furthermore, mutant worms displayed impaired locomotion, including altered swimming patterns resembling those of aging worms, stemming from accelerated, age-dependent sensory neuron dysfunction and structural neurodegeneration.
Kaiser et al. (Mon,) studied this question.