Ubiquitin-fold modifier 1

UFM1 (ubiquitin-fold modifier 1) is a small ubiquitin-like protein that functions as a covalent modifier attached to lysine residues of substrate proteins through an isopeptide bond mechanism called ufmylation (UniProt: P61960). This post-translational modification requires a multi-enzyme system comprising the E1 enzyme UBA5, the E2 enzyme UFC1, and the E3 ligase UFL1, and regulates diverse cellular processes including ribosome recycling, DNA damage response, transcription, and endoplasmic reticulum-associated autophagy (reticulophagy) under ER stress conditions (UniProt: P61960).

UFM1 is implicated in neurodevelopmental disease; mutations cause hypomyelinating leukodystrophy 14 (HLD14), an autosomal recessive disorder characterized by severe neurological deterioration, basal ganglia and cerebellar atrophy, developmental delay, spasticity, and drug-resistant epilepsy with onset in early infancy (UniProt: P61960).

In Alzheimer's disease, UFM1 is significantly upregulated in post-mortem human brain tissue from AD patients compared to age-matched controls (mean log2 fold-change +0.59; Chaparral AD proteomics), suggesting potential involvement in AD-associated pathology, though the functional significance of this elevation remains to be determined.