The UFM1 Conjugation System: A Master Regulator of Cellular Stress Surveillance in Human Disease

Post-translational modification (PTM) encompasses diverse modifications, including phosphorylation, methylation, ubiquitin-like modifications (UBLs), and so on, which profoundly influence cellular functions. UFMylation is a recently identified ubiquitin-like modification, which is mediated by the Ubiquitin-like Ubiquitin Fold Modifier 1 (UFM1) conjugation system. The UFM1 conjugation system comprises UFM1, Ubiquitin-like protein activating enzyme 5 (UBA5), UFM1-conjugating enzyme 1 (UFC1), UFM1-specific ligase 1 (UFL1), UFM1-specific protease 1 (UFSP1), UFM1-specific protease 2 (UFSP2), UFM1-binding protein 1 (UFBP1), and CDK5 regulatory subunit-associated protein 3 (CDK5RAP3). Accumulating research has demonstrated that the UFM1 conjugation system regulates various cellular stress responses, including endoplasmic reticulum (ER) stress, protein trafficking, DNA damage repair, and autophagy. Additionally, abnormal stress adaptations of the UFM1 conjugation system contribute to the pathophysiological complications of inflammatory diseases and cancer, underscoring its significance as a key regulatory node in human health and disease. Therefore, this review provides a comprehensive exploration of the structural characteristics of UFM1 conjugation system members and the mechanistic roles of UFMylation by UFM1 conjugation system-mediated diseases related to cellular stress responses, which will not only facilitate the identification of novel diagnostic and prognostic indicators but also enable the identification of specific therapeutic targets for UFM1 conjugation system-related diseases.