Multifaceted roles of UFMylation in health and disease

Ubiquitin fold modifier 1 (UFM1) is a newly identified post-translational modifier that is involved in the UFMylation process. Similar to ubiquitination, UFMylation enables the conjugation of UFM1 to specific target proteins, thus altering their stability, activity, or localization. UFM1 chains have the potential to undergo cleavage from their associated proteins via UFM1-specific proteases, thus highlighting a reversible feature of UFMylation. This modification is conserved across nearly all eukaryotic organisms, and is associated with diverse biological activities such as hematopoiesis and the endoplasmic reticulum stress response. The disruption of UFMylation results in embryonic lethality in mice and is associated with various human diseases, thus underscoring its essential role in embryonic development, tissue morphogenesis, and organismal homeostasis. In this review, we aim to provide an in-depth overview of the UFMylation system, its importance in disease processes, and its potential as a novel target for therapeutic intervention.