ABSTRACT UFMylation, a ubiquitin‐like post‐translational modification system, plays an essential role in regulating endoplasmic reticulum (ER) function. This process involves a cascade of biochemical reactions mediated by several core molecular components, including UFM1, the E1 enzyme UBA5, the E2 enzyme UFC1, the E3 enzyme UFL1, as well as the accessory proteins DDRGK1 and CDK5RAP3. During UFMylation, UFM1 undergoes maturation, activation, conjugation, and deconjugation in a dynamic process, whereas the ER‐localized UFL1‐DDRGK1 complex governs substrate selection and modification efficiency. The major function of UFMylation is to modulate the ER stress response, thereby balancing adaptive cellular remodeling and apoptotic signaling. Through the modification of key substrate proteins, UFMylation activates a synergistic clearance mechanism that coordinates ER‐phagy with ribosome‐associated quality control, thereby facilitating the removal of stalled ribosomes and damaged ER to maintain ER proteostasis and structural integrity. Dysregulation of UFMylation is frequently associated with various diseases characterized by abnormal ER function. In this review, we will describe the molecular pathways associated with ER‐associated UFMylation process and then discuss its core regulatory functions within the ER and its possible involvements in several congenital human diseases.
Zheng et al. (2026) studied this question.