Ufl1/RCAD, a Ufm1 E3 ligase, has an intricate connection with ER stress

Ufmylation is a type of post-translational modification that deals with complex and fine-tuned cellular activities. This modification proceeds mainly through a three-step enzymatic reaction with ubiquitin-fold modifier 1 (Ufm1), ubiquitin-like modifier-activating enzyme 5 (Uba5), Ufm1-conjugating enzyme 1 (Ufc1) and Ufm1-specific ligase 1 (Ufl1). Ufl1 has previously been reported to function as a Ufm1 E3 ligase in the ufmylation system, but knowledge of its physiological functions remains poor. At the subcellular level, Ufl1 is enriched in the endoplasmic reticulum (ER), implying that it may regulate events closely associated with the ER and ER functions, such as protein synthesis, folding, and secretion, compounding lipids or sterols, and maintaining calcium homeostasis. Different physiological or pathological stress circumstances can, however, disrupt ER homeostasis, giving rise to an incongruous condition that is harmful to cellular activity and ultimately causes ER stress. Understanding the relationship between Ufl1 and ER stress in physiology and pathology may reveal the pathogenesis of some diseases and provide new guidance to create a therapeutic method. Herein, we review the current literature and discuss the relationship between Ufl1 and ER stress (in hematopoietic disease, heart disease, etc.), thus providing insight into additional diseases.