Emerging role of UFMylation in secretory cells involved in the endocrine system by maintaining ER proteostasis

Abstract

Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like molecule (UBL) discovered almost two decades ago, but our knowledge about the cellular and molecular mechanisms of this novel protein post-translational modification is still very fragmentary. In this review, we first summarize the core enzymes and factors involved in the UFMylation cascade, which, similar to ubiquitin, is consecutively catalyzed by UFM1-activating enzyme 5 (UBA5), UFM1-conjugating enzyme 1 (UFC1) and UFM1-specific ligase 1 (UFL1). Inspired by the substantial implications of UFM1 machinery in the secretory pathway, we next concentrate on the puzzling role of UFMylation in maintaining ER protein homeostasis, intending to illustrate the underlying mechanisms and future perspectives. At last, given a robust ER network is a hallmark of healthy endocrine secretory cells, we emphasize the function of UFM1 modification in physiology and pathology in the context of endocrine glands pancreas and female ovaries, aiming to provide precise insight into other internal glands of the endocrine system.

Deacylases—structure, function, and relationship to diseases

“…The buildup of undigested substrates leads to the formation of neuronal depositions and induces NCL [89][90][91]. On the other hand, the ER serves as a crucial site for polysaccharide and triglyceride synthesis, protein folding, and post-translational modification of proteins [92]. ER-localized PPT1 participates in protein sorting and transportation.…”

Patient derived model ofUBA5-associated encephalopathy identifies defects in neurodevelopment and highlights potential therapies

“…UPR relays four interlinked mechanisms to accommodate protein folding during ER stress: 1) translation attenuation (59,60); 2) increase expression of ER chaperones (60); 3) induction of ER-associated degradation (ERAD) machinery (61) and 4) ER size expansion. The ufmylation pathway is implicated in the maintenance of ER homeostasis and stress response (16,(21)(22)(23)(24)(25)(26). To better understand the cellular consequences of UBA5 variants, we examined signaling pathways dictated by the three main proteins that relay UPR at the ER membrane: 1) double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK); 2) activating transcription factor 6 (ATF6) and 3) inositol requiring kinase 1 (IRE1).…”

“…Ufmylation has been implicated in a number of cellular processes including genome stability, vesicle trafficking, cell cycle progression, gene expression, and erythroid differentiation (16)(17)(18)(19)(20)(21). The most prominent role for the ufmylation cascade is regulation of endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR) pathway (16,(21)(22)(23)(24)(25)(26).…”

Eg5 UFMylation promotes spindle organization during mitosis

“…UFMylation is a reversible process, as UFM1 can be cleaved from its target proteins by UFSP1 and UFSP2 (9). UFMylation regulates various cellular functions, such as hematopoiesis, endoplasmic reticulum (ER) proteostasis, DNA damage response, autophagy, transcriptional regulation, and signaling pathways (2,(10)(11)(12). In 2016, we reported for the rst time that compound heterozygous variants of UBA5 lead to neurodevelopmental disorders characterized by cerebellar atrophy and developmental delays (13).…”