Highly Specialized Ubiquitin-Like Modifications: Shedding Light into the UFM1 Enigma

Abstract

Post-translational modification with Ubiquitin-like proteins represents a complex signaling language regulating virtually every cellular process. Among these post-translational modifiers is Ubiquitin-fold modifier (UFM1), which is covalently attached to its substrates through the orchestrated action of a dedicated enzymatic cascade. Originally identified to be involved embryonic development, its biological function remains enigmatic. Recent research reveals that UFM1 regulates a variety of cellular events ranging from DNA repair to autophagy and ER stress response implicating its involvement in a variety of diseases. Given the contribution of UFM1 to numerous pathologies, the enzymes of the UFM1 cascade represent attractive targets for pharmacological inhibition. Here we discuss the current understanding of this cryptic post-translational modification especially its contribution to disease as well as expand on the unmet needs of developing chemical and biochemical tools to dissect its role.

Human UFSP1 is an active protease that regulates UFM1 maturation and UFMylation

“…Considering that 99 DUBs have been identified in the analogous ubiquitin system (Lange, Armstrong and Kulathu, 2021), it seemed remarkable that the UFM1 pathway in humans could be reliant on only one enzyme. Together with the confounding observation of active UFMylation in UFSP2 −/− cell lines, it has been clear to many in the field that additional enzymes must exist to process precursor UFM1 into its mature counterpart (Witting and Mulder, 2021). Our study now reveals that the annotation of UFSP1 as inactive is mistaken.…”

Cyclin-Dependent Kinase 5 Regulatory Subunit Associated Protein 3: Potential Functions and Implications for Development and Disease

“…The UFMylation is referred to as a process of post-translational modification that is orchestrated by the sequential action of ubiquitin fold modifier 1(UFM1) and three enzyme classes, namely the E1 ubiquitin activating enzyme 5 (UBA5), E2 UFM1-conjugase 1 (UFC1) and E3 UFM1-conjugase 1(UFL1) ( 56 , 57 ). The detailed knowledge on UFMylation cascade has be elaborated in published reviews ( 34 , 58 ).…”

“…Overall, The UFMylation conjugation is a vital player in maintaining ER homeostasis. The current advances on the UFMylation system and ER network can be consulted in several published reviews ( 34 , 58 , 72 ). Remarkably, CDK5RAP3, both as a UFMylation component and as a candidate ER-phagy player, may play a master role in ER homeostasis.…”

Editorial: Structure, Function, and Evolution of E3 Ligases and Targets

“…UBLs which use an E1/E2/E3-like reaction cascade for target attachment include SUMO (Small Ublike Modifier), RUB (Related to Ubiquitin, called Nedd8 in yeast and animals), ATG8 (Autophagy-Related 8) and ATG12 (which are conjugated to the lipid phosphatidylethanolamine and the ATG5 protein, respectively), and UFM1 (Ubiquitin-Fold Modifier 1) (Vierstra, 2012;Callis, 2014;Daniel and Liebau, 2014;Augustine and Vierstra, 2018;Witting and Mulder, 2021). The attachment of UBLs to targets is mediated by small families of E3-ligases (Figure 1).…”

“…Another UFL1 interactor, CDK5RAP3 (CDK5 Regulatory Subunit-Associated Protein 3), affects the UFMylation profile and may serve as a substrate adaptor. DDRGK1 and CDK5RAP3 homologs are present in Arabidopsis; the CDK5RAP3 homolog is called C53 (Daniel and Liebau, 2014;Stephani et al, 2021;Witting and Mulder, 2021).…”