UFMylation System: An Emerging Player in Tumorigenesis

Abstract

Ubiquitin-fold modifier 1 (UFM1), a newly identified ubiquitin-like molecule (UBLs), is evolutionarily expressed in multiple species except yeast. Similarly to ubiquitin, UFM1 is covalently attached to its substrates through a well-orchestrated three-step enzymatic reaction involving E1, the UFM1-activating enzyme (ubiquitin-like modifier-activating enzyme 5, UBA5); E2, the UFM1-conjugating enzyme 1 (UFC1); and E3, the UFM1-specific ligase 1 (UFL1). To date, numerous studies have shown that UFM1 modification is implicated in various cellular processes, including endoplasmic reticulum (ER) stress, DNA damage response and erythroid development. An abnormal UFM1 cascade is closely related to a variety of diseases, especially tumors. Herein, we summarize the process and functions of UFM1 modification, illustrating the relationship and mechanisms between aberrant UFMylation and diversified tumors, aiming to provide novel diagnostic biomarkers or therapeutic targets for cancer treatments.

Keywords: UFM1; UFMylation; post-translational modifications; tumorigenesis; ubiquitin-like molecules.

Figure 1

Structure and sequence alignment of UFM1. (A) Comparison between 3D structures and the electrostatic potential surfaces of ubiquitin-fold modifier 1 (UFM1) and ubiquitin (Ub). PDB IDs for ubiquitin and UFM1 are 1UBQ and 5IA7, respectively. Left panel—3D structure, α-helices and β-strands are shown in red and yellow, respectively. Middle panel-electrostatic potential surface, positive and negative potentials are shown in blue and red, respectively. Right panel—the merged image. (B) Sequence alignment of UFM1 in different species. The 83 amino acid residue in all species is indicated by red box.

Figure 2

The UFM1 conjugation system. The precursor form of UFM1 is cleaved by UFSPs to expose its C-terminal conserved Gly residue. Then, matured UFM1 is activated by UBA5 that consumes ATP, forming a high energy thioester bond with Cys250 of UBA5. UFC1 next binds to UBA5 and retrieves UFM1 from UBA5 by forming a thioester bond with UFM1. Finally, UFC1, together with UFL1, transfer UFM1 to its substrate. Both UFBP1 and CDK5RAP3 are possible adaptor proteins that allow the ligase UFL1 to recruit a wider pool of substrates. Additionally, since UFMylation is a reversible process, the UFM1 molecules can be removed from their targets by UFSPs. Abbreviation: VGSC is an amino acid motif (valine–glycine–serine–cysteine). S indicates the thioester bond. K represents the lysine residue of the substrate.