UFMylation: A Unique & Fashionable Modification for Life

Abstract

Ubiquitin-fold modifier 1 (UFM1) is one of the newly-identified ubiquitin-like proteins. Similar to ubiquitin, UFM1 is conjugated to its target proteins by a three-step enzymatic reaction. The UFM1-activating enzyme, ubiquitin-like modifier-activating enzyme 5 (UBA5), serves as the E1 to activate UFM1; UFM1-conjugating enzyme 1 (UFC1) acts as the E2 to transfer the activated UFM1 to the active site of the E2; and the UFM1-specific ligase 1 (UFL1) acts as the E3 to recognize its substrate, transfer, and ligate the UFM1 from E2 to the substrate. This process is called ufmylation. UFM1 chains can be cleaved from its target proteins by UFM1-specific proteases (UfSPs), suggesting that the ufmylation modification is reversible. UFM1 cascade is conserved among nearly all of the eukaryotic organisms, but not in yeast, and associated with several cellular activities including the endoplasmic reticulum stress response and hematopoiesis. Furthermore, the UFM1 cascade is closely related to a series of human diseases. In this review, we summarize the molecular details of this reversible modification process, the recent progress of its functional studies, as well as its implication in tumorigenesis and potential therapeutic targets for cancer.

Keywords: Cancer; Endoplasmic reticulum stress; Post-translation modification; Ubiquitin-fold modifier 1; Ubiquitin-like proteins; Ufmylation.

Figure 1

The human ufmylation pathway Pro-UFM1 is cleaved by the UfSPs to expose its C-terminal conserved Gly residue. The mature form of UFM1 is activated by UBA5 at the expense of ATP hydrolysis, forming a high energy thioester bond with Cys 250 of UBA5. The E2 UFC1 then binds to UBA5, and the activated UFM1 is transferred to UFC1, forming a similar thioester linkage with Cys116 in UFC1. Finally, the E3 ligase UFL1 brings in a substrate (Subs) and UFC1-activated UFM1, UFM1 is then conjugated to its substrate. For the reverse process, UfSP2 cleaves UFM1 chains from its substrate. UFM1, ubiquitin-fold modifier 1; Pro-UFM1, UFM1 precursor; UfSP, UFM1-specific protease; UBA5, ubiquitin-like modifier-activating enzyme 5; UFC1, UFM1-conjugating enzyme 1; UFL1, UFM1-specific ligase 1.