The ufm1 cascade

Abstract

The ubiquitin-fold modifier 1 (Ufm1) is a posttranslational modifier that belongs to the ubiquitin-like protein (UBL) family. Ufm1 is present in nearly all eukaryotic organisms, with the exception of fungi. It resembles ubiquitin in its ability to be ligated to other proteins, as well as in the mechanism of ligation. While the Ufm1 cascade has been implicated in endoplasmic reticulum functions and cell cycle control, its biological role still remains poorly understood. In this short review, we summarize the current state of Ufm1 research and its potential role in human diseases, like diabetes, ischemic heart disease and cancer.

Figure 1

The Ufm1 cascade. The removal of one or two amino acids (XX) at the C-terminus is a prerequisite for the conjugation of Ufm1 to its targets. The maturation of the pro-form of Ufm1 is processed by the proteases, UfSP1 or UfSP2, exposing a conserved glycine (G). Ufm1 is activated in an ATP-dependent reaction by the E1 activating enzyme, Uba5, creating a thioester-bond between the C-terminal glycine of Ufm1 and the active cysteine residue of Uba5. Ufm1 is then transferred to the active cysteine of the E2 conjugating enzyme, Ufc1. With the aid of the E3 ligase, Ufl1, an isopeptide bond between Ufm1 and the target protein is established. Deconjugation is also catalyzed by UfSP1 or UfSP2.

Figure 2

Simplified model of the known functions of the Ufm1 cascade in L. donovani, C. elegans and mammals. The known implications of the Ufm1 cascade are discussed in the text.