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.
Highlights
Post-translational modification (PTM) with Ubiquitin (Ub) or Ubiquitin-like modifiers (Ubl) such as SUMO, NEDD8, FAT10, ISG15, LC3, and UFM1 governs a plethora of cellular processes ranging from DNA damage response, cell cycle progression, transcription, endocytosis, to proteasomal and lysosomal protein degradation or autophagy [1,2,3,4,5,6,7,8,9,10,11,12]
We provide an overview of the current knowledge on UFM1, its enzymes and substrates with focus on the emerging biological role and contribution to disease
E3 ligase UFL1, its adaptor protein DDRGK1 (UFBP1) and the deUFMylase UFSP2 are associated with or anchored in the endoplasmic reticulum (ER), it is logical that the activating enzyme at the apex of the UFMylation cascade is in proximity
Summary
Post-translational modification (PTM) with Ubiquitin (Ub) or Ubiquitin-like modifiers (Ubl) such as SUMO, NEDD8, FAT10, ISG15, LC3, and UFM1 governs a plethora of cellular processes ranging from DNA damage response, cell cycle progression, transcription, endocytosis, to proteasomal and lysosomal protein degradation or autophagy [1,2,3,4,5,6,7,8,9,10,11,12]. E3 ligase UFL1, its adaptor protein DDRGK1 (UFBP1) and the deUFMylase UFSP2 are associated with or anchored in the ER, it is logical that the activating enzyme at the apex of the UFMylation cascade is in proximity This observation, begs the question of how the cytoplasmic E2 enzyme UFC1 translocates to the ER membrane to participate in relaying activated UFM1 to the E3 ligase and the acceptor lysines of its substrates. Originally identified as an interaction partner of UFL1 [33], the highly conserved protein DDRGK1, has been observed to be modified with UFM1 within the PCI domain at lysine 267 [32,33], which modulates its binding affinity to UFL1 in turn stimulating its ligase activity [34] (Figure 2A). The presence of CDK5RAP3 seems to be requisite for poly-UFMylation [34,35]
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