Abstract
Eukaryotic proteomes are enormously sophisticated through versatile post-translational modifications (PTMs) of proteins. A large variety of code generated via PTMs of proteins by ubiquitin (ubiquitination) and ubiquitin-like proteins (Ubls), such as interferon (IFN)-stimulated gene 15 (ISG15), small ubiquitin-related modifier (SUMO) and neural precursor cell expressed, developmentally downregulated 8 (NEDD8), not only provides distinct signals but also orchestrates a plethora of biological processes, thereby underscoring the necessity for sophisticated and fine-tuned mechanisms of code regulation. Deubiquitinases (DUBs) play a pivotal role in the disassembly of the complex code and removal of the signal. Ubiquitin-specific protease 18 (USP18), originally referred to as UBP43, is a major DUB that reverses the PTM of target proteins by ISG15 (ISGylation). Intriguingly, USP18 is a multifaceted protein that not only removes ISG15 or ubiquitin from conjugated proteins in a deconjugating activity-dependent manner but also acts as a negative modulator of type I IFN signaling, irrespective of its catalytic activity. The function of USP18 has become gradually clear, but not yet been completely addressed. In this review, we summarize recent advances in our understanding of the multifaceted roles of USP18. We also highlight new insights into how USP18 is implicated not only in physiology but also in pathogenesis of various human diseases, involving infectious diseases, neurological disorders, and cancers. Eventually, we integrate a discussion of the potential of therapeutic interventions for targeting USP18 for disease treatment.
Highlights
Ubiquitin conjugation to substrates is the most powerful and tightly fine-tuned post-translational modification (PTM) of proteins
In addition to chemical PTMs of ubiquitin, such as phosphorylation and acetylation [9,10,11], several ubiquitin-like proteins (Ubls) such as interferon (IFN)-stimulated gene 15 (ISG15) [12,13,14,15], small ubiquitin-related modifier (SUMO) [16] and neural precursor cell expressed, developmentally downregulated 8 (NEDD8) [17] [18,19] have been demonstrated to modify polyubiquitin chains [18,20,21,22], all of which could change the characteristics of ubiquitin and affect ubiquitin interactions and formation and length of polyubiquitin chain, thereby generating sophisticated and versatile ubiquitin code
DUBs reverse versatile ubiquitin code generated by PTMs with matched complexity and precision of PTMs and switch off the signal
Summary
Ubiquitin conjugation to substrates (ubiquitination) is the most powerful and tightly fine-tuned post-translational modification (PTM) of proteins. In addition to chemical PTMs of ubiquitin, such as phosphorylation and acetylation [9,10,11], several ubiquitin-like proteins (Ubls) such as interferon (IFN)-stimulated gene 15 (ISG15) [12,13,14,15], small ubiquitin-related modifier (SUMO) [16] and neural precursor cell expressed, developmentally downregulated 8 (NEDD8) [17] [18,19] have been demonstrated to modify polyubiquitin chains [18,20,21,22], all of which could change the characteristics of ubiquitin and affect ubiquitin interactions and formation and length of polyubiquitin chain, thereby generating sophisticated and versatile ubiquitin code. It has been demonstrated that USP18 is a multifaceted protein that reverses ubiquitination or ISGylation and disassembles the code generated by ubiquitination or ISGylation as a deconjugating enzyme and plays a pivotal role in the negative regulation of type I IFN signaling, irrespective of its catalytic activity. We highlight new insights into how USP18 is implicated in physiology and in pathophysiology of various human diseases involving infectious diseases, neurological disorders and cancers, suggesting the potential of therapeutic interventions for targeting USP18 for disease treatment
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