Post-Translational Modifications of Deubiquitinating Enzymes: Expanding the Ubiquitin Code

Abstract

Post-translational modifications such as ubiquitination play important regulatory roles in several biological processes in eukaryotes. This process could be reversed by deubiquitinating enzymes (DUBs), which remove conjugated ubiquitin molecules from target substrates. Owing to their role as essential enzymes in regulating all ubiquitin-related processes, the abundance, localization, and catalytic activity of DUBs are tightly regulated. Dysregulation of DUBs can cause dramatic physiological consequences and a variety of disorders such as cancer, and neurodegenerative and inflammatory diseases. Multiple factors, such as transcription and translation of associated genes, and the presence of accessory domains, binding proteins, and inhibitors have been implicated in several aspects of DUB regulation. Beyond this level of regulation, emerging studies show that the function of DUBs can be regulated by a variety of post-translational modifications, which significantly affect the abundance, localization, and catalytic activity of DUBs. The most extensively studied post-translational modification of DUBs is phosphorylation. Besides phosphorylation, ubiquitination, SUMOylation, acetylation, oxidation, and hydroxylation are also reported in DUBs. In this review, we summarize the current knowledge on the regulatory effects of post-translational modifications of DUBs.

USP14: Structure, Function, and Target Inhibition

“…Recently emerging evidence have shown that posttranslational modification of DUBs relates to their abundance, localization, and activity ( Wang and Wang, 2021b ). Dysregulation of these modifications might cause various diseases, such as cancer, inflammatory, and neurodegenerative diseases ( Reyes-Turcu et al, 2009 ; Kessler and Edelmann, 2011 ; Leznicki and Kulathu, 2017 ; Das et al, 2020 ).…”

“…USP14, belonging to the USPs family, is known to be extensively engaged in varying canonical cellular signaling pathways, including nuclear factor kappa B (NF-κB) and Wnt/β catenin signaling pathways ( Harrigan et al, 2018 ; Li et al, 2021 ). Studies have demonstrated that the activity of USP14 is strictly regulated through its association with proteasome and several kinds of postmodifications, such as phosphorylation ( Xu et al, 2015 ; Wang and Wang, 2021b ). Dysregulation of USP14 causes pathological conditions, such as cancer, neurodegenerative disease, autophagy, immune responses, and viral infections ( Wang et al, 2021a ).…”

USP30: Structure, Emerging Physiological Role, and Target Inhibition

“…USP30 plays an important role in various physiological processes and must be tightly regulated to keep its appropriate level and activity in biological events. Nevertheless, understanding of the regulation of USP30 is inadequate, particularly at the post-translational level ( Wang and Wang, 2021 ). Recently, several known regulation ways of USP30 including phosphorylation and ubiquitination were identified, promoting the comprehension and development of appropriate therapeutic strategies.…”

Chimeric Peptides/Proteins Encoded by circRNA: An Update on Mechanisms and Functions in Human Cancers

“…Glycogen synthase kinase 3 beta (GSK3b) interacts with and phosphorylates b-catenin, and the ubiquitin ligase b-TrCP ubiquitinates the b-catenin, leading to degradation by the proteasome (93). Therefore, it is evaluated that b-catenin-370aa binds to GSK3b, which eventually leads to prevent the GSK3B from interacting with full-length b-catenin (92,94).…”