Deubiquitinating enzymes in cellular signaling and disease regulation

Abstract

Protein post-translational modification by ubiquitin represents a complex signaling system that regulates many cellular events including proteostasis to intercellular communications. Deubiquitinating enzymes (DUBs) that specifically disassemble Ub-chains or regulate ubiquitin homeostasis reside as a central component in ubiquitin signaling. Human genome encodes almost 100 DUBs and majority of them are not well characterized. Considerable progress has been made in the understanding of enzymatic mechanism; however, their cellular substrate specificity and regulation are largely unknown. Involvement of DUBs in disease regulation has been depicted since its discovery and several attempts have been made for evaluating DUBs as a drug target. In this review, we have updated briefly a new insight of DUBs activity, their cellular role, disease regulation, and therapeutic potential. V C 2015 IUBMB Life, 67(7): [544][545][546][547][548][549][550][551][552][553][554][555] 2015

Palladium‐Mediated Cleavage of Proteins with Thiazolidine‐Modified Backbone in Live Cells

“…[47] Therefore, failure in its regulation can lead to several pathologies,f or example,cancer and neurodegenerative disease.While aprotein modified with the specific Ub chain can proceed to degradation, this process is further complicated by the activity of DUBs,which remove Ub units from proteins to affect Ub signaling.T he largest sub family of Cys protease DUBs-Ub specific proteases (USPs) [26,47] is involved in av ariety of regulatory processes and has been implicated in various diseases.D espite progress in studying the function of many USPs,c omprehensive understanding of their structure,s pecificities,a nd cellular function is still lacking for many of its members. [47] Therefore, failure in its regulation can lead to several pathologies,f or example,cancer and neurodegenerative disease.While aprotein modified with the specific Ub chain can proceed to degradation, this process is further complicated by the activity of DUBs,which remove Ub units from proteins to affect Ub signaling.T he largest sub family of Cys protease DUBs-Ub specific proteases (USPs) [26,47] is involved in av ariety of regulatory processes and has been implicated in various diseases.D espite progress in studying the function of many USPs,c omprehensive understanding of their structure,s pecificities,a nd cellular function is still lacking for many of its members.…”

De-ubiquitinating enzyme, USP11, promotes transforming growth factor β-1 signaling through stabilization of transforming growth factor β receptor II

“…DUBs have key roles in the regulation of protein stability and signal transduction. 15, 16, 17, 19 Several DUBs have been identified to regulate TGF β -1 signaling through targeting T β RI or SMADs. UCHL37, USP11, and USP15 de-ubiquitinate T β RI, 20, 21, 22 while USP15, CYLD, and USP9X target SMAD4 or SMAD7.…”

“…The process of ubiquitination can be reversed via a process called de-ubiquitination, which is carried out by de-ubiquitinating enzymes (DUBs). 15, 16, 17 This process adds another layer to the protein-regulatory processes carried out by the cells. De-ubiquitination by DUBs promotes target proteins' lifespan and regulates protein localization and biological activity.…”

“…De-ubiquitination by DUBs promotes target proteins' lifespan and regulates protein localization and biological activity. 17, 18, 19 …”

Genomics, Biology, and Human Illness

“…This signaling pathway is in part regulated by ubiquitination, a protein post-transcriptional modification process 23 . The deubiquitinases (DUBs) are a group of enzymes that specifically remove ubiquitin (Ub) moieties from target proteins, and their dysregulation has been reported to result in various human diseases 4 . Several DUBs, including A20, CYLD, OTULIN, and OTUD7B (Cezanne), act as negative regulators of NF-κB signaling 2 .…”