-
International Journal of Molecular... Jul 2020The 26S proteasome, a master player in proteolysis, is the most complex and meticulously contextured protease in eukaryotic cells. While capable of hosting thousands of... (Review)
Review
The 26S proteasome, a master player in proteolysis, is the most complex and meticulously contextured protease in eukaryotic cells. While capable of hosting thousands of discrete substrates due to the selective recognition of ubiquitin tags, this protease complex is also dynamically checked through diverse regulatory mechanisms. The proteasome's versatility ensures precise control over active proteolysis, yet prevents runaway or futile degradation of many essential cellular proteins. Among the multi-layered processes regulating the proteasome's proteolysis, deubiquitination reactions are prominent because they not only recycle ubiquitins, but also impose a critical checkpoint for substrate degradation on the proteasome. Of note, three distinct classes of deubiquitinating enzymes-USP14, RPN11, and UCH37-are associated with the 19S subunits of the human proteasome. Recent biochemical and structural studies suggest that these enzymes exert dynamic influence over proteasome output with limited redundancy, and at times act in opposition. Such distinct activities occur spatially on the proteasome, temporally through substrate processing, and differentially for ubiquitin topology. Therefore, deubiquitinating enzymes on the proteasome may fine-tune the degradation depending on various cellular contexts and for dynamic proteolysis outcomes. Given that the proteasome is among the most important drug targets, the biology of proteasome-associated deubiquitination should be further elucidated for its potential targeting in human diseases.
Topics: Humans; Proteasome Endopeptidase Complex; Trans-Activators; Ubiquitin; Ubiquitin Thiolesterase
PubMed: 32726943
DOI: 10.3390/ijms21155312 -
Biochemical Society Transactions Dec 2019Protein ubiquitination is a posttranslational modification that regulates many aspects of cellular life, including proteostasis, vesicular trafficking, DNA repair and... (Review)
Review
Protein ubiquitination is a posttranslational modification that regulates many aspects of cellular life, including proteostasis, vesicular trafficking, DNA repair and NF-κB activation. By directly targeting intracellular bacteria or bacteria-containing vacuoles to the lysosome, ubiquitination is also an important component of cell-autonomous immunity. Not surprisingly, several pathogenic bacteria encode deubiquitinases (DUBs) and use them as secreted effectors that prevent ubiquitination of bacterial components. A systematic overview of known bacterial DUBs, including their cleavage specificities and biological roles, suggests multiple independent acquisition events from host-encoded DUBs and other proteases. The widely used classification of DUBs into seven well-defined families should only be applied to eukaryotic DUBs, since several bacterial DUBs do not follow this classification.
Topics: Bacteria; Deubiquitinating Enzymes; Ubiquitination
PubMed: 31845741
DOI: 10.1042/BST20190526 -
Experimental Dermatology Dec 2023Melanogenesis is a critical biochemical process in which melanocytes produce melanin, a crucial element involved in the formation of coat colour in mammals. According to... (Review)
Review
Melanogenesis is a critical biochemical process in which melanocytes produce melanin, a crucial element involved in the formation of coat colour in mammals. According to several earlier studies, melanocytes' post-translational modifications of proteins primarily control melanogenesis. Among the many post-translational changes that can affect melanin production, ubiquitination and deubiquitination can keep melanin production going by changing how proteins that are related to melanin are broken down or kept stable. Ubiquitination and deubiquitination maintain ubiquitin homeostasis, which is a highly dynamic process in balance under the action of E3 ubiquitin ligase and deubiquitinating enzymes. However, the regulatory mechanisms underlying ubiquitination and deubiquitination in melanogenesis are yet to be thoroughly investigated. As a result, there has been a growing focus on exploring the potential correlation between melanogenesis, ubiquitination and deubiquitination. This study discusses the mechanisms of ubiquitination and deubiquitination in the context of melanogenesis, a crucial process for enhancing mammalian coat coloration and addressing pigment-related diseases.
Topics: Animals; Melanins; Ubiquitination; Protein Processing, Post-Translational; Ubiquitin-Protein Ligases; Melanocytes; Mammals
PubMed: 37846904
DOI: 10.1111/exd.14953 -
Virology Jun 2007Post-translational modification of proteins and peptides by ubiquitin, a highly evolutionarily conserved 76 residue protein, and ubiquitin-like modifiers has emerged as... (Review)
Review
Post-translational modification of proteins and peptides by ubiquitin, a highly evolutionarily conserved 76 residue protein, and ubiquitin-like modifiers has emerged as a major regulatory mechanism in various cellular activities. Eukaryotic viruses are known to modulate protein ubiquitination to their advantage in various ways. At the same time, the evidence for the importance of deubiquitination as a viral target also is growing. This review centers on known viral interactions with protein deubiquitination, on viral enzymes for which deubiquitinating activities were recently demonstrated, and on the roles of viral ubiquitin-like sequences.
Topics: Enzymes; Eukaryotic Cells; Protein Processing, Post-Translational; Ubiquitins; Viral Proteins; Viruses
PubMed: 17291557
DOI: 10.1016/j.virol.2006.12.035 -
Frontiers in Physiology 2022Protein ubiquitination with general existence in virtually all eukaryotic cells serves as a significant post-translational modification of cellular proteins, which leads... (Review)
Review
Protein ubiquitination with general existence in virtually all eukaryotic cells serves as a significant post-translational modification of cellular proteins, which leads to the degradation of proteins via the ubiquitin-proteasome system. Deubiquitinating enzymes (DUBs) can reverse the ubiquitination effect by removing the ubiquitin chain from the target protein. Together, these two processes participate in regulating protein stability, function, and localization, thus modulating cell cycle, DNA repair, autophagy, and transcription regulation. Accumulating evidence indicates that the ubiquitination/deubiquitination system regulates reproductive processes, including the cell cycle, oocyte maturation, oocyte-sperm binding, and early embryonic development, primarily by regulating protein stability. This review summarizes the extensive research concerning the role of ubiquitin and DUBs in gametogenesis and early embryonic development, which helps us to understand human pregnancy further.
PubMed: 35910557
DOI: 10.3389/fphys.2022.886261 -
Frontiers in Immunology 2023Osteoarthritis is non-inflammatory degenerative joint arthritis, which exacerbates disability in elder persons. The molecular mechanisms of osteoarthritis are elusive.... (Review)
Review
Osteoarthritis is non-inflammatory degenerative joint arthritis, which exacerbates disability in elder persons. The molecular mechanisms of osteoarthritis are elusive. Ubiquitination, one type of post-translational modifications, has been demonstrated to accelerate or ameliorate the development and progression of osteoarthritis targeting specific proteins for ubiquitination and determining protein stability and localization. Ubiquitination process can be reversed by a class of deubiquitinases deubiquitination. In this review, we summarize the current knowledge regarding the multifaceted role of E3 ubiquitin ligases in the pathogenesis of osteoarthritis. We also describe the molecular insight of deubiquitinases into osteoarthritis processes. Moreover, we highlight the multiple compounds that target E3 ubiquitin ligases or deubiquitinases to influence osteoarthritis progression. We discuss the challenge and future perspectives modulation of E3 ubiquitin ligases and deubiquitinases expression for enhancement of the therapeutic efficacy in osteoarthritis patients. We conclude that modulating ubiquitination and deubiquitination could alleviate the osteoarthritis pathogenesis to achieve the better treatment outcomes in osteoarthritis patients.
Topics: Humans; Aged; Ubiquitination; Ubiquitin-Protein Ligases; Deubiquitinating Enzymes; Osteoarthritis; Ubiquitins
PubMed: 37359559
DOI: 10.3389/fimmu.2023.1217466 -
Annual Review of Biochemistry Jun 2018As the endpoint for the ubiquitin-proteasome system, the 26S proteasome is the principal proteolytic machine responsible for regulated protein degradation in eukaryotic... (Review)
Review
As the endpoint for the ubiquitin-proteasome system, the 26S proteasome is the principal proteolytic machine responsible for regulated protein degradation in eukaryotic cells. The proteasome's cellular functions range from general protein homeostasis and stress response to the control of vital processes such as cell division and signal transduction. To reliably process all the proteins presented to it in the complex cellular environment, the proteasome must combine high promiscuity with exceptional substrate selectivity. Recent structural and biochemical studies have shed new light on the many steps involved in proteasomal substrate processing, including recognition, deubiquitination, and ATP-driven translocation and unfolding. In addition, these studies revealed a complex conformational landscape that ensures proper substrate selection before the proteasome commits to processive degradation. These advances in our understanding of the proteasome's intricate machinery set the stage for future studies on how the proteasome functions as a major regulator of the eukaryotic proteome.
Topics: ATPases Associated with Diverse Cellular Activities; Deubiquitinating Enzymes; Humans; Models, Biological; Models, Molecular; Molecular Motor Proteins; Proteasome Endopeptidase Complex; Protein Conformation; Saccharomyces cerevisiae Proteins; Substrate Specificity; Ubiquitin
PubMed: 29652515
DOI: 10.1146/annurev-biochem-062917-011931 -
Journal of Molecular Medicine (Berlin,... Mar 2024N methyladenosine (mA) is the most prevalent RNA epigenetic modification, regulated by methyltransferases and demethyltransferases and recognized by methylation-related... (Review)
Review
N methyladenosine (mA) is the most prevalent RNA epigenetic modification, regulated by methyltransferases and demethyltransferases and recognized by methylation-related reading proteins to impact mRNA splicing, translocation, stability, and translation efficiency. It significantly affects a variety of activities, including stem cell maintenance and differentiation, tumor formation, immune regulation, and metabolic disorders. Ubiquitination refers to the specific modification of target proteins by ubiquitin molecule in response to a series of enzymes. E3 ligases connect ubiquitin to target proteins and usually lead to protein degradation. On the contrary, deubiquitination induced by deubiquitinating enzymes (DUBs) can separate ubiquitin and regulate the stability of protein. Recent studies have emphasized the potential importance of ubiquitination and deubiquitination in controlling the function of mA modification. In this review, we discuss the impact of ubiquitination and deubiquitination on mA functional molecules in diseases, such as metabolism, cellular stress, and tumor growth.
Topics: Humans; Ubiquitination; Ubiquitin-Protein Ligases; Ubiquitin; Proteins; Neoplasms; Adenosine
PubMed: 38289385
DOI: 10.1007/s00109-024-02417-9 -
International Journal of Molecular... May 2020The Wnt signaling pathway plays important roles in embryonic development, homeostatic processes, cell differentiation, cell polarity, cell proliferation, and cell... (Review)
Review
The Wnt signaling pathway plays important roles in embryonic development, homeostatic processes, cell differentiation, cell polarity, cell proliferation, and cell migration via the β-catenin binding of Wnt target genes. Dysregulation of Wnt signaling is associated with various diseases such as cancer, aging, Alzheimer's disease, metabolic disease, and pigmentation disorders. Numerous studies entailing the Wnt signaling pathway have been conducted for various cancers. Diverse signaling factors mediate the up- or down-regulation of Wnt signaling through post-translational modifications (PTMs), and aberrant regulation is associated with several different malignancies in humans. Of the numerous PTMs involved, most Wnt signaling factors are regulated by ubiquitination and deubiquitination. Ubiquitination by E3 ligase attaches ubiquitins to target proteins and usually induces proteasomal degradation of Wnt signaling factors such as β-catenin, Axin, GSK3, and Dvl. Conversely, deubiquitination induced by the deubiquitinating enzymes (DUBs) detaches the ubiquitins and modulates the stability of signaling factors. In this review, we discuss the effects of ubiquitination and deubiquitination on the Wnt signaling pathway, and the inhibitors of DUBs that can be applied for cancer therapeutic strategies.
Topics: Animals; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3; Humans; Mutation; Neoplasms; Protein Binding; Protein Folding; Protein Processing, Post-Translational; Ubiquitin; Ubiquitination; Wnt Signaling Pathway
PubMed: 32486158
DOI: 10.3390/ijms21113904 -
Molecular Cell Sep 2020DNA-protein crosslinks (DPCs) are highly toxic DNA lesions that threaten genomic integrity. Recent findings highlight that SPRTN, a specialized DNA-dependent...
DNA-protein crosslinks (DPCs) are highly toxic DNA lesions that threaten genomic integrity. Recent findings highlight that SPRTN, a specialized DNA-dependent metalloprotease, is a central player in proteolytic cleavage of DPCs. Previous studies suggest that SPRTN deubiquitination is important for its chromatin association and activation. However, the regulation and consequences of SPRTN deubiquitination remain unclear. Here we report that, in response to DPC induction, the deubiquitinase VCPIP1/VCIP135 is phosphorylated and activated by ATM/ATR. VCPIP1, in turn, deubiquitinates SPRTN and promotes its chromatin relocalization. Deubiquitination of SPRTN is required for its subsequent acetylation, which promotes SPRTN relocation to the site of chromatin damage. Furthermore, Vcpip1 knockout mice are prone to genomic instability and premature aging. We propose a model where two sequential post-translational modifications (PTMs) regulate SPRTN chromatin accessibility to repair DPCs and maintain genomic stability and a healthy lifespan.
Topics: Acetylation; Aging; Animals; Cell Line; DNA Damage; DNA Repair; DNA-Binding Proteins; Deubiquitinating Enzymes; Endopeptidases; Female; Genomic Instability; HEK293 Cells; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Protein Domains; Protein Processing, Post-Translational; Ubiquitination
PubMed: 32649882
DOI: 10.1016/j.molcel.2020.06.027