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American Journal of Physiology. Cell... Nov 2022All living organisms experience daily environmental cycles and have consequently evolved to synchronize and adapt to this changing environment. Biological processes such... (Review)
Review
All living organisms experience daily environmental cycles and have consequently evolved to synchronize and adapt to this changing environment. Biological processes such as hormonal secretion, body temperature, and sleep follow daily cycles called circadian rhythms that are driven by a molecular clock running in most cells and tissues of the body. This clock is composed of transcriptional-translational negative feedback loops involving clock genes and proteins. This molecular mechanism functions with a period of ∼24 h, and it promotes daily rhythms in the expression of numerous genes. For this robust mechanism to function, the abundance and activity of clock proteins need to be tightly regulated. One of the mechanisms by which this can be achieved is ubiquitination. Indeed, many ubiquitin ligases can tag core clock proteins to target them for proteasomal degradation. However, deubiquitinases can reverse this process by removing or modifying these ubiquitin signals and are thus important enzymes in clock protein homeostasis and regulation. Recent studies on the mammalian and clock mechanisms have identified a number of deubiquitinases able to stabilize core clock proteins, change their cellular localization or even regulate their activity. In this review, we aim to discuss the fundamental roles of ubiquitination and deubiquitination in the circadian clock by presenting all deubiquitinases found to be involved in circadian rhythms with the aim to give a global view of recent advances in this emerging field.
Topics: Animals; Circadian Clocks; CLOCK Proteins; Circadian Rhythm; Drosophila; Deubiquitinating Enzymes; Ubiquitins; Mammals
PubMed: 36189971
DOI: 10.1152/ajpcell.00289.2022 -
Biomolecules Jun 2022Deubiquitinating enzymes (DUBs) are a group of proteases that are important for maintaining cell homeostasis by regulating the balance between ubiquitination and... (Review)
Review
Deubiquitinating enzymes (DUBs) are a group of proteases that are important for maintaining cell homeostasis by regulating the balance between ubiquitination and deubiquitination. As the only known metalloproteinase family of DUBs, JAB1/MPN/Mov34 metalloenzymes (JAMMs) are specifically associated with tumorigenesis and immunological and inflammatory diseases at multiple levels. The far smaller numbers and distinct catalytic mechanism of JAMMs render them attractive drug targets. Currently, several JAMM inhibitors have been successfully developed and have shown promising therapeutic efficacy. To gain greater insight into JAMMs, in this review, we focus on several key proteins in this family, including AMSH, AMSH-LP, BRCC36, Rpn11, and CSN5, and emphatically discuss their structural basis, diverse functions, catalytic mechanism, and current reported inhibitors targeting JAMMs. These advances set the stage for the exploitation of JAMMs as a target for the treatment of various diseases.
Topics: Deubiquitinating Enzymes; Endopeptidases; Peptide Hydrolases; Proteins; Ubiquitination
PubMed: 35883466
DOI: 10.3390/biom12070910 -
Cells Apr 2023OTUD5 (OTU Deubiquitinase 5) is a functional cysteine protease with deubiquitinase activity and is a member of the ovarian tumor protease (OTU) family. OTUD5 is involved... (Review)
Review
OTUD5 (OTU Deubiquitinase 5) is a functional cysteine protease with deubiquitinase activity and is a member of the ovarian tumor protease (OTU) family. OTUD5 is involved in the deubiquitination of many key proteins in various cellular signaling pathways and plays an important role in maintaining normal human development and physiological functions. Its dysfunction can affect physiological processes, such as immunity and DNA damage repair, and it can even lead to tumors, inflammatory diseases and genetic disorders. Therefore, the regulation of OTUD5 activity and expression has become a hot topic of research. A comprehensive understanding of the regulatory mechanisms of OTUD5 and its use as a therapeutic target for diseases is of great value. Herein, we review the physiological processes and molecular mechanisms of OTUD5 regulation, outline the specific regulatory processes of OTUD5 activity and expression, and link OTUD5 to diseases from the perspective of studies on signaling pathways, molecular interactions, DNA damage repair and immune regulation, thus providing a theoretical basis for future studies.
Topics: Female; Humans; Ubiquitination; DNA Repair; Signal Transduction; Ovarian Neoplasms; Deubiquitinating Enzymes
PubMed: 37190070
DOI: 10.3390/cells12081161 -
International Journal of Molecular... Nov 2019Mitosis is a complex and dynamic process that is tightly regulated by a large number of mitotic proteins. Dysregulation of these proteins can generate daughter cells... (Review)
Review
Mitosis is a complex and dynamic process that is tightly regulated by a large number of mitotic proteins. Dysregulation of these proteins can generate daughter cells that exhibit genomic instability and aneuploidy, and such cells can transform into tumorigenic cells. Thus, it is important for faithful mitotic progression to regulate mitotic proteins at specific locations in the cells at a given time in each phase of mitosis. Ubiquitin-dependent modifications play critical roles in this process by regulating the degradation, translocation, or signal transduction of mitotic proteins. Here, we review how ubiquitination and deubiquitination regulate the progression of mitosis. In addition, we summarize the substrates and roles of some deubiquitinating enzymes (DUBs) crucial for mitosis and describe how they contribute error correction during mitosis and control the transition between the mitotic phases.
Topics: Animals; Deubiquitinating Enzymes; Humans; Mitosis; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 31795161
DOI: 10.3390/ijms20235997 -
Cell Death and Differentiation Aug 2016Post-translational modifications (PTMs) of stemness-related proteins are essential for stem cell maintenance and differentiation. In stem cell self-renewal and... (Review)
Review
Post-translational modifications (PTMs) of stemness-related proteins are essential for stem cell maintenance and differentiation. In stem cell self-renewal and differentiation, PTM of stemness-related proteins is tightly regulated because the modified proteins execute various stem cell fate choices. Ubiquitination and deubiquitination, which regulate protein turnover of several stemness-related proteins, must be carefully coordinated to ensure optimal embryonic stem cell maintenance and differentiation. Deubiquitinating enzymes (DUBs), which specifically disassemble ubiquitin chains, are a central component in the ubiquitin-proteasome pathway. These enzymes often control the balance between ubiquitination and deubiquitination. To maintain stemness and achieve efficient differentiation, the ubiquitination and deubiquitination molecular switches must operate in a balanced manner. Here we summarize the current information on DUBs, with a focus on their regulation of stem cell fate determination and deubiquitinase inhibition as a therapeutic strategy. Furthermore, we discuss the possibility of using DUBs with defined stem cell transcription factors to enhance cellular reprogramming efficiency and cell fate conversion. Our review provides new insight into DUB activity by emphasizing their cellular role in regulating stem cell fate. This role paves the way for future research focused on specific DUBs or deubiquitinated substrates as key regulators of pluripotency and stem cell differentiation.
Topics: Animals; Cell Differentiation; Cell Self Renewal; Deubiquitinating Enzymes; Embryonic Stem Cells; Humans; Neoplasms; Transcription Factors; Tumor Suppressor Proteins; Ubiquitin; Ubiquitination
PubMed: 27285106
DOI: 10.1038/cdd.2016.53 -
The Biochemical Journal Sep 2008Protein modification by ubiquitin and ubiquitin-like molecules is a critical regulatory process. Like most regulated protein modifications, ubiquitination is reversible.... (Review)
Review
Protein modification by ubiquitin and ubiquitin-like molecules is a critical regulatory process. Like most regulated protein modifications, ubiquitination is reversible. Deubiquitination, the reversal of ubiquitination, is quickly being recognized as an important regulatory strategy. Nearly one hundred human DUBs (deubiquitinating enzymes) in five different gene families oppose the action of several hundred ubiquitin ligases, suggesting that both ubiquitination and its reversal are highly regulated and specific processes. It has long been recognized that ubiquitin ligases are modular enzyme systems that often depend on scaffolds and adaptors to deliver substrates to the catalytically active macromolecular complex. Although many DUBs bind ubiquitin with reasonable affinities (in the nM to microM range), a larger number have little affinity but exhibit robust catalytic capability. Thus it is apparent that these DUBs must acquire their substrates by binding the target protein in a conjugate or by associating with other macromolecular complexes. We would then expect that a study of protein partners of DUBs would reveal a variety of substrates, scaffolds, adaptors and ubiquitin receptors. In the present review we suggest that, like ligases, much of the regulation and specificity of deubiquitination arises from the association of DUBs with these protein partners.
Topics: Endopeptidases; Humans; Proteasome Endopeptidase Complex; Protein Binding; Proteins; Ubiquitin; Ubiquitin Thiolesterase; Ubiquitination
PubMed: 18687060
DOI: 10.1042/BJ20080798 -
International Journal of Molecular... Aug 2020Deubiquitinating enzymes regulate various cellular processes, particularly protein degradation, localization, and protein-protein interactions. The dysregulation of... (Review)
Review
Deubiquitinating enzymes regulate various cellular processes, particularly protein degradation, localization, and protein-protein interactions. The dysregulation of deubiquitinating enzyme (DUB) activity has been linked to several diseases; however, the function of many DUBs has not been identified. Therefore, the development of methods to assess DUB activity is important to identify novel DUBs, characterize DUB selectivity, and profile dynamic DUB substrates. Here, we review various methods of evaluating DUB activity using cell lysates or purified DUBs, as well as the types of probes used in these methods. In addition, we introduce some techniques that can deliver DUB probes into the cells and cell-permeable activity-based probes to directly visualize and quantify DUB activity in live cells. This review could contribute to the development of DUB inhibitors by providing important information on the characteristics and applications of various probes used to evaluate and detect DUB activity in vitro and in vivo.
Topics: Animals; Deubiquitinating Enzymes; Enzyme Assays; Fluorescence Polarization; Humans; Molecular Probes; Ubiquitin; Ubiquitination
PubMed: 32781716
DOI: 10.3390/ijms21165638 -
Cells Mar 2023Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that plays a role in the regulation of gene expression, cell cycle progression, and various other functions.... (Review)
Review
Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that plays a role in the regulation of gene expression, cell cycle progression, and various other functions. It was originally identified as the major deubiquitinase for histone H2A and has since been found to deubiquitinate a range of other substrates, including proteins from both the cytoplasm and nucleus. USP16 is phosphorylated when cells enter mitosis and dephosphorylated during the metaphase/anaphase transition. While much of USP16 is localized in the cytoplasm, separating the enzyme from its substrates is considered an important regulatory mechanism. Some of the functions that USP16 has been linked to include DNA damage repair, immune disease, tumorigenesis, protein synthesis, coronary artery health, and male infertility. The strong connection to immune response and the fact that multiple oncogene products are substrates of USP16 suggests that USP16 may be a potential therapeutic target for the treatment of certain human diseases.
Topics: Humans; Male; Histones; Mitosis; DNA Repair; Ubiquitin-Specific Proteases; Deubiquitinating Enzymes
PubMed: 36980227
DOI: 10.3390/cells12060886 -
Cellular and Molecular Life Sciences :... Dec 2015Spermatogenesis is a complex process through which spermatogonial stem cells undergo mitosis, meiosis, and cell differentiation to generate mature spermatozoa. During... (Review)
Review
Spermatogenesis is a complex process through which spermatogonial stem cells undergo mitosis, meiosis, and cell differentiation to generate mature spermatozoa. During this process, male germ cells experience several translational modifications. One of the major post-translational modifications in eukaryotes is the ubiquitination of proteins, which targets proteins for degradation; this enables control of the expression of enzymes and structural proteins during spermatogenesis. It has become apparent that ubiquitination plays a key role in regulating every stage of spermatogenesis starting from gonocytes to differentiated spermatids. It is understood that, where there is ubiquitination, deubiquitination by deubiquitinating enzymes (DUBs) also exists to counterbalance the ubiquitination process in a reversible manner. Normal spermatogenesis is dependent on the balanced actions of ubiquitination and deubiquitination. This review highlights the current knowledge of the role of DUBs and their essential regulatory contribution to spermatogenesis, especially during progression into meiotic phase, acrosome biogenesis, quality sperm production, and apoptosis of germ cells.
Topics: Animals; Cell Differentiation; Male; Mice; Rats; Spermatogenesis; Ubiquitin; Ubiquitin-Specific Proteases; Ubiquitination
PubMed: 26350476
DOI: 10.1007/s00018-015-2030-z -
PeerJ 2023Protein ubiquitination is an important post-translational modification mechanism, which regulates protein stability and activity. The ubiquitination of proteins can be... (Review)
Review
Protein ubiquitination is an important post-translational modification mechanism, which regulates protein stability and activity. The ubiquitination of proteins can be reversed by deubiquitinating enzymes (DUBs). Ubiquitin-specific proteases (USPs), the largest DUB subfamily, can regulate cellular functions by removing ubiquitin(s) from the target proteins. Prostate cancer (PCa) is the second leading type of cancer and the most common cause of cancer-related deaths in men worldwide. Numerous studies have demonstrated that the development of PCa is highly correlated with USPs. The expression of USPs is either high or low in PCa cells, thereby regulating the downstream signaling pathways and causing the development or suppression of PCa. This review summarized the functional roles of USPs in the development PCa and explored their potential applications as therapeutic targets for PCa.
Topics: Male; Humans; Ubiquitin-Specific Proteases; Ubiquitination; Ubiquitin; Prostatic Neoplasms; Protein Processing, Post-Translational
PubMed: 36811009
DOI: 10.7717/peerj.14799