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Cell Death & Disease Sep 2022The mechanistic (formally "mammalian") target of rapamycin (mTOR) pathway serves as a crucial regulator of various biological processes such as cell growth and cancer...
The mechanistic (formally "mammalian") target of rapamycin (mTOR) pathway serves as a crucial regulator of various biological processes such as cell growth and cancer progression. In bladder cancer, recent discoveries showing the cancer-promoting role of mTOR complex 1 have attracted wide attention. However, the regulation of mTOR signaling in bladder cancer is complicated and the underlying mechanism remains elusive. Here, we report that the deubiquitinating enzyme, ovarian tumor domain-containing protein 5 (OTUD5), can activate the mTOR signaling pathway, promote cancer progression, and show its oncogenic potential in bladder cancer. In our study, we found that OTUD5 deubiquitinated a RING-type E3 ligase, RNF186, and stabilized its function. In addition, the stabilization of RNF186 further led to the degradation of sestrin2, which is an inhibitor of the mTOR signaling pathway. Together, we provide novel insights into the pathogenesis of bladder cancer and first prove that OTUD5 can promote bladder cancer progression through the OTUD5-RNF186-sestrin2-mTOR axis, which may be exploited in the future for the diagnosis and treatment of this malignancy.
Topics: Deubiquitinating Enzymes; Endopeptidases; Female; Humans; Mechanistic Target of Rapamycin Complex 1; Neoplasm Proteins; Signal Transduction; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases; Urinary Bladder Neoplasms
PubMed: 36085200
DOI: 10.1038/s41419-022-05128-6 -
MBio Aug 2023The histone acetyltransferase general control non-depressible 5 (Gcn5) plays a critical role in the epigenetic landscape and chromatin modification for regulating a wide...
The histone acetyltransferase general control non-depressible 5 (Gcn5) plays a critical role in the epigenetic landscape and chromatin modification for regulating a wide variety of biological events. However, the post-translational regulation of Gcn5 itself is poorly understood. Here, we found that Gcn5 was ubiquitinated and deubiquitinated by E3 ligase Tom1 and deubiquitinating enzyme Ubp14, respectively, in the important plant pathogenic fungus . Tom1 interacted with Gcn5 in the nucleus and subsequently ubiquitinated Gcn5 mainly at K252 to accelerate protein degradation. Conversely, Ubp14 deubiquitinated Gcn5 and enhanced its stability. In the deletion mutant Δ, protein level of Gcn5 was significantly reduced and resulted in attenuated virulence in the fungus by affecting the mycotoxin production, autophagy process, and the penetration ability. Our findings indicate that Tom1 and Ubp14 show antagonistic functions in the control of the protein stability of Gcn5 via post-translational modification and highlight the importance of Tom1-Gcn5-Ubp14 circuit in the fungal virulence. IMPORTANCE Post-translational modification (PTM) enzymes have been reported to be involved in regulating numerous cellular processes. However, the modification of these PTM enzymes themselves is largely unknown. In this study, we found that the E3 ligase Tom1 and deubiquitinating enzyme Ubp14 contributed to the regulation of ubiquitination and deubiquitination of acetyltransferase Gcn5, respectively, in , the causal agent of Fusarium head blight of cereals. Our findings provide deep insights into the modification of acetyltransferase Gcn5 and its dynamic regulation via ubiquitination and deubiquitination. To our knowledge, this work is the most comprehensive analysis of a regulatory network of ubiquitination that impinges on acetyltransferase in filamentous pathogens. Moreover, our findings are important because we present the novel roles of the Tom1-Gcn5-Ubp14 circuit in fungal virulence, providing novel possibilities and targets to control fungal diseases.
Topics: Fusarium; Virulence; Ubiquitination; Histone Acetyltransferases; Ubiquitin-Protein Ligases; Deubiquitinating Enzymes; Fungal Proteins; Plant Diseases; Spores, Fungal
PubMed: 37504517
DOI: 10.1128/mbio.01499-23 -
Oncogene May 2019The evolutionarily conserved mTOR signaling pathway plays essential roles in cell growth, proliferation, metabolism and responses to cellular stresses. Hyperactivation... (Review)
Review
The evolutionarily conserved mTOR signaling pathway plays essential roles in cell growth, proliferation, metabolism and responses to cellular stresses. Hyperactivation of the mTOR signaling is observed in virtually all solid tumors and has been an attractive drug target. In addition to changes at genetic levels, aberrant activation of the mTOR signaling is also a result from dysregulated posttranslational modifications on key pathway members, such as phosphorylation that has been extensively studied. Emerging evidence also supports a critical role for ubiquitin-mediated modifications in dynamically regulating the mTOR signaling pathway, while a comprehensive review for relevant studies is missing. In this review, we will summarize characterized ubiquitination events on major mTOR signaling components, their modifying E3 ubiquitin ligases, deubiquitinases and corresponding pathophysiological functions. We will also reveal methodologies that have been used to identify E3 ligases or DUBs to facilitate the search for yet-to-be discovered ubiquitin-mediated regulatory mechanisms in mTOR signaling. We hope that our review and perspectives provide rationales and strategies to target ubiquitination for inhibiting mTOR signaling to treat human diseases.
Topics: Animals; Deubiquitinating Enzymes; Humans; Signal Transduction; TOR Serine-Threonine Kinases; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 30705402
DOI: 10.1038/s41388-019-0713-x -
The Biochemical Journal May 2022Apoptosis, pyroptosis, and necroptosis are distinct forms of programmed cell death that eliminate infected, damaged, or obsolete cells. Many proteins that regulate or... (Review)
Review
Apoptosis, pyroptosis, and necroptosis are distinct forms of programmed cell death that eliminate infected, damaged, or obsolete cells. Many proteins that regulate or are a part of the cell death machinery undergo ubiquitination, a post-translational modification made by ubiquitin ligases that modulates protein abundance, localization, and/or activity. For example, some ubiquitin chains target proteins for degradation, while others function as scaffolds for the assembly of signaling complexes. Deubiquitinases (DUBs) are the proteases that counteract ubiquitin ligases by cleaving ubiquitin from their protein substrates. Here, we review the DUBs that have been found to suppress or promote apoptosis, pyroptosis, or necroptosis.
Topics: Cell Death; Deubiquitinating Enzymes; Humans; Inflammation; Ligases; Ubiquitin; Ubiquitination
PubMed: 35608338
DOI: 10.1042/BCJ20210735 -
Cellular and Molecular Life Sciences :... Apr 2016All organs consisting of single cells are consistently maintaining homeostasis in response to stimuli such as free oxygen, DNA damage, inflammation, and microorganisms.... (Review)
Review
All organs consisting of single cells are consistently maintaining homeostasis in response to stimuli such as free oxygen, DNA damage, inflammation, and microorganisms. The cell cycle of all mammalian cells is regulated by protein expression in the right phase to respond to proliferation and apoptosis signals. Post-translational modifications (PTMs) of proteins by several protein-editing enzymes are associated with cell cycle regulation by their enzymatic functions. Ubiquitination, one of the PTMs, is also strongly related to cell cycle regulation by protein degradation or signal transduction. The importance of deubiquitinating enzymes (DUBs), which have a reversible function for ubiquitination, has recently suggested that the function of DUBs is also important for determining the fate of proteins during cell cycle processing. This article reviews and summarizes the diverse roles of DUBs, including DNA damage, cell cycle processing, and regulation of histone proteins, and also suggests the possibility for therapeutic targets.
Topics: Animals; Cell Cycle Checkpoints; DNA Damage; DNA Repair; Histones; Humans; Protein Processing, Post-Translational; Tumor Suppressor Protein p53; Ubiquitin Thiolesterase; Ubiquitin-Specific Proteases
PubMed: 26762302
DOI: 10.1007/s00018-015-2129-2 -
Signal Transduction and Targeted Therapy Jan 2021Cancer immunotherapy has become an attractive approach of cancer treatment with tremendous success in treating various advanced malignancies. The development and... (Review)
Review
Cancer immunotherapy has become an attractive approach of cancer treatment with tremendous success in treating various advanced malignancies. The development and clinical application of immune checkpoint inhibitors represent one of the most extraordinary accomplishments in cancer immunotherapy. In addition, considerable progress is being made in understanding the mechanism of antitumor immunity and characterizing novel targets for developing additional therapeutic approaches. One active area of investigation is protein ubiquitination, a post-translational mechanism of protein modification that regulates the function of diverse immune cells in antitumor immunity. Accumulating studies suggest that E3 ubiquitin ligases and deubiquitinases form a family of potential targets to be exploited for enhancing antitumor immunity in cancer immunotherapy.
Topics: Deubiquitinating Enzymes; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasm Proteins; Neoplasms; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 33436547
DOI: 10.1038/s41392-020-00421-2 -
Journal of Biochemistry Jul 2003Modification of proteins by the covalent attachment of ubiquitin is a key regulatory mechanism of many cellular processes including protein degradation by the 26S... (Review)
Review
Modification of proteins by the covalent attachment of ubiquitin is a key regulatory mechanism of many cellular processes including protein degradation by the 26S proteasome. Deubiquitination, reversal of this modification, must also regulate the fate and function of ubiquitin-conjugated proteins. Deubiquitinating enzymes catalyze the removal of ubiquitin from ubiquitin-conjugated substrate proteins as well as from its precursor proteins. Deubiquitinating enzymes occupy the largest family of enzymes in the ubiquitin system, implying their diverse function in regulation of the ubiquitin-mediated pathways. Here we explore the diversity of deubiquitinating enzymes and their emerging roles as cellular regulators.
Topics: Animals; Cysteine Endopeptidases; Endopeptidases; Humans; Multienzyme Complexes; Transcription, Genetic; Ubiquitin Thiolesterase; Ubiquitins
PubMed: 12944365
DOI: 10.1093/jb/mvg107 -
Cell Research Apr 2016Conjugation and deconjugation of ubiquitin and ubiquitin-like proteins (Ubls) to cellular proteins are highly regulated processes integral to cellular homeostasis. Most... (Review)
Review
Conjugation and deconjugation of ubiquitin and ubiquitin-like proteins (Ubls) to cellular proteins are highly regulated processes integral to cellular homeostasis. Most often, the C-termini of these small polypeptides are attached to lysine side chains of target proteins by an amide (isopeptide) linkage. Deubiquitinating enzymes (DUBs) and Ubl-specific proteases (ULPs) comprise a diverse group of proteases that recognize and remove ubiquitin and Ubls from their substrates. How DUBs and ULPs distinguish among different modifiers, or different polymeric forms of these modifiers, remains poorly understood. The specificity of ubiquitin/Ubl-deconjugating enzymes for particular substrates depends on multiple factors, ranging from the topography of specific substrate features, as in different polyubiquitin chain types, to structural elements unique to each enzyme. Here we summarize recent structural and biochemical studies that provide insights into mechanisms of substrate specificity among various DUBs and ULPs. We also discuss the unexpected specificities of non-eukaryotic proteases in these families.
Topics: Catalytic Domain; Deubiquitinating Enzymes; Humans; Protein Conformation; Structure-Activity Relationship; Substrate Specificity; Ubiquitin; Ubiquitins
PubMed: 27012468
DOI: 10.1038/cr.2016.38 -
Journal of Zhejiang University.... Jan 2021DNA is the hereditary material in humans and almost all other organisms. It is essential for maintaining accurate transmission of genetic information. In the life cycle,... (Review)
Review
DNA is the hereditary material in humans and almost all other organisms. It is essential for maintaining accurate transmission of genetic information. In the life cycle, DNA replication, cell division, or genome damage, including that caused by endogenous and exogenous agents, may cause DNA aberrations. Of all forms of DNA damage, DNA double-strand breaks (DSBs) are the most serious. If the repair function is defective, DNA damage may cause gene mutation, genome instability, and cell chromosome loss, which in turn can even lead to tumorigenesis. DNA damage can be repaired through multiple mechanisms. Homologous recombination (HR) and non-homologous end joining (NHEJ) are the two main repair mechanisms for DNA DSBs. Increasing amounts of evidence reveal that protein modifications play an essential role in DNA damage repair. Protein deubiquitination is a vital post-translational modification which removes ubiquitin molecules or polyubiquitinated chains from substrates in order to reverse the ubiquitination reaction. This review discusses the role of deubiquitinating enzymes (DUBs) in repairing DNA DSBs. Exploring the molecular mechanisms of DUB regulation in DSB repair will provide new insights to combat human diseases and develop novel therapeutic approaches.
Topics: Ataxia Telangiectasia Mutated Proteins; Checkpoint Kinase 1; Checkpoint Kinase 2; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; DNA Repair Enzymes; DNA-Binding Proteins; Deubiquitinating Enzymes; Homologous Recombination; Humans; Ubiquitin-Protein Ligases
PubMed: 33448188
DOI: 10.1631/jzus.B2000309 -
Ageing Research Reviews Aug 2020Most proteins undergo posttranslational modification such as acetylation, methylation, phosphorylation, biotinylation, and ubiquitination to regulate various cellular... (Review)
Review
Most proteins undergo posttranslational modification such as acetylation, methylation, phosphorylation, biotinylation, and ubiquitination to regulate various cellular processes. Ubiquitin-targeted proteins from the ubiquitin-proteasome system (UPS) are degraded by 26S proteasome, along with this, deubiquitinating enzymes (DUBs) have specific activity against the UPS through detaching of ubiquitin on ubiquitin-targeted proteins. Balancing between protein expression and degradation through interplay between the UPS and DUBs is important to maintain cell homeostasis, and abnormal expression and elongation of proteins lead to diverse diseases such as cancer, diabetes, and autoimmune response. Therefore, development of DUB inhibitors as therapeutic targets has been challenging. In addition, understanding of the roles of DUBs in neurodegeneration, specifically brain diseases, has emerged gradually. This review highlights recent studies on the molecular mechanisms for DUBs, and discusses potential therapeutic targets for DUBs in cases of brain diseases.
Topics: Brain Diseases; Deubiquitinating Enzymes; Humans; Ubiquitin; Ubiquitinated Proteins; Ubiquitination
PubMed: 32470641
DOI: 10.1016/j.arr.2020.101088