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Biomolecules May 2024The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The... (Review)
Review
The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.
Topics: Humans; Neoplasms; Ubiquitin Thiolesterase; Animals; Ubiquitination; Inflammation; Signal Transduction; Ubiquitin
PubMed: 38785979
DOI: 10.3390/biom14050572 -
Cellular and Molecular Life Sciences :... May 2024Ubiquitin-proteasome system dysfunction triggers α-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson's disease (PD). However, the...
Ubiquitin-proteasome system dysfunction triggers α-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson's disease (PD). However, the crosstalk between deubiquitinating enzyme (DUBs) and α-synuclein pathology remains unclear. In this study, we observed a decrease in the level of ubiquitin-specific protease 14 (USP14), a DUB, in the cerebrospinal fluid (CSF) of PD patients, particularly females. Moreover, CSF USP14 exhibited a dual correlation with α-synuclein in male and female PD patients. To investigate the impact of USP14 deficiency, we crossed USP14 heterozygous mouse (USP14) with transgenic A53T PD mouse (A53T-Tg) or injected adeno-associated virus (AAV) carrying human α-synuclein (AAV-hα-Syn) in USP14 mice. We found that Usp14 deficiency improved the behavioral abnormities and pathological α-synuclein deposition in female A53T-Tg or AAV-hα-Syn mice. Additionally, Usp14 inactivation attenuates the pro-inflammatory response in female AAV-hα-Syn mice, whereas Usp14 inactivation demonstrated opposite effects in male AAV-hα-Syn mice. Mechanistically, the heterodimeric protein S100A8/A9 may be the downstream target of Usp14 deficiency in female mouse models of α-synucleinopathies. Furthermore, upregulated S100A8/A9 was responsible for α-synuclein degradation by autophagy and the suppression of the pro-inflammatory response in microglia after Usp14 knockdown. Consequently, our study suggests that USP14 could serve as a novel therapeutic target in PD.
Topics: alpha-Synuclein; Animals; Parkinson Disease; Ubiquitin Thiolesterase; Humans; Mice; Female; Male; Mice, Transgenic; Calgranulin B; Calgranulin A; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 38780644
DOI: 10.1007/s00018-024-05246-8 -
Heliyon May 2024Chronic obstructive pulmonary disease (COPD) and other respiratory diseases frequently present with airway mucus hypersecretion, which not only affects the patient's...
Chronic obstructive pulmonary disease (COPD) and other respiratory diseases frequently present with airway mucus hypersecretion, which not only affects the patient's quality of life but also poses a constant threat to their life expectancy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, affects cell differentiation, tissue growth, and disease development. However, its role in airway mucus hypersecretion induced by COPD remains elusive. In this study, USP7 expression was significantly upregulated in airway epithelial samples from patients with COPD, and USP7 was also overexpressed in mouse lung and human airway epithelial cells in models of airway mucus hypersecretion. Inhibition of USP7 reduced the expression of nuclear factor kappa B (NF-κB), phosphorylated-NF-κB (p-NF-κB), and phosphonated inhibitor of nuclear factor kappa B (-IκBα), and alleviated the airway mucus hypersecretion and . Further research revealed that USP7 stimulated airway mucus hypersecretion through the activation of NF-κB nuclear translocation. In addition, the expression of mucin 5AC (MUC5AC) was suppressed by the NF-κB inhibitor erdosteine. These findings suggest that USP7 stimulates the NF-κB signaling pathway, which promotes airway mucus hypersecretion. This study identifies one of the mechanisms regulating airway mucus secretion and provides a new potential target for its prevention and treatment.
PubMed: 38778971
DOI: 10.1016/j.heliyon.2024.e30967 -
Clinical and Translational Medicine May 2024Cerebrovascular diseases (CVDs) are a major threat to global health. Elucidation of the molecular mechanisms underlying the pathology of CVDs is critical for the... (Review)
Review
Cerebrovascular diseases (CVDs) are a major threat to global health. Elucidation of the molecular mechanisms underlying the pathology of CVDs is critical for the development of efficacious preventative and therapeutic approaches. Accumulating studies have highlighted the significance of ubiquitin-modifying enzymes (UMEs) in the regulation of CVDs. UMEs are a group of enzymes that orchestrate ubiquitination, a post-translational modification tightly involved in CVDs. Functionally, UMEs regulate multiple pathological processes in ischemic and hemorrhagic stroke, moyamoya disease, and atherosclerosis. Considering the important roles of UMEs in CVDs, they may become novel druggable targets for these diseases. Besides, techniques applying UMEs, such as proteolysis-targeting chimera and deubiquitinase-targeting chimera, may also revolutionize the therapy of CVDs in the future.
Topics: Humans; Cerebrovascular Disorders; Ubiquitin; Ubiquitination
PubMed: 38778460
DOI: 10.1002/ctm2.1719 -
Frontiers in Immunology 2024OTULIN deficiency is a complex disease characterized by a wide range of clinical manifestations, including skin rash, joint welling, lipodystrophy to pulmonary abscess,... (Review)
Review
OTULIN deficiency is a complex disease characterized by a wide range of clinical manifestations, including skin rash, joint welling, lipodystrophy to pulmonary abscess, and sepsis shock. This disease is mechanistically linked to mutations in the gene, resulting in an immune disorder that compromises the body's ability to effectively combat pathogens and foreign stimuli. The gene is responsible for encoding a deubiquitinating enzyme crucial for hydrolyzing Met1-poly Ub chains, and its dysfunction leads to dysregulated immune responses. Patients with OTULIN deficiency often exhibit an increase in monocytes, including neutrophils and macrophages, along with inflammatory clinical features. The onset of symptoms typically occurs at an early age. However, individuals with haploinsufficiency are particularly susceptible to life-threatening staphylococcal infections. Currently, the most effective treatment for patients with biallelic mutations involves the use of TNF-blocking agents, which target the dysregulated immune response. In conclusion, OTULIN deficiency presents a complex clinical picture with diverse manifestations, attributed to mutations in the gene. Understanding the underlying mechanisms is crucial for developing targeted therapeutic interventions to address this challenging condition. Further research into the pathophysiology of OTULIN deficiency is essential for improving clinical management and outcomes for affected individuals.
Topics: Humans; Immunity, Innate; Mutation; Animals; Endopeptidases
PubMed: 38774872
DOI: 10.3389/fimmu.2024.1371564 -
Journal of Translational Medicine May 2024Miscarriage is a frustrating complication of pregnancy that is common among women of reproductive age. Insufficient decidualization which not only impairs embryo...
BACKGROUND
Miscarriage is a frustrating complication of pregnancy that is common among women of reproductive age. Insufficient decidualization which not only impairs embryo implantation but disturbs fetomaternal immune-tolerance, has been widely regarded as a major cause of miscarriage; however, the underlying mechanisms resulting in decidual impairment are largely unknown.
METHODS
With informed consent, decidual tissue from patients with spontaneous abortion or normal pregnant women was collected to detect the expression profile of UCHL1. Human endometrial stromal cells (HESCs) were used to explore the roles of UCHL1 in decidualization and dNK modulation, as well as the mechanisms involved. C57/BL6 female mice (7-10 weeks old) were used to construct pregnancy model or artificially induced decidualization model to evaluate the effect of UCHL1 on mice decidualization and pregnancy outcome.
RESULTS
The Ubiquitin C-terminal hydrolase L1 (UCHL1), as a deubiquitinating enzyme, was significantly downregulated in decidua from patients with miscarriage, along with impaired decidualization and decreased dNKs. Blockage of UCHL1 led to insufficient decidualization and resultant decreased expression of cytokines CXCL12, IL-15, TGF-β which were critical for generation of decidual NK cells (dNKs), whereas UCHL1 overexpression enhanced decidualization accompanied by increase in dNKs. Mechanistically, the promotion of UCHL1 on decidualization was dependent on its deubiquitinating activity, and intervention of UCHL1 inhibited the activation of JAK2/STAT3 signaling pathway, resulting in aberrant decidualization and decreased production of cytokines associated with dNKs modulation. Furthermore, we found that inhibition of UCHL1 also disrupted the decidualization in mice and eventually caused adverse pregnancy outcome.
CONCLUSIONS
UCHL1 plays significant roles in decidualization and dNKs modulation during pregnancy in both humans and mice. Its deficiency indicates a poor pregnancy outcome due to defective decidualization, making UCHL1 a potential target for the diagnosis and treatment of miscarriage.
Topics: Ubiquitin Thiolesterase; Female; Decidua; Animals; Pregnancy; Abortion, Spontaneous; Humans; Mice, Inbred C57BL; Killer Cells, Natural; Adult; Mice; Stromal Cells; Signal Transduction
PubMed: 38769534
DOI: 10.1186/s12967-024-05253-0 -
Frontiers in RNA Research 2024Ribosome biogenesis is essential for cell growth, proliferation, and animal development. Its deregulation leads to various human disorders such as ribosomopathies and...
Ribosome biogenesis is essential for cell growth, proliferation, and animal development. Its deregulation leads to various human disorders such as ribosomopathies and cancer. Thus, tight regulation of ribosome biogenesis is crucial for normal cell homeostasis. Emerging evidence suggests that posttranslational modifications such as ubiquitination and SUMOylation play a crucial role in regulating ribosome biogenesis. Our recent studies reveal that USP36, a nucleolar deubiquitinating enzyme (DUB), acts also as a SUMO ligase to regulate nucleolar protein group SUMOylation, thereby being essential for ribosome biogenesis. Here, we provide an overview of the current understanding of the SUMOylation regulation of ribosome biogenesis and discuss the role of USP36 in nucleolar SUMOylation.
PubMed: 38764604
DOI: 10.3389/frnar.2024.1389104 -
Biomedicine & Pharmacotherapy =... Jun 2024Ferroptosis is a form of cell death mediated by iron and lipid peroxidation (LPO). Recent studies have provided compelling evidence to support the involvement of... (Review)
Review
Ferroptosis is a form of cell death mediated by iron and lipid peroxidation (LPO). Recent studies have provided compelling evidence to support the involvement of ferroptosis in the pathogenesis of various neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD). Therefore, understanding the mechanisms that regulate ferroptosis in NDDs may improve disease management. Ferroptosis is regulated by multiple mechanisms, and different degradation pathways, including autophagy and the ubiquitinproteasome system (UPS), orchestrate the complex ferroptosis response by directly or indirectly regulating iron accumulation or lipid peroxidation. Ubiquitination plays a crucial role as a protein posttranslational modification in driving ferroptosis. Notably, E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs) are key enzymes in the ubiquitin system, and their dysregulation is closely linked to the progression of NDDs. A growing body of evidence highlights the role of ubiquitin system enzymes in regulating ferroptosis sensitivity. However, reports on the interaction between ferroptosis and ubiquitin signaling in NDDs are scarce. In this review, we first provide a brief overview of the biological processes and roles of the UPS, summarize the core molecular mechanisms and potential biological functions of ferroptosis, and explore the pathophysiological relevance and therapeutic implications of ferroptosis in NDDs. In addition, reviewing the roles of E3s and DUBs in regulating ferroptosis in NDDs aims to provide new insights and strategies for the treatment of NDDs. These include E3- and DUB-targeted drugs and ferroptosis inhibitors, which can be used to prevent and ameliorate the progression of NDDs.
Topics: Ferroptosis; Humans; Neurodegenerative Diseases; Animals; Ubiquitin-Protein Ligases; Deubiquitinating Enzymes; Ubiquitination; Signal Transduction; Molecular Targeted Therapy
PubMed: 38761423
DOI: 10.1016/j.biopha.2024.116753 -
BMC Plant Biology May 2024Ubiquitin-specific proteases (UBPs) are a large family of deubiquitinating enzymes (DUBs). They are widespread in plants and are critical for plant growth, development,...
BACKGROUND
Ubiquitin-specific proteases (UBPs) are a large family of deubiquitinating enzymes (DUBs). They are widespread in plants and are critical for plant growth, development, and response to external stresses. However, there are few studies on the functional characteristics of the UBP gene family in the important staple crop, maize (Zea mays L.).
RESULTS
In this study, we performed a bioinformatic analysis of the entire maize genome and identified 45 UBP genes. Phylogenetic analysis indicated that 45 ZmUBP genes can be divided into 15 subfamilies. Analysis of evolutionary patterns and divergence levels indicated that ZmUBP genes were present before the isolation of dicotyledons, were highly conserved and subjected to purifying selection during evolution. Most ZmUBP genes exhibited different expression levels in different tissues and developmental stages. Based on transcriptome data and promoter element analysis, we selected eight ZmUBP genes whose promoters contained a large number of plant hormones and stress response elements and were up-regulated under different abiotic stresses for RT-qPCR analysis, results showed that these genes responded to abiotic stresses and phytohormones to varying degrees, indicating that they play important roles in plant growth and stress response.
CONCLUSIONS
In this study, the structure, location and evolutionary relationship of maize UBP gene family members were analyzed for the first time, and the ZmUBP genes that may be involved in stress response and plant growth were identified by combining promoter element analysis, transcriptome data and RT-qPCR analysis. This study informs research on the involvement of maize deubiquitination in stress response.
Topics: Zea mays; Phylogeny; Gene Expression Regulation, Plant; Ubiquitin-Specific Proteases; Multigene Family; Genome, Plant; Plant Proteins; Stress, Physiological; Genes, Plant; Gene Expression Profiling; Promoter Regions, Genetic
PubMed: 38750451
DOI: 10.1186/s12870-024-04953-5 -
Translational Oncology Jul 2024Bevacizumab resistance poses barriers to targeted therapy in clear cell renal cell carcinoma (ccRCC). Whether there exist epigenetic targets that modulate bevacizumab...
BACKGROUND
Bevacizumab resistance poses barriers to targeted therapy in clear cell renal cell carcinoma (ccRCC). Whether there exist epigenetic targets that modulate bevacizumab sensitivity in ccRCC remains indefinite. The focus of this study is to explore the role of UCHL1 in ccRCC.
METHODS
Both in vitro and in vivo experiments were utilized to investigate the roles of UCHL1 in ccRCC. In vivo ubiquitination assays were performed to validate the posttranslational modification of KDM4B by UCHL1. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were utilized to explore KDM4B/VEGFA epigenetic regulations.
RESULTS
UCHL1 was increased in ccRCC and associated with unfavorable survival outcomes in patients. UCHL1 was required for ccRCC growth and migration. Mechanistically, the wild-type UCHL1, but not C90A mutant, mediated the deubiquitination of KDM4B and thereby stabilized its proteins. KDM4B was up-regulated in ccRCC and potentiated cell growth. UCHL1 depended on KDM4B to augment ccRCC malignancies. Targeting UCHL1 suppressed tumor growth, colony formation, and migration abilities, which could be rescued by KDM4B. Furthermore, KDM4B was directly bound to the promoter region of VEGFA, abolishing repressive H3K9me3 modifications. KDM4B coordinated with HIF2α to activate VEGFA transcriptional levels. UCHL1-KDM4B axis governs VEGFA levels to sustain the angiogenesis phenotypes. Finally, a specific small-molecule inhibitor (6RK73) targeting UCHL1 remarkably inhibited ccRCC progression and further sensitized ccRCC to bevacizumab treatment.
CONCLUSION
Overall, this study defined an epigenetic mechanism of UCHL1/KDM4B in activating VEGF signaling. The UCHL1-KDM4B axis represents a novel target for treating ccRCC and improving the efficacy of anti-angiogenesis therapy.
PubMed: 38743986
DOI: 10.1016/j.tranon.2024.101987