Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 928
Filter
1.
Biomed Pharmacother ; 175: 116753, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38761423

ABSTRACT

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.


Subject(s)
Ferroptosis , Neurodegenerative Diseases , Ubiquitin-Protein Ligases , Ferroptosis/drug effects , Ferroptosis/physiology , Humans , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/enzymology , Animals , Ubiquitin-Protein Ligases/metabolism , Deubiquitinating Enzymes/metabolism , Ubiquitination , Signal Transduction/drug effects , Molecular Targeted Therapy
2.
Nat Commun ; 15(1): 4519, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38806474

ABSTRACT

Protein ubiquitination regulates a wide range of cellular processes. The degree of protein ubiquitination is determined by the delicate balance between ubiquitin ligase (E3)-mediated ubiquitination and deubiquitinase (DUB)-mediated deubiquitination. In comparison to the E3-substrate interactions, the DUB-substrate interactions (DSIs) remain insufficiently investigated. To address this challenge, we introduce a protein sequence-based ab initio method, TransDSI, which transfers proteome-scale evolutionary information to predict unknown DSIs despite inadequate training datasets. An explainable module is integrated to suggest the critical protein regions for DSIs while predicting DSIs. TransDSI outperforms multiple machine learning strategies against both cross-validation and independent test. Two predicted DUBs (USP11 and USP20) for FOXP3 are validated by "wet lab" experiments, along with two predicted substrates (AR and p53) for USP22. TransDSI provides new functional perspective on proteins by identifying regulatory DSIs, and offers clues for potential tumor drug target discovery and precision drug application.


Subject(s)
Deubiquitinating Enzymes , Proteome , Ubiquitination , Humans , Proteome/metabolism , Deubiquitinating Enzymes/metabolism , Deubiquitinating Enzymes/genetics , Deep Learning , Ubiquitin Thiolesterase/metabolism , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/chemistry , Substrate Specificity , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Machine Learning , Protein Binding , Amino Acid Sequence , Thiolester Hydrolases
3.
PLoS Pathog ; 20(5): e1012279, 2024 May.
Article in English | MEDLINE | ID: mdl-38814988

ABSTRACT

The influenza A virus (IAV) consists of 8 single-stranded, negative-sense viral RNA (vRNA) segments. After infection, vRNA is transcribed, replicated, and wrapped by viral nucleoprotein (NP) to form viral ribonucleoprotein (vRNP). The transcription, replication, and nuclear export of the viral genome are regulated by the IAV protein, NS2, which is translated from spliced mRNA transcribed from viral NS vRNA. This splicing is inefficient, explaining why NS2 is present in low abundance after IAV infection. The levels of NS2 and its subsequent accumulation are thought to influence viral RNA replication and vRNP nuclear export. Here we show that NS2 is ubiquitinated at the K64 and K88 residues by K48-linked and K63-linked polyubiquitin (polyUb) chains, leading to the degradation of NS2 by the proteasome. Additionally, we show that a host deubiquitinase, OTUB1, can remove polyUb chains conjugated to NS2, thereby stabilizing NS2. Accordingly, knock down of OTUB1 by siRNA reduces the nuclear export of vRNP, and reduces the overall production of IAV. These results collectively demonstrate that the levels of NS2 in IAV-infected cells are regulated by a ubiquitination-deubiquitination system involving OTUB1 that is necessary for optimal IAV replication.


Subject(s)
Cysteine Endopeptidases , Influenza A virus , Viral Nonstructural Proteins , Virus Replication , Animals , Dogs , Humans , Cysteine Endopeptidases/metabolism , Cysteine Endopeptidases/genetics , Deubiquitinating Enzymes/metabolism , HEK293 Cells , Influenza A virus/metabolism , Influenza, Human/metabolism , Influenza, Human/virology , RNA, Viral/metabolism , RNA, Viral/genetics , Ubiquitination , Viral Nonstructural Proteins/metabolism , Viral Nonstructural Proteins/genetics , Virus Replication/physiology , Cell Line , Vero Cells , Chlorocebus aethiops
4.
Cancer Lett ; 594: 216978, 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38795760

ABSTRACT

Ubiquitination and related cellular processes control a variety of aspects in human cell biology, and defects in these processes contribute to multiple illnesses. In recent decades, our knowledge about the pathological role of ubiquitination in lymphoid cancers and therapeutic strategies to target the modified ubiquitination system has evolved tremendously. Here we review the altered signalling mechanisms mediated by the aberrant expression of cancer-associated E2s/E3s and deubiquitinating enzymes (DUBs), which result in the hyperactivation of oncoproteins or the frequently allied downregulation of tumour suppressors. We discuss recent highlights pertaining to the several different therapeutic interventions which are currently being evaluated to effectively block abnormal ubiquitin-proteasome pathway and the use of heterobifunctional molecules which recruit the ubiquitination system to degrade or stabilize non-cognate substrates. This review aids in comprehension of ubiquitination aberrance in lymphoid cancers and current targeting strategies and elicits further investigations to deeply understand the link between cellular ubiquitination and lymphoid pathogenesis as well as to ameliorate corresponding treatment interventions.


Subject(s)
Signal Transduction , Ubiquitin , Ubiquitination , Humans , Ubiquitin/metabolism , Animals , Lymphoma/metabolism , Lymphoma/drug therapy , Lymphoma/pathology , Molecular Targeted Therapy , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Proteasome Endopeptidase Complex/metabolism , Deubiquitinating Enzymes/metabolism
5.
Cell Commun Signal ; 22(1): 259, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38715050

ABSTRACT

Ubiquitination and deubiquitination are important forms of posttranslational modification that govern protein homeostasis. Deubiquitinating enzymes (DUBs), a protein superfamily consisting of more than 100 members, deconjugate ubiquitin chains from client proteins to regulate cellular homeostasis. However, the dysregulation of DUBs is reportedly associated with several diseases, including cancer. The tumor microenvironment (TME) is a highly complex entity comprising diverse noncancerous cells (e.g., immune cells and stromal cells) and the extracellular matrix (ECM). Since TME heterogeneity is closely related to tumorigenesis and immune evasion, targeting TME components has recently been considered an attractive therapeutic strategy for restoring antitumor immunity. Emerging studies have revealed the involvement of DUBs in immune modulation within the TME, including the regulation of immune checkpoints and immunocyte infiltration and function, which renders DUBs promising for potent cancer immunotherapy. Nevertheless, the roles of DUBs in the crosstalk between tumors and their surrounding components have not been comprehensively reviewed. In this review, we discuss the involvement of DUBs in the dynamic interplay between tumors, immune cells, and stromal cells and illustrate how dysregulated DUBs facilitate immune evasion and promote tumor progression. We also summarize potential small molecules that target DUBs to alleviate immunosuppression and suppress tumorigenesis. Finally, we discuss the prospects and challenges regarding the targeting of DUBs in cancer immunotherapeutics and several urgent problems that warrant further investigation.


Subject(s)
Deubiquitinating Enzymes , Tumor Microenvironment , Humans , Tumor Microenvironment/immunology , Deubiquitinating Enzymes/metabolism , Animals , Neoplasms/immunology , Neoplasms/pathology , Neoplasms/enzymology , Neoplasms/metabolism , Tumor Escape , Ubiquitination , Immune Evasion
6.
Cell Biochem Funct ; 42(4): e4020, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38702967

ABSTRACT

The regulatory potential of long noncoding RNA (lncRNA) FBXL19-AS1 has been highlighted in various cancers, but its effect on triple-negative breast cancer (TNBC) remains unclear. Here, we aimed to elucidate the role of FBXL19-AS1 in TNBC and its underlying mechanism. RT-qPCR was employed to detect the expressions of FBXL19-AS1 and miR-378a-3p in tissues and cells. Immunohistochemical staining and western blot were utilized to detect the expression levels of proteins. Cell activities were detected using flow cytometry, CCK-8, and transwell assay. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were deployed to investigate interactions of different molecules. Protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathways were used to analyze the downstream pathway. In vivo xenograft model was conducted to detect the effect of FBXL19-AS1 on tumor growth. FBXL19-AS1 was overexpressed in TNBC tissues and cell lines compared with counterparts. FBXL19-AS1 knockdown suppressed TNBC cell activities, whereas its overexpression exhibited the opposite effect. Mechanistically, FBXL19-AS1 was found to interact with miR-378a-3p. Further analysis revealed that miR-378a-3p exerted tumor-suppressive effects in TNBC cells. Additionally, miR-378a-3p targeted and downregulated the expression of ubiquitin aldehyde binding 2 (OTUB2), a deubiquitinase associated with TNBC progression. In vivo experiments substantiated the inhibitory effects of FBXL19-AS1 knockdown on TNBC tumorigenesis, and a miR-378a-3p inhibitor partially rescued these effects. The downstream pathway of the miR-378a-3p/OTUB2 axis was explored, revealing connections with proteins involved in modifying other proteins, removing ubiquitin molecules, and influencing signaling pathways, including the Hippo signaling pathway. Western blot analysis confirmed changes in YAP and TAZ expression levels, indicating a potential regulatory network. In summary, FBXL19-AS1 promotes exacerbation in TNBC by suppressing miR-378a-3p, leading to increased OTUB2 expression. The downstream mechanism may be related to the Hippo signaling pathway. These findings propose potential therapeutic targets for TNBC treatment.


Subject(s)
MicroRNAs , RNA, Long Noncoding , Triple Negative Breast Neoplasms , Animals , Female , Humans , Mice , Cell Line, Tumor , Cell Proliferation , Deubiquitinating Enzymes/metabolism , F-Box Proteins/metabolism , F-Box Proteins/genetics , Gene Expression Regulation, Neoplastic , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/metabolism , MicroRNAs/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/genetics
7.
Oncogene ; 43(24): 1852-1860, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38664499

ABSTRACT

The deubiquitinase OTUB1, implicated as a potential oncogene in various tumors, lacks clarity in its regulatory mechanism in tumor progression. Our study investigated the effects and underlying mechanisms of OTUB1 on the breast cancer cell cycle and proliferation in IFNγ stimulation. Loss of OTUB1 abrogated IFNγ-induced cell cycle arrest by regulating p27 protein expression, whereas OTUB1 overexpression significantly enhanced p27 expression even without IFNγ treatment. Tyr26 phosphorylation residue of OTUB1 directly bound to p27, modulating its post-translational expression. Furthermore, we identified crucial lysine residues (K134, K153, and K163) for p27 ubiquitination. Src downregulation reduced OTUB1 and p27 expression, suggesting that IFNγ-induced cell cycle arrest is mediated by the Src-OTUB1-p27 signaling pathway. Our findings highlight the pivotal role of OTUB1 in IFNγ-induced p27 expression and cell cycle arrest, offering therapeutic implications.


Subject(s)
Cell Cycle Checkpoints , Cyclin-Dependent Kinase Inhibitor p27 , Deubiquitinating Enzymes , Interferon-gamma , Ubiquitination , Humans , Interferon-gamma/pharmacology , Interferon-gamma/metabolism , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Cyclin-Dependent Kinase Inhibitor p27/genetics , Cell Cycle Checkpoints/genetics , Deubiquitinating Enzymes/metabolism , Cysteine Endopeptidases/metabolism , Cysteine Endopeptidases/genetics , Cell Line, Tumor , Female , Cell Proliferation , Phosphorylation , Signal Transduction , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/genetics , Protein Stability
8.
J Biol Chem ; 300(5): 107264, 2024 May.
Article in English | MEDLINE | ID: mdl-38582446

ABSTRACT

The ubiquitin (Ub)-proteasome system (UPS) is the major machinery mediating specific protein turnover in eukaryotic cells. By ubiquitylating unwanted, damaged, or harmful proteins and driving their degradation, UPS is involved in many important cellular processes. Several new UPS-based technologies, including molecular glue degraders and PROTACs (proteolysis-targeting chimeras) to promote protein degradation, and DUBTACs (deubiquitinase-targeting chimeras) to increase protein stability, have been developed. By specifically inducing the interactions between different Ub ligases and targeted proteins that are not otherwise related, molecular glue degraders and PROTACs degrade targeted proteins via the UPS; in contrast, by inducing the proximity of targeted proteins to deubiquitinases, DUBTACs are created to clear degradable poly-Ub chains to stabilize targeted proteins. In this review, we summarize the recent research progress in molecular glue degraders, PROTACs, and DUBTACs and their applications. We discuss immunomodulatory drugs, sulfonamides, cyclin-dependent kinase-targeting molecular glue degraders, and new development of PROTACs. We also introduce the principle of DUBTAC and its applications. Finally, we propose a few future directions of these three technologies related to targeted protein homeostasis.


Subject(s)
Drug Discovery , Proteasome Endopeptidase Complex , Proteolysis , Ubiquitination , Humans , Ubiquitination/drug effects , Proteolysis/drug effects , Proteasome Endopeptidase Complex/metabolism , Deubiquitinating Enzymes/metabolism , Ubiquitin/metabolism , Animals , Ubiquitin-Protein Ligases/metabolism
9.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167132, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38565386

ABSTRACT

The Epstein-Barr virus (EBV) is implicated in several cancers, including EBV-associated gastric cancer (EBVaGC). This study focuses on EBV-encoded BALF1 (BamH1 A fragment leftward reading frame 1), a key apoptosis regulator in EBV-related cancers, whose specific impact on EBVaGC was previously unknown. Our findings indicate that BALF1 overexpression in gastric cancer cells significantly enhances their proliferation, migration, and resistance to chemotherapy-induced apoptosis, confirming BALF1's oncogenic potential. A novel discovery is that BALF1 undergoes degradation via the ubiquitin-proteasome pathway. Through analysis of 69 deubiquitinating enzymes (DUBs), ovarian tumor protease (OTU) domain-containing protein 1 (OTUD1) emerged as a vital regulator for maintaining BALF1 protein stability. Furthermore, BALF1 was found to play a role in regulating the stability of the B-cell lymphoma-2 (Bcl-2) protein, increasing its levels through deubiquitination. This mechanism reveals BALF1's multifaceted oncogenic role in gastric cancer, as it contributes both directly and indirectly to cancer progression, particularly by stabilizing Bcl-2, known for its anti-apoptotic characteristics. These insights significantly deepen our understanding of EBV's involvement in the pathogenesis of gastric cancer. The elucidation of OTUD1's role in BALF1 regulation and its influence on Bcl-2 stabilization provide new avenues for therapeutic intervention in EBVaGC, bridging the gap between viral oncogenesis and cellular protein regulation and offering a more holistic view of gastric cancer development under the influence of EBV.


Subject(s)
Apoptosis , Proto-Oncogene Proteins c-bcl-2 , Stomach Neoplasms , Ubiquitination , Humans , Stomach Neoplasms/pathology , Stomach Neoplasms/virology , Stomach Neoplasms/metabolism , Stomach Neoplasms/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Cell Line, Tumor , Herpesvirus 4, Human/metabolism , Herpesvirus 4, Human/genetics , Viral Proteins/metabolism , Viral Proteins/genetics , Cell Proliferation , Ubiquitin-Specific Proteases/metabolism , Ubiquitin-Specific Proteases/genetics , Epstein-Barr Virus Infections/virology , Epstein-Barr Virus Infections/metabolism , Epstein-Barr Virus Infections/pathology , Epstein-Barr Virus Infections/genetics , Protein Stability , Cell Movement , Animals , Deubiquitinating Enzymes/metabolism , Deubiquitinating Enzymes/genetics , Viral Regulatory and Accessory Proteins
10.
J Invertebr Pathol ; 204: 108111, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38631560

ABSTRACT

Ubiquitin-specific proteases (UBPs), the largest subfamily of deubiquitinating enzymes, regulate ubiquitin homeostasis and play diverse roles in eukaryotes. Ubp4 is essential for the growth, development, and pathogenicity of various fungal pathogens. However, its functions in the growth, stress responses, and virulence of entomopathogenic fungi remain unclear. In this study, we elucidated the role of the homolog of Ubp4, MrUbp4, in the entomopathogenic fungus Metarhizium robertsii. Deletion of MrUbp4 led to a notable increase in ubiquitination levels, demonstrating the involvement of MrUbp4 in protein deubiquitination. Furthermore, the ΔMrUbp4 mutant displayed a significant reduction in conidial yield, underscoring the pivotal role of MrUbp4 in conidiation. Additionally, the mutant exhibited heightened resistance to conidial heat treatment, emphasizing the role of MrUbp4 in thermotolerance. Notably, insect bioassays unveiled a substantial impairment in the virulence of the ΔMrUbp4 mutant. This was accompanied by a notable decrease in cuticle penetration ability and appressorium formation upon further analysis. In summary, our findings highlight the essential role of MrUbp4 in regulating the conidial yield, thermotolerance, and contributions to the virulence of M. robertsii.


Subject(s)
Metarhizium , Spores, Fungal , Thermotolerance , Metarhizium/pathogenicity , Metarhizium/genetics , Metarhizium/physiology , Virulence , Fungal Proteins/genetics , Fungal Proteins/metabolism , Animals , Deubiquitinating Enzymes/genetics , Deubiquitinating Enzymes/metabolism
11.
Int Immunopharmacol ; 132: 112026, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38583240

ABSTRACT

Ubiquitination (Ub) and deubiquitination are crucial post-translational modifications (PTMs) that precisely regulate protein degradation. Under the catalysis of a cascade of E1-E2-E3 ubiquitin enzymes, ubiquitination extensively regulates protein degradation exerting direct impact on various cellular processes, while deubiquitination opposes the effect of ubiquitination and prevents proteins from degradation. Notably, such dynamic modifications have been widely investigated to be implicated in cell cycle, transcriptional regulation, apoptosis and so on. Therefore, dysregulation of ubiquitination and deubiquitination could lead to certain diseases through abnormal protein accumulation and clearance. Increasing researches have revealed that the dysregulation of catalytic regulators of ubiquitination and deubiquitination triggers imbalance of cartilage homeostasis that promotes osteoarthritis (OA) progression. Hence, it is now believed that targeting on Ub enzymes and deubiquitinating enzymes (DUBs) would provide potential therapeutic pathways. In the following sections, we will summarize the biological role of Ub enzymes and DUBs in the development and progression of OA by focusing on the updating researches, with the aim of deepening our understanding of the underlying molecular mechanism of OA pathogenesis concerning ubiquitination and deubiquitination, so as to explore novel potential therapeutic targets of OA treatment.


Subject(s)
Osteoarthritis , Ubiquitination , Humans , Osteoarthritis/metabolism , Animals , Deubiquitinating Enzymes/metabolism , Protein Processing, Post-Translational
12.
Mol Cancer ; 23(1): 86, 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38685067

ABSTRACT

BACKGROUND: CDC6 is an oncogenic protein whose expression level fluctuates during the cell cycle. Although several E3 ubiquitin ligases responsible for the ubiquitin-mediated proteolysis of CDC6 have been identified, the deubiquitination pathway for CDC6 has not been investigated. METHODS: The proteome-wide deubiquitinase (DUB) screening was used to identify the potential regulator of CDC6. Immunofluorescence, protein half-life and deubiquitination assays were performed to determine the protein stability of CDC6. Gain- and loss-of-function experiments were implemented to analyse the impacts of OUTD6A-CDC6 axis on tumour growth and chemosensitivity in vitro. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced conditional Otud6a knockout (CKO) mouse model and tumour xenograft model were performed to analyse the role of OTUD6A-CDC6 axis in vivo. Tissue specimens were used to determine the association between OTUD6A and CDC6. RESULTS: OTUD6A interacts with, depolyubiquitinates and stabilizes CDC6 by removing K6-, K33-, and K48-linked polyubiquitination. Moreover, OTUD6A promotes cell proliferation and decreases sensitivity to chemotherapy by upregulating CDC6. CKO mice are less prone to BCa tumorigenesis induced by BBN, and knockdown of OTUD6A inhibits tumour progression in vivo. Furthermore, OTUD6A protein level has a positive correlation with CDC6 protein level, and high protein levels of OTUD6A and CDC6 are associated with poor prognosis in patients with bladder cancer. CONCLUSIONS: We reveal an important yet missing piece of novel DUB governing CDC6 stability. In addition, our findings propose a model for the OTUD6A-CDC6 axis that provides novel insights into cell cycle and chemosensitivity regulation, which may become a potential biomarker and promising drug target for cancer treatment.


Subject(s)
Cell Cycle Proteins , Drug Resistance, Neoplasm , Nuclear Proteins , Ubiquitination , Animals , Humans , Mice , Drug Resistance, Neoplasm/genetics , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Cell Line, Tumor , Cell Proliferation , Disease Progression , Mice, Knockout , Xenograft Model Antitumor Assays , Gene Expression Regulation, Neoplastic , Deubiquitinating Enzymes/metabolism , Deubiquitinating Enzymes/genetics , Disease Models, Animal
13.
J Exp Med ; 221(6)2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38630025

ABSTRACT

OTU deubiquitinase with linear linkage specificity (OTULIN) regulates inflammation and cell death by deubiquitinating linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC). Biallelic loss-of-function mutations causes OTULIN-related autoinflammatory syndrome (ORAS), while OTULIN haploinsuffiency has not been associated with spontaneous inflammation. However, herein, we identify two patients with the heterozygous mutation p.Cys129Ser in OTULIN. Consistent with ORAS, we observed accumulation of linear ubiquitin chains, increased sensitivity to TNF-induced death, and dysregulation of inflammatory signaling in patient cells. While the C129S mutation did not affect OTULIN protein stability or binding capacity to LUBAC and linear ubiquitin chains, it did ablate OTULIN deubiquitinase activity. Loss of activity facilitated the accumulation of autoubiquitin chains on LUBAC. Altered ubiquitination of LUBAC inhibits its recruitment to the TNF receptor signaling complex, promoting TNF-induced cell death and disease pathology. By reporting the first dominant negative mutation driving ORAS, this study expands our clinical understanding of OTULIN-associated pathology.


Subject(s)
Inflammation , Ubiquitin , Humans , Cell Death , Cell Membrane , Deubiquitinating Enzymes , Inflammation/genetics , Syndrome , Ubiquitin-Protein Ligase Complexes
14.
Aging (Albany NY) ; 16(7): 6613-6626, 2024 Apr 08.
Article in English | MEDLINE | ID: mdl-38613804

ABSTRACT

Ubiquitination of the proteins is crucial for governing protein degradation and regulating fundamental cellular processes. Deubiquitinases (DUBs) have emerged as significant regulators of multiple pathways associated with cancer and other diseases, owing to their capacity to remove ubiquitin from target substrates and modulate signaling. Consequently, they represent potential therapeutic targets for cancer and other life-threatening conditions. USP43 belongs to the DUBs family involved in cancer development and progression. This review aims to provide a comprehensive overview of the existing scientific evidence implicating USP43 in cancer development. Additionally, it will investigate potential small-molecule inhibitors that target DUBs that may have the capability to function as anti-cancer medicines.


Subject(s)
Neoplasms , Humans , Neoplasms/metabolism , Neoplasms/drug therapy , Animals , Ubiquitination , Endopeptidases/metabolism , Deubiquitinating Enzymes/metabolism , Signal Transduction , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology
15.
Biol Direct ; 19(1): 31, 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38658981

ABSTRACT

BACKGROUND: Deubiquitinating enzymes (DUBs) cleave ubiquitin on substrate molecules to maintain protein stability. DUBs reportedly participate in the tumorigenesis and tumour progression of hepatocellular carcinoma (HCC). OTU deubiquitinase 5 (OTUD5), a DUB family member, has been recognized as a critical regulator in bladder cancer, breast cancer and HCC. However, the expression and biological function of OTUD5 in HCC are still controversial. RESULTS: We determined that the expression of OTUD5 was significantly upregulated in HCC tissues. High levels of OTUD5 were also detected in most HCC cell lines. TCGA data analysis demonstrated that high OTUD5 expression indicated poorer overall survival in HCC patients. OTUD5 silencing prominently suppressed HCC cell proliferation, while its overexpression markedly enhanced the proliferation of HCC cells. Mass spectrometry analysis revealed solute carrier family 38 member 1 (SLC38A1) as a candidate downstream target protein of OTUD5. Coimmunoprecipitation analysis confirmed the interaction between OTUD5 and SLC38A1. OTUD5 knockdown reduced and OTUD5 overexpression increased SLC38A1 protein levels in HCC cells. However, OTUD5 alteration had no effect on SLC38A1 mRNA expression. OTUD5 maintained SLC38A1 stability by preventing its ubiquitin-mediated proteasomal degradation. SLC38A1 silencing prominently attenuated the OTUD5-induced increase in HCC cell proliferation. Finally, OTUD5 knockdown markedly suppressed the growth of HCC cells in vivo. CONCLUSIONS: OTUD5 is an oncogene in HCC. OTUD5 contributes to HCC cell proliferation by deubiquitinating and stabilizing SLC38A1. These results may provide a theoretical basis for the development of new anti-HCC drugs.


Subject(s)
Carcinoma, Hepatocellular , Cell Proliferation , Liver Neoplasms , Animals , Humans , Mice , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Deubiquitinating Enzymes/metabolism , Deubiquitinating Enzymes/genetics , Endopeptidases/genetics , Endopeptidases/metabolism , Gene Expression Regulation, Neoplastic , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Ubiquitination
16.
Virus Res ; 344: 199368, 2024 06.
Article in English | MEDLINE | ID: mdl-38588924

ABSTRACT

Several viruses are now known to code for deubiquitinating proteases in their genomes. Ubiquitination is an essential post-translational modification of cellular substrates involved in many processes in the cell, including in innate immune signalling. This post-translational modification is regulated by the ubiquitin conjugation machinery, as well as various host deubiquitinating enzymes. The conjugation of ubiquitin chains to several innate immune related factors is often needed to induce downstream signalling, shaping the antiviral response. Viral deubiquitinating proteins, besides often having a primary function in the viral replication cycle by cleaving the viral polyprotein, are also able to cleave ubiquitin chains from such host substrates, in that way exerting a function in innate immune evasion. The presence of viral deubiquitinating enzymes has been firmly established for numerous animal-infecting viruses, such as some well-researched and clinically important nidoviruses, and their presence has now been confirmed in several plant viruses as well. Viral proteases in general have long been highlighted as promising drug targets, with a current focus on small molecule inhibitors. In this review, we will discuss the range of viral deubiquitinating proteases known to date, summarise the various avenues explored to inhibit such proteases and discuss novel strategies and models intended to inhibit and study these specific viral enzymes.


Subject(s)
Deubiquitinating Enzymes , Deubiquitinating Enzymes/metabolism , Deubiquitinating Enzymes/antagonists & inhibitors , Deubiquitinating Enzymes/genetics , Humans , Viral Proteases/metabolism , Protein Processing, Post-Translational , Ubiquitination , Animals , Virus Replication , Antiviral Agents/pharmacology , Protease Inhibitors/pharmacology , Viruses/drug effects , Viruses/enzymology , Viral Proteins/metabolism , Viral Proteins/genetics , Ubiquitin/metabolism , Immunity, Innate
17.
Acta Biochim Biophys Sin (Shanghai) ; 56(4): 564-575, 2024 04 25.
Article in English | MEDLINE | ID: mdl-38449391

ABSTRACT

Triple negative breast cancer (TNBC) has a high recurrence rate, metastasis rate and mortality rate. The aim of this study is to identify new targets for the treatment of TNBC. Clinical samples are used for screening deubiquitinating enzymes (DUBs). MDA-MB-231 cells and a TNBC mouse model are used for in vitro and in vivo experiments, respectively. Western blot analysis is used to detect the protein expressions of DUBs, zinc finger E-box binding homeobox 1 (ZEB1), and epithelial-mesenchymal transition (EMT)-related markers. Colony formation and transwell assays are used to detect the proliferation, migration and invasion of TNBC cells. Wound healing assay is used to detect the mobility of TNBC cells. Immunoprecipitation assay is used to detect the interaction between breast cancer susceptibility gene 1/2-containing complex subunit 3 (BRCC3) and ZEB1. ZEB1 ubiquitination levels, protein stability, and protein degradation are also examined. Pathological changes in the lung tissues are detected via HE staining. Our results show a significant positive correlation between the expressions of BRCC3 and ZEB1 in clinical TNBC tissues. Interference with BRCC3 inhibits TNBC cell proliferation, migration, invasion and EMT. BRCC3 interacts with ZEB1 and interferes with BRCC3 to inhibit ZEB1 expression by increasing ZEB1 ubiquitination. Interference with BRCC3 inhibits TNBC cell tumorigenesis and lung metastasis in vivo. In all, this study demonstrates that BRCC3 can increase the stability of ZEB1, upregulate ZEB1 expression, and promote the proliferation, migration, invasion, EMT, and metastasis of TNBC cells, providing a new direction for cancer therapy.


Subject(s)
Breast Neoplasms , Deubiquitinating Enzymes , Triple Negative Breast Neoplasms , Zinc Finger E-box-Binding Homeobox 1 , Animals , Humans , Mice , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Deubiquitinating Enzymes/genetics , Deubiquitinating Enzymes/metabolism , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic , Triple Negative Breast Neoplasms/pathology , Zinc Finger E-box-Binding Homeobox 1/genetics , Zinc Finger E-box-Binding Homeobox 1/metabolism
18.
Expert Rev Mol Med ; 26: e3, 2024 Mar 25.
Article in English | MEDLINE | ID: mdl-38525836

ABSTRACT

Deubiquitinases are a group of proteins that identify and digest monoubiquitin chains or polyubiquitin chains attached to substrate proteins, preventing the substrate protein from being degraded by the ubiquitin-proteasome system. Deubiquitinases regulate cellular autophagy, metabolism and oxidative stress by acting on different substrate proteins. Recent studies have revealed that deubiquitinases act as a critical regulator in various cardiac diseases, and control the onset and progression of cardiac disease through a board range of mechanism. This review summarizes the function of different deubiquitinases in cardiac disease, including cardiac hypertrophy, myocardial infarction and diabetes mellitus-related cardiac disease. Besides, this review briefly recapitulates the role of deubiquitinases modulators in cardiac disease, providing the potential therapeutic targets in the future.


Subject(s)
Myocardial Infarction , Ubiquitin , Humans , Ubiquitin/metabolism , Polyubiquitin/metabolism , Proteasome Endopeptidase Complex/metabolism , Deubiquitinating Enzymes/genetics
19.
J Biol Chem ; 300(4): 107152, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38462165

ABSTRACT

Prostate cancer is a leading cause of cancer-related mortality in males. Dysregulation of RNA adenine N-6 methylation (m6A) contributes to cancer malignancy. m6A on mRNA may affect mRNA splicing, turnover, transportation, and translation. m6A exerts these effects, at least partly, through dedicated m6A reader proteins, including YTH domain-containing family protein 2 (YTHDF2). YTHDF2 is necessary for development while its dysregulation is seen in various cancers, including prostate cancer. However, the mechanism underlying the dysregulation and function of YTHDF2 in cancer remains elusive. Here, we find that the deubiquitinase OUT domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) increases YTHDF2 protein stability by inhibiting its ubiquitination. With in vivo and in vitro ubiquitination assays, OTUB1 is shown to block ubiquitin transfer to YTHDF2 independent of its deubiquitinase activity. Furthermore, analysis of functional transcriptomic data and m6A-sequencing data identifies PRSS8 as a potential tumor suppressor gene. OTUB1 and YTHDF2 decrease mRNA and protein levels of PRSS8, which is a trypsin-like serine protease. Mechanistically, YTHDF2 binds PRSS8 mRNA and promotes its degradation in an m6A-dependent manner. Further functional study on cellular and mouse models reveals PRSS8 is a critical downstream effector of the OTUB1-YTHDF2 axis in prostate cancer. We find in prostate cancer cells, PRSS8 decreases nuclear ß-catenin level through E-cadherin, which is independent of its protease activity. Collectively, our study uncovers a key regulator of YTHDF2 protein stability and establishes a functional OTUB1-YTHDF2-PRSS8 axis in prostate cancer.


Subject(s)
Cell Proliferation , Deubiquitinating Enzymes , Prostatic Neoplasms , RNA-Binding Proteins , Serine Endopeptidases , Animals , Humans , Male , Mice , Cell Line, Tumor , Cell Proliferation/genetics , Deubiquitinating Enzymes/metabolism , Deubiquitinating Enzymes/genetics , Gene Expression Regulation, Neoplastic , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Protein Stability , RNA Stability/genetics , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Serine Endopeptidases/metabolism , Ubiquitination
20.
J Obstet Gynaecol Res ; 50(5): 864-872, 2024 May.
Article in English | MEDLINE | ID: mdl-38480480

ABSTRACT

BACKGROUND: Ovarian cancer (OVCA) is prevalent in female reproductive organs. Despite recent advances, clinical outcomes remain poor, warranting fresh treatment avenues. Honokiol has an inhibitory effect on proliferation, invasion, and survival of cancer cells in vitro and in vivo. Therefore, this study intended to explore specific molecular mechanism by which honokiol affected OVCA progression. METHODS: Bioinformatics analyzed the drug honokiol that bound to OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2). Cellular thermal shift assay (CETSA) verified the binding relationship between honokiol and OTUB2. Cell counting kit 8 (CCK-8) tested the IC50 value and cell viability of OVCA cells after honokiol treatment. Corresponding assay kits determined malonic dialdehyde (MDA) and Fe2+ levels in OVCA cells. Flow cytometry measured reactive oxygen species levels. Western blot detected OTUB2, SLC7A11, and transcriptional co-activators Yes-associated protein (YAP) expression, and quantitative polymerase chain reaction (qPCR) detected OTUB2 expression. Immunohistochemistry (IHC) detected the expression level of Ki67 protein in tumor tissues. RESULTS: Honokiol was capable of inducing ferroptosis in OVCA cells. CETSA confirmed that honokiol could bind to OTUB2. Further cell functional and molecular experiments revealed that honokiol induced ferroptosis in OVCA cells via repression of YAP signaling pathway through binding to OTUB2. In addition, in vivo experiments have confirmed that honokiol could inhibit the growth of OVCA. CONCLUSION: Honokiol induced ferroptosis in OVCA cells via repression of YAP signaling pathway through binding to OTUB2, implicating that OTUB2 may be an effective target for OVCA treatment, and our study results may provide new directions for development of more effective OVCA treatment strategies.


Subject(s)
Allyl Compounds , Biphenyl Compounds , Ferroptosis , Lignans , Ovarian Neoplasms , Phenols , Humans , Female , Lignans/pharmacology , Ferroptosis/drug effects , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Biphenyl Compounds/pharmacology , Cell Line, Tumor , Transcription Factors/metabolism , YAP-Signaling Proteins/metabolism , Deubiquitinating Enzymes/metabolism , Adaptor Proteins, Signal Transducing/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...