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1.
Biomed Pharmacother ; 172: 116204, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38364733

ABSTRACT

HACE1 is a member of the HECT domain-containing E3 ligases with 909 amino acid residues, containing N-terminal ankyrin-repeats (ANK) and C-terminal HECT domain. Previously, it was shown that HACE1 is inactive in human tumors and plays a crucial role in the initiation, progression, and invasion of malignant tumors. Recent studies indicated that HACE1 might be closely involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. HACE1 interacts with its substrates, including Ras-related C3 botulinum toxin substrate 1 (Rac1), nuclear factor erythroid 2-related factor 2 (Nrf2), tumor necrosis factor receptor (TNFR), and optineurin (OPTN), through which participates in several pathophysiological processes, such as oxidative stress, autophagy and inflammation. Therefore, in this review, we elaborately describe the essential substrates of HACE1 and illuminate the pathophysiological processes by which HACE1 is involved in neurodegenerative diseases. We provide a new molecular target for neurodegenerative diseases.


Subject(s)
Neurodegenerative Diseases , Ubiquitin-Protein Ligases , Humans , Alzheimer Disease , Amino Acids , Huntington Disease , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Parkinson Disease , Ubiquitin-Protein Ligases/antagonists & inhibitors
2.
Nature ; 626(8000): 874-880, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38297121

ABSTRACT

Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health1-3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.


Subject(s)
Mitochondria , Mitochondrial Proteins , Mutation , Neurodegenerative Diseases , Stress, Physiological , Ubiquitin-Protein Ligases , Apoptosis/drug effects , Ataxia/genetics , Cell Survival/drug effects , Dementia/genetics , Mitochondria/genetics , Mitochondria/metabolism , Mitochondria/pathology , Mitochondrial Proteins/chemistry , Mitochondrial Proteins/metabolism , Multiprotein Complexes/antagonists & inhibitors , Multiprotein Complexes/genetics , Multiprotein Complexes/metabolism , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Protein Stability/drug effects , Protein Transport/drug effects , Proteolysis/drug effects , Stress, Physiological/drug effects , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitination/drug effects
3.
Proc Natl Acad Sci U S A ; 120(52): e2308853120, 2023 Dec 26.
Article in English | MEDLINE | ID: mdl-38109536

ABSTRACT

The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.


Subject(s)
Amyotrophic Lateral Sclerosis , Ubiquitin-Protein Ligases , Animals , Mice , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/immunology , Endosomal Sorting Complexes Required for Transport/metabolism , Immunity, Innate/genetics , Nucleotidyltransferases/metabolism , Proteolysis , Signal Transduction/physiology , Disease Models, Animal , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/immunology , Ubiquitin-Protein Ligases/metabolism
4.
Int J Mol Sci ; 24(4)2023 Feb 11.
Article in English | MEDLINE | ID: mdl-36835047

ABSTRACT

In clinical conditions such as diaphragm paralysis or mechanical ventilation, disuse-induced diaphragmatic dysfunction (DIDD) is a condition that poses a threat to life. MuRF1 is a key E3-ligase involved in regulating skeletal muscle mass, function, and metabolism, which contributes to the onset of DIDD. We investigated if the small-molecule mediated inhibition of MuRF1 activity (MyoMed-205) protects against early DIDD after 12 h of unilateral diaphragm denervation. Wistar rats were used in this study to determine the compound's acute toxicity and optimal dosage. For potential DIDD treatment efficacy, diaphragm contractile function and fiber cross-sectional area (CSA) were evaluated. Western blotting investigated potential mechanisms underlying MyoMed-205's effects in early DIDD. Our results indicate 50 mg/kg bw MyoMed-205 as a suitable dosage to prevent early diaphragmatic contractile dysfunction and atrophy following 12 h of denervation without detectable signs of acute toxicity. Mechanistically, treatment did not affect disuse-induced oxidative stress (4-HNE) increase, whereas phosphorylation of (ser632) HDAC4 was normalized. MyoMed-205 also mitigated FoxO1 activation, inhibited MuRF2, and increased phospho (ser473) Akt protein levels. These findings may suggest that MuRF1 activity significantly contributes to early DIDD pathophysiology. Novel strategies targeting MuRF1 (e.g., MyoMed-205) have potential therapeutic applications for treating early DIDD.


Subject(s)
Diaphragm , Muscular Atrophy , Tripartite Motif Proteins , Ubiquitin-Protein Ligases , Animals , Rats , Diaphragm/metabolism , Diaphragm/pathology , Muscular Atrophy/metabolism , Oxidative Stress , Rats, Wistar , Respiration, Artificial/adverse effects , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/metabolism , Tripartite Motif Proteins/antagonists & inhibitors , Tripartite Motif Proteins/metabolism
5.
Biochem Cell Biol ; 100(4): 309-324, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35544948

ABSTRACT

Liver fibrosis is a very common health problem and currently lacks effective treatments. Cullin RING E3 ligases (CRLs) regulate the turnover of ∼20% of mammalian cell proteins. Neddylation, the process by which NEDD8 is covalently attached to cullin proteins through sequential enzymatic reactions, is critical for the activation of CRLs and was recently found to be elevated in liver fibrosis. NEDD8-activating enzyme E1-specific inhibition led to the reduced liver damage characterized by decreased apoptosis, inflammation, and fibrosis. However, the relevance of a co-E3 ligase, DCN1, in liver fibrosis remains unclear. Here, a novel and potent DCN1-UBC12 interaction inhibitor HZX-960 was discovered with an IC50 value of 9.37 nmol/L, which could inhibit the neddylation of cullin3. Importantly, we identified that HZX-960 treatment could attenuate transforming growth factor ß-induced liver fibrotic responses by reducing the deposition of collagen I and α-smooth muscle actin, and upregulating cellular NF-E2-related factor 2, hemeoxygenase 1, and NADPH quinone oxidoreductase-1 levels in two hepatic stellate cell lines. Additionally, DCN1 was shown to be unregulated in CCl4-induced mice liver tissue, and liver fibrotic signaling in mice was reduced by HZX-960. Therefore, our data demonstrated that HZX-960 possessed anti-liver fibrosis ability and that DCN1 may be a potential therapeutic target for liver fibrosis treatment.


Subject(s)
Enzyme Inhibitors , Liver Cirrhosis , Ubiquitin-Conjugating Enzymes , Ubiquitin-Protein Ligases , Animals , Cullin Proteins/metabolism , Enzyme Inhibitors/pharmacology , Liver Cirrhosis/drug therapy , Mice , Ubiquitin-Conjugating Enzymes/antagonists & inhibitors , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitination
6.
J Cachexia Sarcopenia Muscle ; 13(3): 1565-1581, 2022 06.
Article in English | MEDLINE | ID: mdl-35301823

ABSTRACT

BACKGROUND: About half of heart failure (HF) patients, while having preserved left ventricular function, suffer from diastolic dysfunction (so-called HFpEF). No specific therapeutics are available for HFpEF in contrast to HF where reduced ejection fractions (HFrEF) can be treated pharmacologically. Myocardial titin filament stiffening, endothelial dysfunction, and skeletal muscle (SKM) myopathy are suspected to contribute to HFpEF genesis. We previously described small molecules interfering with MuRF1 target recognition thereby attenuating SKM myopathy and dysfunction in HFrEF animal models. The aim of the present study was to test the efficacy of one small molecule (MyoMed-205) in HFpEF and to describe molecular changes elicited by MyoMed-205. METHODS: Twenty-week-old female obese ZSF1 rats received the MuRF1 inhibitor MyoMed-205 for 12 weeks; a comparison was made to age-matched untreated ZSF1-lean (healthy) and obese rats as controls. LV (left ventricle) function was assessed by echocardiography and by invasive haemodynamic measurements until week 32. At week 32, SKM and endothelial functions were measured and tissues collected for molecular analyses. Proteome-wide analysis followed by WBs and RT-PCR was applied to identify specific genes and affected molecular pathways. MuRF1 knockout mice (MuRF1-KO) SKM tissues were included to validate MuRF1-specificity. RESULTS: By week 32, untreated obese rats had normal LV ejection fraction but augmented E/e' ratios and increased end diastolic pressure and myocardial fibrosis, all typical features of HFpEF. Furthermore, SKM myopathy (both atrophy and force loss) and endothelial dysfunction were detected. In contrast, MyoMed-205 treated rats had markedly improved diastolic function, less myocardial fibrosis, reduced SKM myopathy, and increased SKM function. SKM extracts from MyoMed-205 treated rats had reduced MuRF1 content and lowered total muscle protein ubiquitination. In addition, proteomic profiling identified eight proteins to respond specifically to MyoMed-205 treatment. Five out of these eight proteins are involved in mitochondrial metabolism, dynamics, or autophagy. Consistent with the mitochondria being a MyoMed-205 target, the synthesis of mitochondrial respiratory chain complexes I + II was increased in treated rats. MuRF1-KO SKM controls also had elevated mitochondrial complex I and II activities, also suggesting mitochondrial activity regulation by MuRF1. CONCLUSIONS: MyoMed-205 improved myocardial diastolic function and prevented SKM atrophy/function in the ZSF1 animal model of HFpEF. Mechanistically, SKM benefited from an attenuated ubiquitin proteasome system and augmented synthesis/activity of proteins of the mitochondrial respiratory chain while the myocardium seemed to benefit from reduced titin modifications and fibrosis.


Subject(s)
Heart Failure , Muscle Proteins , Muscle, Skeletal , Small Molecule Libraries , Tripartite Motif Proteins , Ubiquitin-Protein Ligases , Animals , Connectin/metabolism , Diastole/drug effects , Female , Fibrosis , Heart Failure/drug therapy , Heart Failure/metabolism , Heart Failure/pathology , Mice , Mice, Knockout , Muscle Proteins/antagonists & inhibitors , Muscle Proteins/metabolism , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Muscular Atrophy/drug therapy , Muscular Atrophy/metabolism , Muscular Atrophy/pathology , Myocardium/pathology , Rats , Small Molecule Libraries/pharmacology , Stroke Volume/drug effects , Tripartite Motif Proteins/antagonists & inhibitors , Tripartite Motif Proteins/metabolism , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/metabolism
7.
Proc Natl Acad Sci U S A ; 119(6)2022 02 08.
Article in English | MEDLINE | ID: mdl-35101976

ABSTRACT

Blood-brain barrier (BBB) breakdown and inflammation occurring at the BBB have a key, mainly a deleterious role in the pathophysiology of ischemic stroke. Neddylation is a ubiquitylation-like pathway that is critical in various cellular functions by conjugating neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to target proteins. However, the roles of neddylation pathway in ischemic stroke remain elusive. Here, we report that NEDD8 conjugation increased during acute phase after ischemic stroke and was present in intravascular and intraparenchymal neutrophils. Inhibition of neddylation by MLN4924, also known as pevonedistat, inactivated cullin-RING E3 ligase (CRL), and reduced brain infarction and improved functional outcomes. MLN4924 treatment induced the accumulation of the CRL substrate neurofibromatosis 1 (NF1). By using virus-mediated NF1 silencing, we show that NF1 knockdown abolished MLN4924-dependent inhibition of neutrophil trafficking. These effects were mediated through activation of endothelial P-selectin and intercellular adhesion molecule-1 (ICAM-1), and blocking antibodies against P-selectin or anti-ICAM-1 antibodies reversed NF1 silencing-induced increase in neutrophil infiltration in MLN4924-treated mice. Furthermore, we found that NF1 silencing blocked MLN4924-afforded BBB protection and neuroprotection through activation of protein kinase C δ (PKCδ), myristoylated alanine-rich C-kinase substrate (MARCKS), and myosin light chain (MLC) in cerebral microvessels after ischemic stroke, and treatment of mice with the PKCδ inhibitor rottlerin reduced this increased BBB permeability. Our study demonstrated that increased neddylation promoted neutrophil trafficking and thus exacerbated injury of the BBB and stroke outcomes. We suggest that the neddylation inhibition may be beneficial in ischemic stroke.


Subject(s)
Brain Injuries , Brain Ischemia , Cyclopentanes/pharmacology , NEDD8 Protein/metabolism , Nerve Tissue Proteins , Protein Processing, Post-Translational/drug effects , Pyrimidines/pharmacology , Ubiquitin-Protein Ligases , Animals , Brain Injuries/drug therapy , Brain Injuries/enzymology , Brain Ischemia/drug therapy , Brain Ischemia/enzymology , Male , Mice , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/metabolism , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/metabolism
8.
J Enzyme Inhib Med Chem ; 37(1): 527-530, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35220840

ABSTRACT

The advent of proteolysis-targeting chimaeras (PROTACs) mandates that new ligands for the recruitment of E3 ligases are discovered. The traditional immunomodulatory drugs (IMiDs) such as thalidomide and its analogues (all based on the phthalimide glutarimide core) bind to Cereblon, the substrate receptor of the CRL4ACRBN E3 ligase. We designed a thalidomide analogue in which the phthalimide moiety was replaced with benzotriazole, using an innovative synthesis strategy. Compared to thalidomide, the resulting "benzotriazolo thalidomide" has a similar binding mode, but improved properties, as revealed in crystallographic analyses, affinity assays and cell culture.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Triazoles/pharmacology , Ubiquitin-Protein Ligases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , Ubiquitin-Protein Ligases/metabolism
9.
Oxid Med Cell Longev ; 2022: 7502632, 2022.
Article in English | MEDLINE | ID: mdl-35126820

ABSTRACT

AIM: The study is aimed at verifying miR-154-5p and Smurf1 combination in glomerular mesangial cells regulating TGFß1/Smad3 pathway-related protein ubiquitination in the model of diabetic rats renal tissues, primary mesangial cells, and cell lines. METHODS: The diabetic SD rat model and high-glucose-cultured primary mesangial cells and cell lines were established. miR-154-5p mimic and inhibitor, Smurf1 siRNA, and TGF ß 1/Smad3 inhibitor (SB431542) were pretreated to make the TGFß1/Smad3 pathway and ubiquitin changes. Fluorescence in situ hybridization was used for the miR-154-5p renal localization; molecular biological detection was adopted for cell proliferation, renal function, urine protein, and pathway proteins. After bioinformatics predicted binding sites, luciferase and Co-IP were used to detect miRNA and protein binding. RESULTS: miR-154-5p was significantly increased and mainly concentrated in the glomerular of renal cortex in well-established diabetic rat renal tissues. Rno-miR-154-5p combined Rno-Smurf1 3' UTR, while Smurf1 combined Smad3 directly. Meanwhile, miR-154-5p regulates TGFß1/Smad3-mediated cell proliferation via Smurf1 ubiquitination. CONCLUSION: miR-154-5p regulates the TGFß1/Smads pathway through Smurf1 ubiquitination and promotes the fibrosis process of diabetic kidney disease.


Subject(s)
MicroRNAs/metabolism , Signal Transduction , Smad3 Protein/metabolism , Transforming Growth Factor beta1/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Antagomirs/metabolism , Cell Proliferation , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/pathology , Diabetic Nephropathies/etiology , Diabetic Nephropathies/metabolism , Fibrosis , Kidney/metabolism , Kidney/pathology , Male , Mesangial Cells/cytology , Mesangial Cells/metabolism , MicroRNAs/antagonists & inhibitors , MicroRNAs/genetics , Protein Binding , RNA Interference , RNA, Small Interfering/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction/genetics , Smad3 Protein/antagonists & inhibitors , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/genetics , Ubiquitination
10.
Future Med Chem ; 14(3): 187-201, 2022 01.
Article in English | MEDLINE | ID: mdl-35100004

ABSTRACT

Ubiquitylation is a posttranslational modification of proteins that is necessary for a variety of cellular processes. E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligase are all involved in transferring ubiquitin to the target substrate to regulate cellular function. The objective of this review is to provide an overview of different aspects of E3 ubiquitin ligases that can lead to major biological system failure in several deadly diseases. The first part of this review covers the important characteristics of E3 ubiquitin ligases and their classification based on structural domains. Further, the authors provide some online resources that help researchers explore the data relevant to the enzyme. The following section delves into the involvement of E3 ubiquitin ligases in various diseases and biological processes, including different types of cancer and neurological disorders.


Subject(s)
Enzyme Inhibitors/pharmacology , Neoplasms/drug therapy , Nervous System Diseases/drug therapy , Ubiquitin-Protein Ligases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Humans , Neoplasms/metabolism , Nervous System Diseases/metabolism , Ubiquitin-Protein Ligases/metabolism
12.
Chem Commun (Camb) ; 58(14): 2383-2386, 2022 Feb 15.
Article in English | MEDLINE | ID: mdl-35080528

ABSTRACT

In this study, we identified 3-aminophthalic acid as a new ligand of cereblon (CRBN) E3 ubiquitin ligase and developed a phthalic acid-based O'PROTAC for degradation of the ERG transcription factor. This phthalic acid-based O'PROTAC presented an efficacy in degrading ERG comparable to those displayed by pomalidomide-based ERG O'PROTACs. Moreover, phthalic acid-being more chemically stable and economical than classical immunomodulatory drugs (IMiDs)-represents, as a ligand, a new alternative for the development of PROTACs, especially O'PROTACs.


Subject(s)
Phthalic Acids/pharmacology , Transcription Factors/antagonists & inhibitors , Ubiquitin-Protein Ligases/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Ligands , Molecular Structure , Phthalic Acids/chemistry , Proteolysis/drug effects , Structure-Activity Relationship , Transcription Factors/metabolism , Ubiquitin-Protein Ligases/metabolism
13.
Sci Rep ; 12(1): 45, 2022 01 07.
Article in English | MEDLINE | ID: mdl-34997070

ABSTRACT

Head-and-neck squamous cell carcinomas (HNSCCs) are relatively common in patients with Fanconi anemia (FA), a hereditary chromosomal instability disorder. Standard chemo-radiation therapy is not tolerated in FA due to an overall somatic hypersensitivity to such treatment. The question is how to find a suitable alternative treatment. We used whole-exome and whole genome mRNA sequencing to identify major genomic and transcriptomic events associated with FA-HNSCC. CRISPR-engineered FA-knockout models were used to validate a number of top hits that were likely to be druggable. We identified deletion of 18q21.2 and amplification of 11q22.2 as prevailing copy-number alterations in FA HNSCCs, the latter of which was associated with strong overexpression of the cancer-related genes YAP1, BIRC2, BIRC3 (at 11q22.1-2). We then found the drug AZD5582, a known small molecule inhibitor of BIRC2-3, to selectively kill FA tumor cells that overexpressed BIRC2-3. This occurred at drug concentrations that did not affect the viability of untransformed FA cells. Our data indicate that 11q22.2 amplifications are relatively common oncogenic events in FA-HNSCCs, as holds for non FA-HNSCC. Therefore, chemotherapeutic inhibition of overexpressed BIRC2-3 may provide the basis for an approach to develop a clinically realistic treatment of FA-HNSCCs that carry 11q22.2 amplifications.


Subject(s)
Baculoviral IAP Repeat-Containing 3 Protein/genetics , Baculoviral IAP Repeat-Containing 3 Protein/metabolism , Fanconi Anemia/drug therapy , Fanconi Anemia/genetics , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics , Inhibitor of Apoptosis Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Alkynes/pharmacology , Baculoviral IAP Repeat-Containing 3 Protein/antagonists & inhibitors , Cell Line , Cell Survival/drug effects , Cell Survival/genetics , DNA Copy Number Variations , DNA Mutational Analysis , Fanconi Anemia/complications , Fanconi Anemia/immunology , Gene Expression Regulation, Neoplastic , Head and Neck Neoplasms/complications , Head and Neck Neoplasms/immunology , Humans , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Inhibitor of Apoptosis Proteins/genetics , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Oligopeptides/pharmacology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/genetics , YAP-Signaling Proteins/genetics , YAP-Signaling Proteins/metabolism
14.
J Cell Biochem ; 123(2): 161-182, 2022 02.
Article in English | MEDLINE | ID: mdl-34520596

ABSTRACT

Viruses are known to cause various diseases in human and also infect other species such as animal plants, fungi, and bacteria. Replication of viruses depends upon their interaction with hosts. Human cells are prone to such unwanted viral infections. Disintegration and reconstitution require host machinery and various macromolecules like DNA, RNA, and proteins are invaded by viral particles. E3 ubiquitin ligases are known for their specific function, that is, recognition of their respective substrates for intracellular degradation. Still, we do not understand how ubiquitin proteasome system-based enzymes E3 ubiquitin ligases do their functional interaction with different viruses. Whether E3 ubiquitin ligases help in the elimination of viral components or viruses utilize their molecular capabilities in their intracellular propagation is not clear. The first time our current article comprehends fundamental concepts and new insights on the different viruses and their interaction with various E3 Ubiquitin Ligases. In this review, we highlight the molecular pathomechanism of viruses linked with E3 Ubiquitin Ligases dependent mechanisms. An enhanced understanding of E3 Ubiquitin Ligase-mediated removal of viral proteins may open new therapeutic strategies against viral infections.


Subject(s)
Ubiquitin-Protein Ligases/physiology , Viral Proteins/physiology , Virus Diseases/enzymology , Virus Replication/physiology , Cell Transformation, Viral/physiology , Cullin Proteins/physiology , Endosomes/virology , Host-Pathogen Interactions , Humans , Immunity, Innate , Inflammation/enzymology , Inflammation/virology , Neoplasms/enzymology , Neoplasms/virology , Oncogenic Viruses/physiology , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Tripartite Motif Proteins/physiology , Ubiquitin-Protein Ligases/antagonists & inhibitors , Virus Diseases/immunology , Virus Diseases/virology , Virus Replication/drug effects , COVID-19 Drug Treatment
17.
Bioorg Chem ; 119: 105505, 2022 02.
Article in English | MEDLINE | ID: mdl-34838332

ABSTRACT

Targeted protein degradation offers new opportunities to inactivate cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.


Subject(s)
Antineoplastic Agents/pharmacology , Gastrointestinal Neoplasms/drug therapy , Thalidomide/pharmacology , Thiazoles/pharmacology , Ubiquitin-Protein Ligases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Gastrointestinal Neoplasms/metabolism , Gastrointestinal Neoplasms/pathology , Humans , Molecular Structure , Structure-Activity Relationship , Thalidomide/chemical synthesis , Thalidomide/chemistry , Thiazoles/chemical synthesis , Thiazoles/chemistry , Tumor Cells, Cultured , Ubiquitin-Protein Ligases/metabolism
18.
Int J Mol Sci ; 22(23)2021 Dec 01.
Article in English | MEDLINE | ID: mdl-34884830

ABSTRACT

The RING-type E3 ubiquitin ligases play an important role in plant growth, development, and defense responses to abiotic stresses and pathogens. However, their roles in the resistance of plants to herbivorous insects remain largely unknown. In this study, we isolated the rice gene OsJMJ715, which encodes a RING-domain containing protein, and investigated its role in rice resistance to brown planthopper (BPH, Nilaparvata lugens). OsJMJ715 is a nucleus-localized E3 ligase whose mRNA levels were upregulated by the infestation of gravid BPH females, mechanical wounding, and treatment with JA or ABA. Silencing OsJMJ715 enhanced BPH-elicited levels of ABA, JA, and JA-Ile as well as the amount of callose deposition in plants, which in turn increased the resistance of rice to BPH by reducing the feeding of BPH and the hatching rate of BPH eggs. These findings suggest that OsJMJ715 negative regulates the BPH-induced biosynthesis of ABA, JA, and JA-Ile and that BPH benefits by enhancing the expression of OsJMJ715.


Subject(s)
Abscisic Acid/metabolism , Cyclopentanes/metabolism , Hemiptera/physiology , Oryza/metabolism , Oxylipins/metabolism , Plant Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Abscisic Acid/pharmacology , Animals , Cyclopentanes/pharmacology , Gene Expression Regulation, Plant/drug effects , Glucans/metabolism , Herbivory , Isoleucine/analogs & derivatives , Isoleucine/metabolism , Oryza/growth & development , Oryza/parasitology , Oxylipins/pharmacology , Plant Leaves/metabolism , Plant Leaves/parasitology , Plant Proteins/antagonists & inhibitors , Plant Proteins/metabolism , Plants, Genetically Modified/genetics , Plants, Genetically Modified/metabolism , Plants, Genetically Modified/parasitology , RNA Interference , RNA, Messenger/metabolism , Signal Transduction/drug effects , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/metabolism
19.
Nat Commun ; 12(1): 6662, 2021 11 18.
Article in English | MEDLINE | ID: mdl-34795264

ABSTRACT

SPOP, an E3 ubiquitin ligase, acts as a prostate-specific tumor suppressor with several key substrates mediating oncogenic function. However, the mechanisms underlying SPOP regulation are largely unknown. Here, we have identified G3BP1 as an interactor of SPOP and functions as a competitive inhibitor of Cul3SPOP, suggesting a distinctive mode of Cul3SPOP inactivation in prostate cancer (PCa). Transcriptomic analysis and functional studies reveal a G3BP1-SPOP ubiquitin signaling axis that promotes PCa progression through activating AR signaling. Moreover, AR directly upregulates G3BP1 transcription to further amplify G3BP1-SPOP signaling in a feed-forward manner. Our study supports a fundamental role of G3BP1 in disabling the tumor suppressive Cul3SPOP, thus defining a PCa cohort independent of SPOP mutation. Therefore, there are significantly more PCa that are defective for SPOP ubiquitin ligase than previously appreciated, and these G3BP1high PCa are more susceptible to AR-targeted therapy.


Subject(s)
Cullin Proteins/antagonists & inhibitors , DNA Helicases/metabolism , Nuclear Proteins/antagonists & inhibitors , Poly-ADP-Ribose Binding Proteins/metabolism , Prostatic Neoplasms/metabolism , RNA Helicases/metabolism , RNA Recognition Motif Proteins/metabolism , Receptors, Androgen/metabolism , Repressor Proteins/antagonists & inhibitors , Androgen Receptor Antagonists/pharmacology , Animals , Carcinogenesis , Cell Line, Tumor , Cell Movement , Cell Survival/drug effects , Cullin Proteins/metabolism , DNA Helicases/genetics , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Mutation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Poly-ADP-Ribose Binding Proteins/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , RNA Helicases/genetics , RNA Recognition Motif Proteins/genetics , Repressor Proteins/genetics , Repressor Proteins/metabolism , Signal Transduction/drug effects , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
20.
Bioorg Med Chem ; 52: 116500, 2021 12 15.
Article in English | MEDLINE | ID: mdl-34801826

ABSTRACT

The accumulation of epigenetic alterations is one of the major causes of tumorigenesis. Aberrant DNA methylation patterns cause genome instability and silencing of tumor suppressor genes in various types of tumors. Therefore, drugs that target DNA methylation-regulating factors have great potential for cancer therapy. Ubiquitin-like containing PHD and RING finger domain 1 (UHRF1) is an essential factor for DNA methylation maintenance. UHRF1 is overexpressed in various cancer cells and down-regulation of UHRF1 in these cells reactivates the expression of tumor suppressor genes, thus UHRF1 is a promising target for cancer therapy. We have previously shown that interaction between the tandem Tudor domain (TTD) of UHRF1 and DNA ligase 1 (LIG1) di/trimethylated on Lys126 plays a key role in the recruitment of UHRF1 to replication sites and replication-coupled DNA methylation maintenance. An arginine binding cavity (Arg-binding cavity) of the TTD is essential for LIG1 interaction, thus the development of inhibitors that target the Arg-binding cavity could potentially repress UHRF1 function in cancer cells. To develop such an inhibitor, we performed in silico screening using not only static but also dynamic metrics based on all-atom molecular dynamics simulations, resulting in efficient identification of 5-amino-2,4-dimethylpyridine (5A-DMP) as a novel TTD-binding compound. Crystal structure of the TTD in complex with 5A-DMP revealed that the compound stably bound to the Arg-binding cavity of the TTD. Furthermore, 5A-DMP inhibits the full-length UHRF1:LIG1 interaction in Xenopus egg extracts. Our study uncovers a UHRF1 inhibitor which can be the basis of future experiments for cancer therapy.


Subject(s)
CCAAT-Enhancer-Binding Proteins/antagonists & inhibitors , DNA Ligase ATP/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Molecular Dynamics Simulation , Pyridines/pharmacology , Ubiquitin-Protein Ligases/antagonists & inhibitors , Animals , CCAAT-Enhancer-Binding Proteins/genetics , CCAAT-Enhancer-Binding Proteins/metabolism , Cell Line, Tumor , DNA Ligase ATP/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Pyridines/chemistry , Structure-Activity Relationship , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Xenopus
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