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The Fanconi anemia ubiquitin E3 ligase complex as an anti-cancer target.

Agents that induce DNA damage can cure some cancers. However, the side effects of chemotherapy are severe because of the indiscriminate action of DNA-damaging agents on both healthy and cancerous cells. DNA repair pathway inhibition provides a less toxic and targeted alternative to chemotherapy. A compelling DNA repair target is the Fanconi anemia (FA) E3 ligase core complex due to its critical-and likely singular-role in the efficient removal of specific DNA lesions. FA pathway inactivation has been demonstrated to specifically kill some types of cancer cells without the addition of exogenous

Ubiquitin-proteasome system-targeted therapy for uveal melanoma: what is the evidence?

Uveal melanoma (UM) is a rare ocular tumor. The loss of BRCA1-associated protein 1 (BAP1) and the aberrant activation of G protein subunit a … es (DUBs), which work coordinately to dictate the fate of intracellular proteins through regulating ubiquitination, thus influencing cell viability. Due to the critical role of UPS in tumors, we here provide an overview of the crosstalk between UPS and the malignancy of UM, discuss the current UPS-targeted therapies in UM and highlight its potential in developin …

Reciprocal surface expression of arylsulfatase A and ubiquitin in normal and defective mammalian spermatozoa.

Defective mammalian spermatozoa are marked on their surface by proteolytic chaperone ubiquitin. To identify potential ubiquitinated substrat … ctive bull spermatozoa. Defective sperm surface thus differs from normal sperm surface by increased ubiquitination, reduced ARSA binding, and altered glycosylation.

The E3 ubiquitin ligase HectD3 attenuates cardiac hypertrophy and inflammation in mice.

Myocardial inflammation has recently been recognized as a distinct feature of cardiac hypertrophy and heart failure. HectD3, a HECT domain containing E3 ubiquitin ligase has previously been investigated in the host defense against infections as well as neuroinflammation; its cardiac function however is still unknown. Here we show that HectD3 simultaneously attenuates Calcineurin-NFAT driven cardiomyocyte hypertrophy and the pro-inflammatory actions of LPS/interferon-γ via its cardiac substrates SUMO2 and Stat1, respectively. AAV9-mediated overexpression of HectD3 in mice in vivo not only reduc

The E3 ubiquitin ligase MARCHF6 as a metabolic integrator in cholesterol synthesis and beyond.

MARCHF6 is a large multi-pass E3 ubiquitin ligase embedded in the membranes of the endoplasmic reticulum. It participates in endoplasmic reticulum associated degradation, including autoubiquitination, and many of its identified substrates are involved in sterol and lipid metabolism. Post-translationally, MARCHF6 expression is attuned to cholesterol status, with high cholesterol preventing its degradation and hence boosting MARCHF6 levels. By modulating MARCHF6 activity, cholesterol may regulate other aspects of cell metabolism beyond the known repertoire. Whilst we have learnt much about MARCH…

Ubiquitin and SUMO conjugation as biomarkers of acute myeloid leukemias response to chemotherapies.

Ubiquitin and the ubiquitin-like SUMO are covalently conjugated to thousands of proteins to modulate their function and fate. Many of the enzymes involved in their conjugation are dysregulated in cancers and involved in cancer cell response to therapies. We describe here the identification of biomarkers of the activity of these enzymes and their use to predict acute myeloid leukemias (AML) response to standard chemotherapy (daunorubicin-DNR and cytarabine-Ara-C). We compared the ability of extracts from chemosensitive and chemoresistant AML cells to conjugate ubiquitin or SUMO-1 on 9,000 prote

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… Their conjugation involves dedicated enzymatic cascades comprising E1 UbL–activating enzymes (two for ubiquitin, one for SUMO), E2 UbL–conjugating enzymes (46 for ubiquitin, one for SUMO) and several E3 factors (∼700 for ubiquitin, ∼15 for SUMO) ( Streich & Lima, 2014 ). … Blood 124: 2081–2090. 10.1182/blood-2014-06-584524 Kwon YT, Ciechanover A (2017) The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem Sci 42: 873–886. 10.1016/j.tibs.2017.09.002 Mansour MA. (2018) Ubiquitination: Friend and foe in cancer. …

Development of ADPribosyl Ubiquitin Analogues to Study Enzymes Involved in Legionella Infection.

Legionnaires' disease is caused by infection with the intracellularly replicating Gram-negative bacterium Legionella pneumophila. This pathogen uses an unconventional way of ubiquitinating host proteins by generating a phosphoribosyl linkage between substrate proteins and ubiquitin by making use of an ADPribosylated ubiquitin (UbADPr ) intermediate. The family of SidE effector enzymes that catalyze this reaction is counteracted by Legionella hydrolases, which are called Dups. This unusual ubiquitination process is important for Legionella proliferation and understanding these processes on a mo…

The GID ubiquitin ligase complex is a regulator of AMPK activity and organismal lifespan.

UNLABELLED: The AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by sensing the metabolic status of the cell. AMPK is regulated by phosphorylation and dephosphorylation as a result of changing AMP/ATP levels and by removal of inhibitory ubiquitin residues by USP10. In this context, we identified the GID-complex, an evolutionarily conserved ubiquitin-ligase-complex (E3), as a negative regulator of AMPK activity. Our data show that the GID-complex targets AMPK for ubiquitination thereby altering its activity. Cells depleted of GID-subunits mimic a state of starvation as …

TRAIL signals through the ubiquitin ligase MID1 to promote pulmonary fibrosis.

BACKGROUND: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has previously been demonstrated to play a pro-inflammatory role in allergic airways disease and COPD through the upregulation of the E3 ubiquitin ligase MID1 and the subsequent deactivation of protein phosphatase 2A (PP2A). METHODS: Biopsies were taken from eight IPF patients presenting to the Second Affiliated Hospital of Jilin University, China between January 2013 and February 2014 with control samples obtained from resected lung cancers. Serum TRAIL, MID1 protein and PP2A activity in biopsies, and patients' lung

Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads.

BACKGROUND: Protein ubiquitylation is an important post-translational regulation, which has been shown to be necessary for life cycle progression and survival of Plasmodium falciparum. Ubiquitin is a highly conserved 76 amino acid polypeptide, which attaches covalently to target proteins through combined action of three classes of enzymes namely, the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin-protein ligase (E3). Ubiquitin E1 and E2 are highly conserved within eukaryotes. However, the P. falciparum E3 ligase is substantially variable and divergent compare

Early Origin and Evolution of the Angelman Syndrome Ubiquitin Ligase Gene Ube3a.

The human Ube3a gene encodes an E3 ubiquitin ligase and exhibits brain-specific genomic imprinting. Genetic abnormalities that affect the maternal copy of this gene cause the neurodevelopmental disorder Angelman syndrome (AS), which is characterized by severe mental retardation, speech impairment, seizure, ataxia and some unique behavioral phenotypes. In this review article, I highlight the evolution of the Ube3a gene and its imprinting to provide evolutionary insights into AS. Recent comparative genomic studies have revealed that Ube3a is most phylogenetically similar to HECTD2 among the huma

Ubiquitin-Dependent Modification of Skeletal Muscle by the Parasitic Nematode, Trichinella spiralis.

Trichinella spiralis is a muscle-specific parasitic worm that is uniquely intracellular. T. spiralis reprograms terminally differentiated sk … 7/UBE2L3. Expression of TsUBE2L3 in skeletal muscle cells causes a global downregulation in protein ubiquitination, most predominantly affecting motor, sarcomeric and extracellular matrix proteins, thus mediating their stabilization with regards to proteasomal degradation. This effect is not observed in the presence of the mammalian ortholog, suggesting function …

Global-genome Nucleotide Excision Repair Controlled by Ubiquitin/Sumo Modifiers.

Global-genome nucleotide excision repair (GG-NER) prevents genome instability by excising a wide range of different DNA base adducts and cro … l action of cullin-type CRL4(DDB2) and sumo-targeted RNF111 ubiquitin ligases. This twofold protein ubiquitination system promotes GG-NER reactions by spatially and temporally regulating the interaction of XPC protein with damaged DNA across the nucleosome landscape of chromatin. In the absence of either CRL4(DDB2) or RNF111, the DNA excision repair of UV lesion …

The ubiquitin-activating enzyme E1 as a novel therapeutic target for the treatment of restenosis.

AIMS: The ubiquitin-activating enzyme E1 (UBA1, E1), the apex of the ubiquitin proteasome pathway, plays a critical role in protein degradation and in pathological processes. Whether UBA1 participates the development of vascular restenosis remains unknown. This study aims to determine the role of UBA1 in the development of balloon injury induced neointimal formation. METHODS AND RESULTS: Immunostaining and western blots were used to examine the expression of the ubiquitinated protein in the injured carotid after angioplasty. Higher levels of ubiquitinated protein were observed in the neointim

The ubiquitin-proteasome system and its potential application in hepatocellular carcinoma therapy.

The ubiquitin-proteasome system (UPS) is a complicated tightly controlled system in charge of degrading 80-90% of proteins, and is central to regulating cellular function and keeping protein homeostasis. Therefore, the components of UPS attract considerable attention as potential targets for hepatocellular carcinoma (HCC) therapy. The clinical success of bortezomib in multiple myeloma and mantle cell lymphoma patients has set the precedent for therapeutically targeting this pathway. This review will provide an overview of the UPS in HCC and the current status of therapeutic strategies.

The ubiquitin proteasome system as a potential therapeutic target for treatment of neurodegenerative diseases.

Impairment of "protein quality control" in neurons is associated with etiopathogenesis of neurodegenerative diseases. The worn-out products of cell metabolism should be safely eliminated via the proteasome, autophago-lysosome and exocytosis. Insufficient activity of these degradation mechanisms within neurons leads to the accumulation of toxic protein oligomers, which represent a starting material for development of neurodegenerative proteinopathy. The spectrum of CNS linked proteinopathies is particularly broad and includes Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementi

The role of spartin and its novel ubiquitin binding region in DALIS occurrence.

Troyer syndrome is an autosomal recessive hereditary spastic paraplegia (HSP) caused by frameshift mutations in the SPG20 gene that results in a lack of expression of the truncated protein. Spartin is a multifunctional protein, yet only two conserved domains--a microtubule-interacting and trafficking domain and a plant-related senescence domain involved in cytokinesis and mitochondrial physiology, respectively--have been defined. We have shown that overexpressed spartin binds to the Ile44 hydrophobic pocket of ubiquitin, suggesting spartin might contain a ubiquitin-binding domain. In the prese

The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation.

Linear ubiquitination is a newly discovered posttranslational modification that is currently restricted to a small number of known protein substrates. The linear ubiquitination assembly complex (LUBAC), consisting of HOIL-1L, HOIP, and Sharpin, has been reported to activate NF-κB-mediated transcription in response to receptor signaling by ligating linear ubiquitin chains to Nemo and Rip1. Despite recent advances, the detailed roles of LUBAC in immune cells remain elusive. We demonstrate a novel HOIL-1L function as an essential regulator of the activation of the NLRP3/ASC inflammasome in primar…

Ubiquitin ligase defect by DCAF8 mutation causes HMSN2 with giant axons.

OBJECTIVE: To identify the genetic cause of axonal hereditary motor and sensory neuropathy (HMSN2) with infrequent giant axons. METHODS: We studied 11 members of a previously described HMSN2 family with infrequent giant axons and variable cardiomyopathy. Whole-exome sequencing (WES) was performed on 2 affected persons and 1 unaffected person. Sanger sequencing was utilized to confirm the identified novel variant tracking with the affected status. Linkage analysis and haplotype mapping were obtained to confirm the causal nature of the identified variant. Cotransfection of HEK293 cells and co-i

Hepatitis B virus HBx protein interactions with the ubiquitin proteasome system.

The hepatitis B virus (HBV) causes acute and chronic hepatitis, and the latter is a major risk factor for the development of hepatocellular carcinoma (HCC). HBV encodes a 17-kDa regulatory protein, HBx, which is required for virus replication. Although the precise contribution(s) of HBx to virus replication is unknown, many viruses target cellular pathways to create an environment favorable for virus replication. The ubiquitin proteasome system (UPS) is a major conserved cellular pathway that controls several critical processes in the cell by regulating the levels of proteins involved in cell