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The RAG1 N-terminal region regulates the efficiency and pathways of synapsis for V(D)J recombination.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal proliferation of differentiated myeloid cells leading to bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. In late 2019, the FDA approved the highly selective JAK2 inhibitor, fedratinib, for intermediate-2 or high-risk primary or secondary MF, making it the second drug approved for MF after ruxolitinib, a JAK1/2 inhibitor, which was approved for MF in 2011. The approval of fedratinib was based on phase II trials and the phase III JAKARTA trial, in which the drug significantly reduced splenomegaly and s

Identification of Key Genes Involved in Lactic Acid Metabolism in Periodontitis Based on Bioinformatics Analysis.

Lactic acid metabolism correlates with periodontitis progression. Using machine learning (LASSO and SVM-RFE) on GSE16134 and GSE173078 datasets, CFI and COQ2 were identified as key genes, with good diagnostic performance (AUC > 0.75). GSEA linked these genes to MAPK signalling, endocytosis, and ubiquitin-mediated proteolysis. Immune infiltration analysis revealed higher plasma cells and lower CD8 T cells in periodontitis. Molecular docking identified amiodarone as a potential compound with strong binding affinity to CFI and COQ2. The expression trends of CFI (upregulated) and COQ2 (downregulat

An integrated drug repositioning analysis identifies rosiglitazone as a treatment for sarcopenia.

Age-related sarcopenia is a growing global health challenge with no approved pharmacotherapies. Here, we integrate network-based drug repurposing and Mendelian randomization to identify rosiglitazone, a PPARγ agonist used in diabetes, as a potential therapeutic candidate for sarcopenia. In aged male C57BL/6JRj murine models, rosiglitazone administration significantly improved muscle strength, mass, and endurance. Multi-omics profiling revealed its mechanism involves gut microbiota remodeling, activation of skeletal muscle Igf1 signaling, suppression of atrophy-related ubiquitin ligases (Atrogi

TRIM14 Knockdown is Associated with Attenuated Sevoflurane-Induced Ferroptosis and Mitochondrial Dysfunction in Hippocampal Neurons.

Sevoflurane (SEV) is widely used in clinical anesthesia, but its exposure is increasingly being linked to neurocognitive dysfunction, particularly in hippocampal neurons. TRIM14, an E3 ubiquitin ligase, is essential for regulating inflammation, apoptosis, and mitochondrial function; however, its involvement in SEV-induced neuronal damage remains unclear. In this study, we investigated the role of TRIM14 in SEV-induced hippocampal neuronal damage, focusing on mitochondrial dysfunction, iron homeostasis, and inflammation. The results show that TRIM14 knockdown significantly increased cell viabil

UBE2N inhibition abrogates cancer chemoresistance and metastasis in lung adenocarcinoma.

Chemoresistance and metastasis remain significant challenges in cancer therapy, resulting in treatment failures for cancer patients. Therefore, there is a need to investigate the mechanisms underlying cancer chemoresistance and metastasis, identify novel drug targets, and develop innovative antitumor medications. In this study, we have shown that the ubiquitin conjugating enzyme UBE2N plays a crucial role in promoting chemoresistance and metastasis in lung adenocarcinoma (LUAD) both in vitro and in vivo. Significantly, our study revealed that the natural compound wilforine functions as a poten

Doxorubicin, a DNA intercalator, inhibits transcription elongation.

Doxorubicin is a chemotherapeutic drug for cancer that intercalates into nucleosome-free regions at promoters. Doxorubicin was reported to result in loss of histone H3 trimethylated lysine 4 (H3K4me3). To further explore doxorubicin's mechanism of action, we determined the genomic location of the binding sites of doxorubicin in leukemic cells. The effect of doxorubicin intercalation into the chromatin of leukemic cells on histone modifications was also determined. We show that doxorubicin binding sites were present in the nucleosome-free regions associated with regulatory regions (promoters, e

The genetics of neurodegenerative diseases is the genetics of age-related damage clearance failure.

In this perspective we draw together the data from the genome wide association studies for Alzheimer's disease, Parkinson's disease and the tauopathies and reach the conclusion that in each case, most of the risk loci are involved in the clearance of the deposited proteins: in Alzheimer's disease, the microglial removal of Aβ, in the synucleinopathies, the lysosomal clearance of synuclein and in the tauopathies, the removal of tau protein by the ubiquitin proteasome. We make the point that most loci identified through genome wide association studies are not strictly pathogenic but rather relat

Emerging roles of Midnolin in Cancer, Parkinson's Disease, and Metabolic dysfunction.

Midnolin has emerged as a versatile protein involved in gene regulation, metabolism and disease. It controls Early Response Genes by promoting their ubiquitin-independent proteasomal degradation. It also affects glucose metabolism by interacting with glucokinase in pancreatic beta cells. Recent studies have highlighted the significant role of Midnolin in various human diseases, including non-alcoholic fatty liver disease, Parkinson's disease, and several malignancies such as liver cancer, breast cancer, gastric cancer, multiple myeloma and B-cell leukemias and lymphomas. Moreover, it has also

The Role of A20 in Cancer: Friend or Foe?

A20 is a ubiquitin-editing enzyme that has emerged as a key regulator of inflammatory signaling with paradoxical roles in cancer. Acting as both an oncogene and a tumor suppressor gene depending on the cellular context, A20 modulates important cell pathways, such as NF-κB signaling and autophagy. In this review, we summarize the dual roles of A20 in tumorigenesis, highlighting its ability to promote tumor progression in cancers, such as breast and melanoma, while functioning as a tumor suppressor in lymphomas and hepatocellular carcinoma. We discuss the interplay of A20 with autophagy, a proce

Protease regulation of tumor-immune cell symbiosis.

Proteases play a crucial role in cancer progression and are traditionally known for their protumorigenic role by degrading the extracellular matrix (ECM). Emerging evidence indicates that proteases, such as caspases, cathepsins, and ubiquitin-specific proteases (USPs), regulate diverse immunomodulatory substrates or signals in the tumor microenvironment (TME), generating symbiotic interactions between cancer cells and immune cells. These interactions are critical for tumor progression and immunotherapy resistance across cancer types. In this review, we highlight recent insights into protease-m

Discovery of New Azaindole Metallo-Deubiquitinase CSN5 Inhibitors.

CSN5 is responsible for the deneddylation of cullin-RING E3 ubiquitin ligases and is closely linked to the development of various cancers. We previously developed a noncatalytic activity assay platform using novel fluorescent probes derived from azaindole inhibitors, which also highlighted the potential for further structural optimization of azaindoles. Herein, we report a series of new 4-NH-substituted azaindole derivatives, some of which showed nanomolar activity against the CSN5 subunit. Cellular assays revealed that the new azaindoles increase the cullin 1 neddylation in cancer cells. Impo

From Acute Injury to Chronic Neurodegeneration: Molecular Mechanisms Linking Secondary Brain Injury to Long-Term Pathology.

Traumatic brain injury (TBI) initiates a complex cascade of pathophysiological events that have far-reaching consequences beyond the initial injury. This review examines the current state of the literature on the mechanisms underlying neurotrauma and neuroinflammation, with particular emphasis on the molecular cross-talk between these disparate pathways that ultimately precipitates the development of chronic traumatic encephalopathy (CTE). We integrate this mechanistic knowledge with potential diagnostic biomarkers, such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL

Bombyx mori UFL1 facilitates BmNPV proliferation by regulating host cell apoptosis through PERK.

Ubiquitin-fold modifier 1 (UFM1) is attached to protein substrates through the sequential activity of an E1 (UBA5)-E2 (UFC1)-E3 (UFL1) cascade. UFL1 is the E3 ligase for UFMylation in vertebrates. However, there have been no studies on UFL1 in silkworm to date. In this study, we identified a UFL1 ortholog in Bombyx mori genome. Spatio-temporal expression profiles showed that BmUFL1 expression was high in the midgut, epidermis, and testis and in the pupa-adult stage. BmUFL1 knockdown inhibited B. mori nucleopolyhedrovirus (BmNPV) proliferation, while BmUFL1 overexpression promoted BmNPV prolife

The role of PINK1-Parkin in mitochondrial quality control.

Mitophagy mediated by the recessive Parkinson's disease genes PINK1 and Parkin responds to mitochondrial damage to preserve mitochondrial function. In the pathway, PINK1 is the damage sensor, probing the integrity of the mitochondrial import pathway, and activating Parkin when import is blocked. Parkin is the effector, selectively marking damaged mitochondria with ubiquitin for mitophagy and other quality-control processes. This selective mitochondrial quality-control pathway may be especially critical for dopamine neurons affected in Parkinson's disease, in which the mitochondrial network is

ZX703: A Small-Molecule Degrader of GPX4 Inducing Ferroptosis in Human Cancer Cells.

Ferroptosis is a novel form of oxidative cell death triggered by iron-dependent lipid peroxidation. The induction of ferroptosis presents an attractive therapeutic strategy for human diseases, such as prostate cancer and breast cancer. Herein, we describe our design, synthesis, and biological evaluation of endogenous glutathione peroxidase 4 (GPX4) degraders using the proteolysis targeting chimera (PROTAC) approach with the aim of inducing ferroptosis in cancer cells. Our efforts led to the discovery of compound 5i (ZX703), which significantly degraded GPX4 through the ubiquitin-proteasome and

ATXN3: a multifunctional protein involved in the polyglutamine disease spinocerebellar ataxia type 3.

ATXN3 is a ubiquitin hydrolase (or deubiquitinase, DUB), product of the ATXN3 gene, ubiquitously expressed in various cell types including peripheral and neuronal tissues and involved in several cellular pathways. Importantly, the expansion of the CAG trinucleotides within the ATXN3 gene leads to an expanded polyglutamine domain in the encoded protein, which has been associated with the onset of the spinocerebellar ataxia type 3, also known as Machado-Joseph disease, the most common dominantly inherited ataxia worldwide. ATXN3 has therefore been under intensive investigation for decades. In th

A Pellino-2 variant is associated with constitutive NLRP3 inflammasome activation in a family with ocular pterygium-digital keloid dysplasia.

Ocular pterygium-digital keloid dysplasia (OPDKD) is a rare hereditary disease characterized by corneal ingrowth of vascularized conjunctival tissue early in life. Later, patients develop keloids on fingers and toes but are otherwise healthy. In a recently described family with OPDKD, we report the presence of a de novo c.770C > T, p.(Thr257Ile) variant in PELI2 in the affected individual. PELI2 encodes for the E3 ubiquitin ligase Pellino-2. In transgenic U87MG cells overexpressing Pellino-2 with the p.(Thr257Ile) amino acid substitution, constitutive activation of the NLRP3 inflammasome was o

VEXAS Syndrome-Review.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined refractory adult-onset autoinflammatory syndrome caused by somatic mutations in the ubiquitin-like modifier-activating enzyme 1 (UBA1) gene in hematopoietic stem and progenitor cells, resulting in a shift in UBA1 isoform expression. Thus, patients develop a spectrum of systemic inflammatory manifestations and hematologic symptoms. To date, patients respond poorly to immune suppressive drugs, except high-dose glucocorticoids, and no treatment guidelines have been established. Given the high mortality ra

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… They identified somatic mutations in myeloid-restricted ubiquitin-like modifier-activating enzyme 1 (UBA1) gene methionine-41 (p. … E1 Enzyme The UBA1 gene encodes the ubiquitin-activating enzyme (E1 enzyme) which is the crucial enzyme of cellular ubiquitylation. 14 Ubiquitination is a protein posttranslational modification process for the degradation of misfolded proteins, in which ubiquitin-activating (E1), conjugating (E2), and …

Research progress on the dermatomyositis specific autoantibodies and malignancy associated dermatomyositis.

Dermatomyositis (DM) is an autoimmune disease often complicated with malignant tumors. More than 50% of DM patients have myositis specific autoantibodies in their bodies. DM specific autoantibodies [including anti-migration inhibitory factor (Mi)-2 antibody, anti-nuclear matrix protein (NXP)-2 antibody, anti-transcription intermediary factor (TIF) 1-γ antibody, and anti-small ubiquitin like modifier activating enzyme (SAE) antibody] play important roles in the pathogenesis of malignancy associated DM. Revealing the role of DM specific autoantibodies in the development of malignant tumors in DM

Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, of the so-called minority diseases, due to its low prevalence. It is caused by an abnormally long track of glutamines (polyQs) in mutant huntingtin (mHtt), which makes the protein toxic and prone to aggregation. Many pathways of clearance of badly-folded proteins are disrupted in neurons of patients with HD. In this work, we show that one Mn(II) quinone complex (4QMn), designed to work as an artificial superoxide dismutase, is able to activate both the ubiquitin-proteasome system and the autophagy pathway in vitro a