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Cx47 Phosphorylation Exacerbates White Matter Damage and Kainic Acid Induced Epilepsy.

AIMS: Growing evidence implicates dysfunctional myelin in the pathogenesis of temporal lobe epilepsy (TLE). Connexin 47 (Cx47), an oligodendrocytic gap junction protein, maintains myelin integrity. This study investigates the role of Cx47 in myelin impairment and seizure progression in TLE. METHODS: Cx47 and phosphorylated Cx47 (p-Cx47) expression was analyzed in human and mouse TLE brain tissues via Western blot and immunofluorescence. Candidate Cx47 phosphorylation kinases revealed by single-cell RNA sequencing were validated through immunofluorescence, protein docking, and co-immunoprecipi…

Discovery and optimization of oxidative phosphorylation inhibitors from a phenotypic screen.

Tumor metabolism and metabolic reprogramming in cancer cells represent a promising area in oncology research, offering new avenues for therapeutic intervention. While the 'Warburg effect' highlights the reliance of many tumors on aerobic glycolysis, emerging evidence indicates that some cancers also depend on mitochondrial oxidative phosphorylation (OXPHOS) for energy production, cancer cell survival, tumor progression, metastasis, and drug resistance. We conducted a high-throughput, differential, phenotypic screening followed by a focused medicinal chemistry campaign, leading to the identific…

A Coordinated Translational Control Mediated by eEF2 Phosphorylation Safeguards Erythroid Differentiation.

Translational control is crucial for maintaining cellular homeostasis, yet the distinct features and regulatory requirements governing protein synthesis during erythropoiesis remain unclear. Here, we reveal that erythroid cells exhibit an extraordinarily high demand for protein synthesis, which is required for their differentiation but also implies the need for tight regulation to prevent excessive erythropoiesis. Notably, we identify significant phosphorylation of eukaryotic elongation factor 2 (eEF2) at threonine 56 during erythroid differentiation, which reduces protein synthesis and acts a…

Interactions between Tau Phosphorylation and Endoplasmic Reticulum Stress in Diabetic Nephropathy.

BACKGRUOUND: Tau is a microtubule-associated protein whose abnormal phosphorylation disrupts the cytoskeleton and induces cell death. While its role is well known in neurodegenerative diseases, its function in kidney pathology, particularly diabetic nephropathy (DN), is not well understood. METHODS: DN was induced in NADPH oxidase 5 (NOX5) pod+ mice through a high-fat diet (HFD; 60% kcal fat) for 3, 6, and 12 weeks. Kidney tissues and cultured mesangial cells were analyzed for tau phosphorylation at specific residues (Ser202 and Thr205), fibrosis markers (e.g., α-smooth muscle actin), and end…

Phosphorylation: new star of pathogenesis and treatment in steatotic liver disease.

Steatotic liver disease poses a serious threat to human health and has emerged as one of the most significant burdens of chronic liver disease worldwide. Currently, the research mechanism is not clear, and there is no specific targeted drug for direct treatment. Phosphorylation is widely regarded as the most common type of protein modification, closely linked to steatotic liver disease in previous studies. However, there is no systematic review to clarify the relationship and investigate from the perspective of phosphorylation. Phosphorylation has been found to mainly regulate molecule stabili…

Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva.

Heterotopic ossification (HO) is a non-physiological bone formation where soft tissue progenitor cells differentiate into chondrogenic cells. In fibrodysplasia ossificans progressiva (FOP), a rare genetic disease characterized by progressive and systemic HO, the Activin A/mutated ACVR1/mTORC1 cascade induces HO in progenitors in muscle tissues. The relevant biological processes aberrantly regulated by activated mTORC1 remain unclear, however. RNA-sequencing analyses revealed the enrichment of genes involved in oxidative phosphorylation (OXPHOS) during Activin A-induced chondrogenesis of mesenc…

Human neural stem cell-derived artificial organelles to improve oxidative phosphorylation.

Oxidative phosphorylation (OXPHOS) in the mitochondrial inner membrane is a therapeutic target in many diseases. Neural stem cells (NSCs) show progress in improving mitochondrial dysfunction in the central nervous system (CNS). However, translating neural stem cell-based therapies to the clinic is challenged by uncontrollable biological variability or heterogeneity, hindering uniform clinical safety and efficacy evaluations. We propose a systematic top-down design based on membrane self-assembly to develop neural stem cell-derived oxidative phosphorylating artificial organelles (SAOs) for targ…

Mass spectrometry identifies tau C-terminal phosphorylation cluster during neuronal hyperexcitation.

Tau is a microtubule-associated protein implicated in Alzheimer's disease (AD) and other neurodegenerative disorders termed tauopathies. Pathological, aggregated forms of tau form neurofibrillary tangles (NFTs), impairing its ability to stabilize microtubules and promoting neurotoxicity. Indeed, NFTs correlate with neuronal loss and cognitive impairment. Hyperphosphorylation of tau is seen in all tauopathies and mirrors disease progression, suggesting an essential role in pathogenesis. However, hyperphosphorylation remains a generic and ill-defined term, obscuring the functional importance of …

Novel mTORC2/HSPB4 Взаимодействие: роль и регулирование HSPB4 T148 фосфорилации.

HSPB4 и HSPB5 (α-кристаллины) демонстрируют растущие надежды в качестве нейропозащитных агентов, демонстрируя несколько антиапоптотических и защитных функций в таких расстройствах, как множественный склероз и диабетическая ретинопатия. ХОСТРАГ в значительной степени регулируются послепереходной модификацией, включая деамидацию, гликозилу и фосфорилацию. В частности, было продемонстрировано, что фосфориляция Т148 регулирует структурные и функциональные характеристики HSPB4 и частично определяет ее нейрозащитную способность. Недавно мы продемонстрировали, что фосфорилация уменьшается в сетчатках

Совпадение в аннотации оригинала
HSPB4 and HSPB5 (α-crystallins) have shown increasing promise as neuroprotective agents, demonstrating several anti-apoptotic and protective roles in disorders such as multiple sclerosis and diabetic retinopathy. HSPs are highly regulated by post-translational modification, including deamidation, glycosylation, and phosphorylation. Among them, T148 phosphory…

Dynamic regulatory phosphorylation of mouse CDK2 occurs during meiotic prophase I.

During prophase I of meiosis, DNA double-strand breaks form throughout the genome, with a subset repairing as crossover events, enabling the accurate segregation of homologous chromosomes during the first meiotic division. The mechanism by which DSBs become selected to repair as crossovers is unknown, although the crossover positioning and levels in each cell indicate it is a highly regulated process. One of the proteins that localises to crossover sites is the serine/threonine cyclin-dependent kinase CDK2. Regulation of CDK2 occurs via phosphorylation at tyrosine 15 (Y15) and threonine 160 (T…

Real-time observation of functional specialization among phosphorylation sites in CFTR.

Phosphoregulation is ubiquitous in biology. Defining the functional roles of individual phosphorylation sites within a multivalent system remains particularly challenging. We have therefore applied a chemical biology approach to light-control the state of single candidate phosphoserines in the canonical anion channel CFTR while simultaneously measuring channel activity. The data show striking non-equivalency among protein kinase A consensus sites, which vary from <10% to >1,000% changes in channel activity upon phosphorylation. Of note, slow phosphorylation of S813 suggests that this site is r…

Status of Mitochondrial Oxidative Phosphorylation during the Development of Heart Failure.

Mitochondria are specialized organelles, which serve as the "Power House" to generate energy for maintaining heart function. These organelles contain various enzymes for the oxidation of different substrates as well as the electron transport chain in the form of Complexes I to V for producing ATP through the process of oxidative phosphorylation (OXPHOS). Several studies have shown depressed OXPHOS activity due to defects in one or more components of the substrate oxidation and electron transport systems which leads to the depletion of myocardial high-energy phosphates (both creatine phosphate …

Piperine ameliorates psoriatic skin inflammation by inhibiting the phosphorylation of STAT3.

Psoriasis is a common chronic inflammatory skin disease that is easy to relapse and difficult to cure. Piperine is the main alkaloid extract … roteins in IMQ-induced psoriasiform dermatitis. Moreover, we determined that piperine inhibited the phosphorylation of STAT3 in M5- and IMQ-induced psoriasis-like skin lesions. Our data demonstrated that piperine ameliorated psoriatic skin inflammation by inhibiting the phosphorylation of STAT3. Therefore, piperine may be one potential compound candidate for psor …

Novel Conformation-Dependent Tau Antibodies Are Modulated by Adjacent Phosphorylation Sites.

Tau proteins within the adult central nervous system (CNS) are found to be abnormally aggregated into heterogeneous filaments in neurodegene … o218-Glu222, but are sensitive to denaturing conditions and highly modulated by adjacent downstream phosphorylation sites. These epitopes are present in the neuropathological hallmarks of several tauopathies, including AD, PiD, CBD, and PSP. These novel antibodies will further enable investigation of tau-dependent pathological inclusion formation and enhance our …

RBM20 phosphorylation and its role in nucleocytoplasmic transport and cardiac pathogenesis.

Arginine-serine (RS) domain(s) in splicing factors are critical for protein-protein interaction in pre-mRNA splicing. Phosphorylation of RS domain is important for splicing control and nucleocytoplasmic transport in the cell. RNA-binding motif 20 (RBM20) is a splicing factor primarily expressed in the heart. A previous study using phospho-antibody against RS domain showed that RS domain can be phosphorylated. However, its actual phosphorylation sites and function have not been characterized. Using middle-down mass spectrometry, we identified 16 phosphorylation sites, two of which (S638 and S64…

MeCP2 heterochromatin organization is modulated by arginine methylation and serine phosphorylation.

Rett syndrome is a human intellectual disability disorder that is associated with mutations in the X-linked MECP2 gene. The epigenetic reader MeCP2 binds to methylated cytosines on the DNA and regulates chromatin organization. We have shown previously that MECP2 Rett syndrome missense mutations are impaired in chromatin binding and heterochromatin reorganization. Here, we performed a proteomics analysis of post-translational modifications of MeCP2 isolated from adult mouse brain. We show that MeCP2 carries various post-translational modifications, among them phosphorylation on S80 and S421, wh…

Mitochondrial oxidative phosphorylation response overrides glucocorticoid-induced stress in a reptile.

Stress hormones and their impacts on whole organism metabolic rates are usually considered as appropriate proxies for animal energy budget t … tigated whole organism metabolism, muscle cellular O2 consumption and liver mitochondrial oxidative phosphorylation processes (O2 consumption and ATP production) and ROS production. The data showed that while skeletal muscle is not impacted, stress regulates the liver mitochondrial functionality in a time-dependent manner with opposing pictures between the differ …

Tyrosine phosphorylation tunes chemical and thermal sensitivity of TRPV2 ion channel.

Transient receptor potential vanilloid 2 (TRPV2) is a multimodal ion channel implicated in diverse physiopathological processes. Its important involvement in immune responses has been suggested such as in the macrophages' phagocytosis process. However, the endogenous signaling cascades controlling the gating of TRPV2 remain to be understood. Here, we report that enhancing tyrosine phosphorylation remarkably alters the chemical and thermal sensitivities of TRPV2 endogenously expressed in rat bone marrow-derived macrophages and dorsal root ganglia (DRG) neurons. We identify that the protein tyro…

Role of VP30 Phosphorylation in Ebola Virus Nucleocapsid Assembly and Transport.

Ebola virus (EBOV) VP30 regulates viral genome transcription and replication by switching its phosphorylation status. However, the importance of VP30 phosphorylation and dephosphorylation in other viral replication processes such as nucleocapsid and virion assembly is unclear. Interestingly, VP30 is predominantly dephosphorylated by cellular phosphatases in viral inclusions, while it is phosphorylated in the released virions. Thus, uncertainties regarding how VP30 phosphorylation in nucleocapsids is achieved and whether VP30 phosphorylation provides any advantages in later steps in viral repli…

Serum response factor deletion 5 regulates phospholamban phosphorylation and calcium uptake.

AIMS: Pediatric dilated cardiomyopathy (pDCM) is characterized by unique age-dependent molecular mechanisms that include myocellular responses to therapy. We previously showed that pDCM, but not adult DCM patients respond to phosphodiesterase 3 inhibitors (PDE3i) by increasing levels of the second messenger cAMP and consequent phosphorylation of phospholamban (PLN). However, the molecular mechanisms involved in the differential pediatric and adult response to PDE3i are not clear. METHODS AND RESULTS: Quantification of serum response factor (SRF) isoforms from the left ventricle of explanted h…