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Tyr39 Phosphorylation of α-Synuclein Accelerates Heterotypic Aggregation and Drives Toxic Amplification.

c-Abl-mediated Tyr39 phosphorylation of α-synuclein correlates strongly with Parkinson's disease (PD) progression, yet the mechanistic basis of Tyr39-phosphorylated α-synuclein (pY39-α-syn) in synucleinopathies remains elusive. Here, we show that a minor fraction of pY39-α-syn markedly accelerates the aggregation of wild-type α-synuclein (WT-α-syn), overriding the inhibitory effect of Hsc70. Kinetics, continuous-wave electron paramagnetic resonance (EPR), cryo-transmission electron microscopy (cryo-TEM), and [15N,1H]-NMR spectral analyses reveal that pY39-α-syn participates in primary nucleati…

Withania somnifera (Ashwagandha) Improves Fitness in Aged Drosophila by Reducing AKT Phosphorylation.

With increasing global life expectancy, there is a growing need for strategies to mitigate age-related declines in fitness and health. Witha … es were treated at middle-age (4 weeks from eclosion) for two weeks. We found that WSAq reduced Akt phosphorylation in fly heads and that Akt is required to improve fitness in the fast phototaxis assays. We also determined that the effects of WSAq treatment depended on the Akt downstream pathways Tsc/mTOR, FOXO, and NRF. This supports that WS provides resilience …

Integrated omics analyses reveal natamycin disrupts oxidative phosphorylation pathways in Magnaporthe oryzae.

Magnaporthe oryzae, the causative agent of rice blast, is a devastating fungal pathogen that threatens global rice production. While natamyc … ption of key metabolic processes, including amino acid biosynthesis and, most critically, oxidative phosphorylation. Functional validation suggested the involvement of oxidative phosphorylation, as overexpression of two key genes in this pathway MGG_17901 and MGG_04969 conferred significant natamycin tolerance to the fungus. Consistent with this, the overexpressi …

Halofuginone induces ERK phosphorylation and synergizes with trametinib in gastric cancer cells.

OBJECTIVE: The aim of this study was to investigate the effects of halofuginone (HF) on gastric cancer cells and whether the combination of HF and trametinib has synergistic effects. INTRODUCTION: Halofuginone, a natural small molecule isolated from the plant Dichroa febrifuga, has been found to have anticancer activity in a variety of cancers, but few studies on HF in gastric cancer. METHODS: cell viability was performed using the CellTiterGlo assay and apoptosis and cell cycle analysis was performed by Annexin V-FITC staining and PI staining. We also analyzed RNA sequencing and differentia

Deciphering the phosphorylation-based regulatory strategies of Haemaphysalis longicornis in heat stress.

BACKGROUND: The Asian hard tick (Haemaphysalis longicornis) is an obligate hematophagous ectoparasite belonging to the family Ixodidae (hard … ticks adopt effective behavioral strategies and physiological adaptations to cope with heat stress. Phosphorylation, a kind of important protein post-translational modification (PTM), is vital for cellular signal transduction, gene expression, and rapid cell cycle regulation. METHODS: This study systematically analyzed phosphorylation changes in proteins from th …

Seed structure and phosphorylation in the fuzzy coat impact tau seeding competency.

Tau misfolding into β-sheet-rich filaments and subsequent recruitment of monomeric tau are central to Alzheimer's disease (AD) pathogenesis. … fficient to fully replicate AD tau's biological activity. The unstructured fuzzy coat, particularly phosphorylation within this region, is essential for full seeding competence. Importantly, recombinant tau filaments bearing twelve phospho-mimetic residues (PAD12 tau) and adopting the AD fold recapitulate the seeding activity of native AD tau. These results demon …

GnomAD Missense Variants of Uncertain Significance: Implications for p53 Stability and Phosphorylation.

The TP53 gene, frequently mutated across multiple cancer types, plays a pivotal role in regulating the cell cycle and apoptosis through its protein, p53. Missense variants of uncertain significance (VUSs) in TP53 present challenges in understanding their impact on protein function and complicate clinical interpretation. This study aims to analyze the effects of missense VUSs in p53, as reported in the gnomAD database, with a specific focus on their impact on protein stability and phosphorylation. In this study, 33 missense VUSs in TP53 reported in the gnomAD database were analyzed using in sil…

Protein interactions, calcium, phosphorylation, and cholesterol modulate CFTR cluster formation on membranes.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel whose dysfunction leads to intracellular accumulation o … , calcium, and membrane cholesterol can induce mesoscale CFTR cluster formation on model membranes. Phosphorylation of the intracellular domains of CFTR also promotes mesoscale cluster formation in the absence of calcium, indicating that multiple mechanisms can contribute to CFTR cluster formation. Our findings reveal that coupling of multivalent protein and lipi …

Nrf2 phosphorylation contributes to acquisition of pericyte reprogramming via the PKCδ pathway.

Pericytes (PCs) are vascular mural cells embedded in the basement membrane of micro blood vessels. It has been proposed using a C.B-17 mouse … bitor treatment also suppressed the production of iPCs. These results suggest the potential of Nrf2 phosphorylation via PKCδ as a novel strategy for the treatment of ischemic injury.

MIOX Aggravated DEHP-Induced Ferroptosis in Chicken Hepatocytes by Targeting STAT3 Phosphorylation.

Global health issues have been heightened by di-(2-ethylhexyl) phthalate (DEHP), a commonly utilized plasticizer, due to its liver toxicity and potential to cause liver damage. Ferroptosis, a type of nonapoptotic cell death reliant on iron, is associated with multiple liver disorders. This research aimed to explore the role and mechanisms of ferroptosis in DEHP-induced liver toxicity in chickens. In vivo experiments showed that DEHP exposure caused liver damage. Transcriptomic analysis revealed that DEHP exposure activated ferroptosis and significantly upregulated myo-inositol oxygenase (MIOX)

A Methanolic Urea-Enhanced Protein Extraction Enabling the Largest Bacterial Phosphorylation Resource.

Mass spectrometry (MS)-based phosphoproteomics analysis is a powerful approach for elucidating the regulatory roles of protein phosphorylation across all domains of life. However, bacterial phosphoproteomics still faces significant technical challenges due to the extremely low substoichiometry of phosphorylation evens and the structural complexity of bacterial cell envelopes, which impede efficient cell lysis, protein recovery, and purity. To address these obstacles, we developed Methanolic Urea-enhanced Protein Extraction (MUPE), a streamlined, detergent-free, solvent-based method that levera…

Nuclear DAB2IP regulates DNA replication initiation through activating PLK1-mediated HBO1 phosphorylation.

DAB2IP (Disabled homolog 2 interacting protein), a recognized tumor suppressor, plays a pivotal role in regulating various oncogenic pathways. Our previous research demonstrated that DAB2IP functions as a cell cycle regulator by facilitating PLK1-mediated mitosis progression. Here, we elucidate a novel function of DAB2IP in promoting DNA replication origin firing. Mechanistically, we identified that DAB2IP localizes to the nucleus, where it interacts with the histone acetyltransferase HBO1 and enhances the HBO1-PLK1 interaction. DAB2IP facilitates PLK1-mediated phosphorylation of HBO1, which s…

Manganese mediates antiviral effects by driving an ATM -TBK1 phosphorylation signaling pathway.

We previously reported that manganese (Mn) enhances innate immune responses to viral infection by inducing phosphorylation of TANK-binding kinase 1 (TBK1) in an Ataxia-telangiectasia mutated (ATM)-dependent manner. However, the underlying mechanism by which how Mn induces TBK1 phosphorylation remained unclear. Here, we show that Mn dose-dependently induced TBK1 phosphorylation in the presence of ATM across multiple cell lines, as well as in primary human macrophages and T cells. This phosphorylation was abolished in ATM-deficient cells, and we identified cytoplasmic ATM as a key mediator. Immu…

Manganese mediates antiviral effects by driving an ATM -TBK1 phosphorylation signaling pathway.

Ataxia-telangiectasia mutated (ATM) is traditionally recognized as a nuclear kinase involved in DNA damage repair. We were the first to report that ATM also participates in a manganese (Mn)-dependent TBK1 phosphorylation pathway. However, the underlying mechanism by which how Mn induces TBK1 phosphorylation through ATM remained unclear. Here, we show that Mn dose-dependently induced TBK1 phosphorylation in the presence of ATM across multiple cell lines, as well as in primary human macrophages and T cells. This phosphorylation was abolished in ATM-deficient cells, and we identified cytoplasmic …

Phosphorylation-State Modulated Binding of HSP70: Structural Insights and Compensatory Protein Engineering.

Protein quality control is crucial for cellular homeostasis, involving the heat shock response, the ubiquitin-proteasome system, and the autophagy-lysosome pathway. Central to these systems are the chaperone homologs heat shock protein 70 (HSP70) and heat shock cognate 70 (HSC70), which manage protein folding and degradation. This study investigated the impact of the C-terminal phosphorylation of HSP70 on its interaction with the co-chaperone CHIP (C-terminus of HSC70 interacting protein), an E3 ligase that ubiquitinates protein substrates for degradation. Using both cell-free and cell-based a…

Electrical stimulation promotes peripheral nerve regeneration by upregulating glycolysis and oxidative phosphorylation.

Peripheral nerve injury (PNI) frequently results in motor and sensory dysfunction due to the limited regenerative capacity of axonal neurons … rgy metabolism in the sciatic nerve post-PNI by enhancing glucose uptake, glycolysis, and oxidative phosphorylation. Furthermore, ES increased the expression of neurotrophic factors and modulated the AMPK/mTOR/p70S6K signaling pathway, which are crucial for cellular metabolism and nerve regeneration. Collectively, these findings underscore the critical role of ES …

Oxidative Phosphorylation Pathway in Ankylosing Spondylitis: Multi-Omics Analysis and Machine Learning.

INTRODUCTION: Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the axial skeleton, characterized by immune microenvironment dysregulation and elevated cytokines like TNF-α and IL-17. Mitochondrial oxidative phosphorylation (OXPHOS), crucial for immune cell function and survival, is implicated in AS pathogenesis. This study explores OXPHOS-related mechanisms in AS, identifies key genes using machine learning, and highlights potential therapeutic targets for precision medicine. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) bulk transcriptomic and singl…

STAT3 S727 фосфорилация вызывает патогенную дифференциацию ТH17 и нейроинфламмацию в аутоиммунной болезни.

Telper 17 (Th17) — разнородная подгруппа клеток CD4+T, которая выступает посредником в защите хост-компьютеров и патологии аутоиммунной системы. Хотя фосфорилирование СТАТ3 в тиросине 705 (Y705) имеет важное значение для дифференциации Тх17, функциональная роль серин 727 (S727) фосфорилации остается нерешенной. Здесь мы показываем, что СТАТ3 S727 фосфорилирование избирательно требуется для дифференциации и функции воздействия патогенных клеток TH17 (pTH17). Механистически, S727 фосфорилирование облегчает взаимодействие STAT3 с транскрипционными сорегуляторами и хроматином, реконструирующими ко

Совпадение в аннотации оригинала
T helper 17 (Th17) cells are a heterogeneous subset of CD4⁺ T cells that mediate host defense and drive autoimmune pathology. While phosphorylation of STAT3 at tyrosine 705 (Y705) is essential for Th17 differentiation, the functional role of serine 727 (S727) phosphorylation remains unresolved. Here, we show that STAT3 S727 phosphorylation is selectively req…

HNF4α-CDKL3 axis restricts MASLD progression by targeting FoxO1 via noncanonical phosphorylation.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease with a broad spectrum of symptoms. Though mild in early stages, further development of MASLD causes steatohepatitis, cirrhosis, liver cancers, and accompanied diabetes. Discovery of the critical regulators in MASLD progression hold great values in both basic and translational medicine. APPROACH AND RESULTS: Herein, we identified cyclin-dependent kinase-like 3 (CDKL3) as a primary guardian against MASLD progression. Mice with liver-specific Cdkl3 ablation developed severe MASLD-related

Increased LACTB2 Expression Regulates Oxidative Phosphorylation and mTORC1 Signaling of Colorectal Cancer.

This study aimed to investigate the mechanisms of LACTB2 in colorectal cancer (CRC). Microarrays and sequencing data of CRC were acquired fr … to DNA synthesis and repair, mitochondrial translational elongation and translational termination, phosphorylation, and mTORC1 signaling. Finally, molecular docking simulations confirmed the ability of quercitin to target and bind to LACTB2. This is the first study to demonstrate that LACTB2 is upregulated in CRC. LACTB2 promotes colorectal tumorigenesis and tum …