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Amine oxide lipid nanoparticles for delivery of cyclic dinucleotides.

The clinical potential of cyclic dinucleotides (CDNs) as potent agonists of the stimulator of interferon gene (STING) has been hampered by t … 6.8%. Compared to cationic liposomes, AOL-incorporating LNP exhibits superior tumor penetration and cytosolic cargo delivery, eliciting broad and potent intratumoral STING activation. In line with growing emphasis on combination therapy in oncology, we further incorporate lipidated mitoxantrone in the LNP as an inducer of immunogenic cell death to enhance …

Prodh2-Mediated Mitochondrial Stress Drives TNF-α-Induced Myoblast Dysfunction and Sarcopenia in COPD.

Sarcopenia in chronic obstructive pulmonary disease (COPD) is driven by elevated tumor necrosis factor-alpha (TNF-α), yet the underlying mechanism remains unclear. Here, we identify the mitochondrial metabolic enzyme Prodh2 as a pivotal mediator. Prodh2 was significantly upregulated in sarcopenic COPD patients and a corresponding mouse model. Mechanistically, TNF-α induced Prodh2 transcription in myoblasts via a p53-dependent pathway. This upregulation triggered excessive mitochondrial reactive oxygen species, leading to the release of mitochondrial DNA (mtDNA). Cytosolic mtDNA subsequently ac…

Atomic-Level Structures Reveal How a Repurposed 3‑Aminopyrazine-2-carboxamide Scaffold Inhibits Mycobacterium tuberculosis Prolyl-tRNA Synthetase.

Tuberculosis (TB) is again the world's leading cause of death from a single infectious agent. Aminoacyl-tRNA synthetases are essential for p … t disrupt the proline pocket, supporting a dual-site mechanism of inhibition. Comparison with human cytosolic and mitochondrial ProRS reveals differences in active-site residues, electrostatics, and dynamics that explain species selectivity. Together, these structures provide a framework for designing next-generation, Mtb-selective ProRS inhibitors as new …

Yeast-Based High-Throughput Screening Platform for Identifying Modulators of Mitochondrial Protein Import.

Mitochondrial protein import is essential for overall cellular homeostasis, yet scalable approaches to systematically interrogate mitochondr … chondrial protein import is coupled to an auxotrophic growth readout. Disruption of import leads to cytosolic accessibility of the URA3 reporter, producing a GoG phenotype under selective conditions. As a proof of concept, we applied this model to PTEN-induced kinase 1 (PINK1), a mitochondrial imported regulator of mitochondrial quality control. Using thi …

Elevation of the mechanically-sensitive e protein emerin links nuclear mechanotransduction to tau-induced cytoskeletal remodeling in neurons.

Neurodegenerative tauopathies, including Alzheimer's disease, are neuropathologically defined by pathological tau deposition. While tau driv … ion, mimicking cellular phenotypes of tauopathy. Alterations in emerin binding partners reflect its cytosolic relocalization in iTau neurons, suggesting that pathogenic tau may impact nuclear mechanotransduction by altering emerin levels and localization. Overall, we identify emerin as a potential mediator of cytoskeletal and nucleoskeletal remodeling in …

Expression of Active Apurinic Apyrimidinic Endodeoxyribonuclease 1 in Human Platelets.

The pivotal role of platelets (PLTs) in hemostasis, thrombosis, innate immunity, and tissue repair is sustained by mitochondria, whose dysfunctions can impair ATP generation and redox signaling, thus affecting optimal levels of PLTs' functionality. Maintenance of mtDNA integrity is essential for mitochondria functioning and is primarily exerted by the base excision repair (BER) pathway, never described in PLTs. Here, we provide the first evidence for the expression levels and subcellular localization of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1), evaluated alongside cytosolic and mit…

Expression and Detection of Heterologous Proteins in Ustilago maydis.

Expression of transgenes of both bacterial and eukaryotic origin is critical for the versatility of model species. A range of heterologous genes has been successfully transplanted to and cognate proteins functionally synthesized in Ustilago maydis, ranging from cytosolic reporters like the enhanced green fluorescent protein and its derivatives to cytoplasmic or secreted enzymes from bacterial, plant, or filamentous ascomycete sources. Here, a brief summary of the most important considerations for expression of heterologous genes, including expression strain selection, codon optimization, the c…

Plant organelle division orchestrated by the mosaic machinery of endosymbiotic relics and eukaryotic host factors.

Plastids retain the imprint of their cyanobacterial ancestry by dividing primarily through binary fission. This process is executed by elabo … positioning factors, the stromal FtsZ ring, envelope-associated ARC6, PARC6, and PDV proteins, and cytosolic ARC5/DRP5B proteins, which act in concert to position the division site and drive plastid separation under developmental and environmental regulation. Comparisons with mitochondrial and peroxisomal proliferation unveil shared division factors amon …

Tail approach synthesis of novel benzenesulfonamides incorporating 1,4-disubstituted triazole hybrids as potent inhibitors of carbonic anhydrase I, II, IX and XII isoenzymes.

A series of twenty novel 1,4-disubstituted-1,2,3-triazole containing benzenesulfonamides were designed, synthesized and evaluated for their inhibition potential against human carbonic anhydrase (hCA) isoforms I, II, IX and XII. Most of the newly synthesized sulfonamides moderately inhibited the physiologically important and off-target isoform hCA II while the cytosolic isoform hCA I was weakly inhibited with inhibition constants (KIs) in the low nanomolar range (KI = 65.2 nM-2.590 μM). Cytotoxicity studies were also carried out for all synthesized compounds, along with in-silico ADMET and drug…

Ligand-induced activation of RyR1 in native membranes.

Synchronized calcium release through arrays of the ryanodine receptor RyR1, fundamental to skeletal muscle excitation-contraction coupling, … mpared with purified RyR1s, receptors in native membranes follow an activation pathway with reduced cytosolic-shell tilt and greater consecutive in-plane rotation. Activation-induced rotation remodels the inter-receptor interface, lowering the energy barrier to the cooperative opening of the receptor cluster. Our analysis demonstrates how the native membr …

Tissue tension permits β-catenin phosphorylation to drive mesoderm specification in human embryonic stem cells.

The role of morphogenetic forces in cell fate specification is an area of intense interest. Using an ectopically expressed nonphosphorylatab … 4 initiates a force-dependent junctional β-catenin translocation upstream of both Wnt secretion and cytosolic Wnt/β-catenin stabilization to drive mesoderm specification. Ultimately, our work highlights the importance of force-dependent Wnt/β-catenin signaling in the self-organization of tissues during developmental processes, such as gastrulation, and em …

The polymerized protein response (PPR) is activated by genetic variants that polymerize in the ER and is mediated by NFκBp50.

In previous studies we have shown that accumulation of the polymerogenic variant ATZ that causes α1-antitrypsin deficiency (ATD) activates N … cytoplasm and nucleus. The PPR is blocked by specific genetic substitutions within the luminal and cytosolic domains of Derlin-2 providing evidence that the ERAD retrotranslocation complex is a proximal transducer of this signaling mechanism. We hypothesize that the PPR is a proteostasis response pathway complementary to the UPR, designed to protect the …

PTPN22 mediates delayed negative feedback of T cell activation by forming an inhibitory signaling complex.

PTPN22 is a cytosolic tyrosine phosphatase expressed in immune cells that negatively regulates T cell receptor (TCR) signaling and implicated in autoimmune diseases through a common (R620W) variant. The molecular mechanisms by which PTPN22 modulates TCR activation remain incompletely understood. Here we show that upon T cell activation, PTPN22 forms delayed clusters at TCR microclusters (MCs) alongside Csk, STS-1 and PSTPIP, constituting a feedback inhibitory complex. Using imaging analyses, MS, and knockout mouse models, we demonstrate that this complex functions as a delayed negative regulat…

Overcoming Cellular Barriers with Cell-Penetrating Peptides: Functional Roles of Individual Amino Acids.

The delivery efficiency of cell-penetrating peptides (CPPs) is much lower than that of other non-viral delivery systems, mainly because of cellular barriers such as the plasma membrane, endosomal acidification, cytosolic degradation, and nuclear entry. The plasma membrane is a significant extracellular barrier that regulates the entry of biomolecules into cells. This challenge can be addressed by using peptides containing functional groups, such as basic amino acids. After internalization, CPPs must cross intercellular barriers, and their ability to do so mainly depends on the specific amino a…

Loss of killifish cGAS attenuates age-related signatures but does not affect organismal life span.

The cGAS/STING pathway is a central innate immune signaling pathway responsive to cytosolic DNA. Chronic activation of this pathway promotes numerous age-related pathologies, but its impact on lifespan remains unknown. Here we engineer a cGAS knockout (KO) in the turquoise killifish Nothobranchius furzeri to assess effects on physiology and aging. In cultured fibroblasts, cGAS deficiency results in elevated DNA damage but reduces radiation-induced senescence and enhances cellular proliferation. In vivo, cGAS KO attenuates DNA damage-induced transcriptional responses in young fish, and blunts a…

Проектирование, биологическая характеристика и открытие мозгового питанта NLRP3 Inhibitor на основе [1,2,4]Триазоло[1,5- а) Пиримидин Скаффольд для лечения заболеваний центральной нервной системы.

NLRP3 является критическим цитосолическим многопротеиновым комплексом, центральным для врожденной иммунной реакции. После активации NLRP3 олигомеризирует и вербует адаптационный протеин ASC; этот ломафольд рекрутирует и активирует pro-caspase-1. Активные caspase-1 катализирует протеолитическое созревание и секрецию мощных про-воспаление цитокиновых ил--1β и IL-18, и вызывает запрограммированную клеточную смерть под названием пироптоз. Регулируемая или хроническая активация NLRP3 воспаления является одним из основных факторов патогенеза в широком спектре периферийных подстрекательских заболеван

Совпадение в аннотации оригинала
NLRP3 inflammasome is a critical cytosolic multiprotein complex central to the innate immune response. Upon activation, NLRP3 oligomerizes and recruits the adapter protein ASC; this scaffold recruits and activates pro-caspase-1. Active caspase-1 catalyzes the proteolytic maturation and secretion of the potent pro-inflammatory cytokines IL-1β and IL-18, and i…

Cleavage of CAD by caspase-3 determines the cancer cell fate during chemotherapy.

Metabolic heterogeneity resulting from the intra-tumoral heterogeneity mediates massive adverse outcomes of tumor therapy, including chemotherapeutic resistance, but the mechanisms inside remain largely unknown. Here, we find that the de novo pyrimidine synthesis pathway determines the chemosensitivity. Chemotherapeutic drugs promote the degradation of cytosolic Carbamoyl-phosphate synthetase II, Aspartate transcarbamylase, and Dihydroorotase (CAD), an enzyme that is rate-limiting for pyrimidine synthesis, leading to apoptosis. We also find that CAD needs to be cleaved by caspase-3 on its Asp1…

The integral membrane protein smim4 modulates redox balance via malate compartmentalization in pancreatic cancer.

Reshaping metabolic compartmentalization is frequently observed in cancer cells, however, the underlying mechanisms and physiological implic … by reshaping of malate compartmentalization. This shift promotes NADPH generation through increased cytosolic conversion of malate to pyruvate, protecting cells from glucose deprivation-induced apoptosis. Moreover, PDAC cells with low level of SMIM4 are resistant to RSL3-induced toxicity, indicating that PDAC tumors with high SMIM4 expression are promisin …

Novel Perspectives in Hepatic Ischemia-Reperfusion Injury: The cGAS-STING Pathway.

In hepatic ischemia-reperfusion injury (HIRI), the cGAS-STING pathway serves as a central regulatory hub by sensing aberrant mitochondrial DNA (mtDNA) release. Ischemia-reperfusion triggers mtDNA leakage through mechanisms including mitochondrial permeability transition pore (mPTP) opening, voltage-dependent anion channel (VDAC) oligomerization, and excessive fission. Cytosolic mtDNA activates cyclic GMP-AMP synthase (cGAS), catalyzing the synthesis of cGAMP, which stimulates stimulator of interferon genes (STING) oligomerization and translocation. This activates the TBK1-IRF3/NF-κB axis, driv…

Induced proximity to PML protects TDP-43 from aggregation via SUMO-ubiquitin networks.

The established role of cytosolic and nuclear inclusions of TDP-43 in the pathogenesis of neurodegenerative disorders has multiplied efforts to understand mechanisms that control TDP-43 aggregation and has spurred searches for approaches limiting this process. Formation and clearance of TDP-43 aggregates are controlled by an intricate interplay of cellular proteostasis systems that involve post-translational modifications and frequently rely on spatial control. We demonstrate that attachment of the ubiquitin-like SUMO2 modifier compartmentalizes TDP-43 in promyelocytic leukemia protein (PML) n…