TMAO accelerates cellular aging by disrupting endoplasmic reticulum integrity and mitochondrial unfolded protein response

Cellular and Molecular Life Sciences, Год журнала: 2025, Номер 82(1)

Опубликована: Янв. 21, 2025

Язык: Английский

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Role of TMEM230 in the Aberrant Glycosylation in Human Autoimmunity and Cancer

Proteoglycan Research, Год журнала: 2025, Номер 3(1)

Опубликована: Янв. 1, 2025

ABSTRACT Alterations in glycoconjugate profiles are thought to promote changes cell‐to‐cell and cell‐to‐intracellular extracellular scaffold interactions human disease. The nearly unlimited number of “glycoforms” that may exist nature difficult study due glycosylation modifications being associated with non‐genome coded posttranscription post‐translation processes. Specific products generated by dependent on concentration sub‐cellular locations glycan synthesis processing enzymes. An indirect “high‐throughput” approach is characterize enzymes (hydrolases transferases) single cell sequencing all types tissue diseases. We previously identified TMEM230 as an endoplasmic reticulum (ER) protein regulates NOTCH glycoprotein receptor ligand signaling zebrafish blood vessel formation destructive remodeling capacities diverse including fibroblast, phagocytic immune system cells patients cancer or granulomatous systemic vasculitis autoimmune disorder. represents a paradigm mediated signal transduction supports the role modifications. ER initiates earliest steps synthesis, sorting, trafficking. As remodeling, Notch hallmarks disorders, we investigated whether aberrant expression was also rheumatoid arthritis (RA). In this current study, analysis supported downregulated synovial RA while were predominantly upregulated. contrast, upregulated high‐grade compared low‐grade gliomas it N‐linked (GlcNAc), glycosaminoglycan expression. Our collective results support glycan/glycoconjugate aggressive gliomas. therefore be therapeutic target marker for clinical treatment induced autoimmunity disorders cancer.

Язык: Английский

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Transmission of unfolded protein response—a regulator of disease progression, severity, and spread in virus infections

mBio, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

ABSTRACT The unfolded protein response (UPR) is a cell-autonomous stress aimed at restoring homeostasis due to the accumulation of misfolded proteins in endoplasmic reticulum (ER). Viruses often hijack host cell machinery, leading an ER. UPR immediate infected this stress, aiming restore normal function by halting translation, degrading proteins, and activating signaling pathways that increase production molecular chaperones. cell-non-autonomous involves spreading signals from initially stressed cells neighboring unstressed lack stressor. Though viruses are known modulators UPR, recent advancements have highlighted plays critical role elucidating how local infections cause systemic effects, thereby contributing disease symptoms progression. Additionally, utilizing devised novel strategies establish pro-viral state, promoting virus spread. This review discusses examples broadened understanding progression looking beyond non-autonomous processes mechanistic details inducers, spreaders, receivers signals.

Язык: Английский

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Structure and function of the EDEM:PDI ERAD checkpoint complex

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

The ERAD glycoprotein misfolding checkpoint complex de-mannosylates misfolded glycoproteins to enable retrotranslocation, ubiquitination, and proteasomal degradation. comprises an Endoplasmic Reticulum-Degradation Enhancing α-Mannosidase (EDEM) a Protein Disulfide Isomerase (PDI). We solved Cryo-EM structures of Chaetomium thermophilum ( Ct ) CtEDEM:CtPDI, both as the heterodimer with no client in α1-antitrypsin (A1AT-NHK). EDEM catalytic domain nests within PDI arc, while A1AT-NHK binds EDEM's C-terminal flexible domains. Mass spectrometry reveals disulfide bond between exposed Cys PAD EDEM. Co-transfection EDEM, A1AT-NHK, shifts EDEM:PDI higher molecular weight non-reducing SDS-PAGE. Redox chemistry bonds generates oxidized, demannosylation-competent reduced PDI, priming function reductase, facilitating retrotranslocation.

Язык: Английский

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PERK-Olating Through Cancer: A Brew of Cellular Decisions

Biomolecules, Год журнала: 2025, Номер 15(2), С. 248 - 248

Опубликована: Фев. 8, 2025

The type I protein kinase PERK is an endoplasmic reticulum (ER) transmembrane that plays a multifaceted role in cancer development and progression, influencing tumor growth, metastasis, cellular stress responses. activation of represents one the three signaling pathways induced during unfolded response (UPR), which triggered, particular, cells constitutively experience various intracellular extracellular stresses impair folding within ER. can lead to both pro-survival proapoptotic outcomes, depending on context extent ER stress. It helps reprogramming gene expression cells, thereby ensuring survival face oncogenic stress, such as replicative DNA damage, also microenvironmental challenges, including hypoxia, angiogenesis, metastasis. Consequently, contributes initiation, transformation, adaptation microenvironment, chemoresistance. However, sustained cell proliferation promote apoptotic death by interconnected processes, mitochondrial dysfunction, translational inhibition, accumulation stresses, specific induction multifunctional factors, CHOP. dual promoting progression suppression makes it complex target for therapeutic interventions. A comprehensive understanding intricacies pathway their impact essential effective strategies, particularly diseases like cancer, where deregulated most, if not all, solid liquid tumors. This article provides overview knowledge acquired from study animal models lines cultured vitro PERK’s functions thus highlighting potential new avenues could this protein.

Язык: Английский

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Glycosylation Regulation by TMEM230 in Aging and Autoimmunity

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(6), С. 2412 - 2412

Опубликована: Март 7, 2025

Aging is often a choice between developing cancer or autoimmune disorders, due in part to loss of self-tolerance immunological recognition rogue-acting tumor cells. Self-tolerance and cell by the immune system are processes very much dependent on specific signatures glycans glycosylated factors present plasma membrane stromal components tissue. Glycosylated generated nearly innumerable variations nature, allowing for immensely diverse role these aging flexibility necessary cellular interactions tissue functionality. In previous studies, we showed that differential expression TMEM230, an endoplasmic reticulum (ER) protein was associated with enzymes regulating glycan synthesis processing glycosylation rheumatoid arthritis synovial using single-cell transcript sequencing. this current study, characterize genes pathways co-modulated all types processing, as well glycosylation. Genes biological molecular hallmarks were mitochondria-dependent oxidative phosphorylation reactive oxygen species synthesis, ER-dependent stress unfolded response, DNA repair (UV response P53 signaling pathways), senescence, glycolysis apoptosis regulation through PI3K-AKT-mTOR have been shown play important roles neurodegeneration (such Parkinson’s Alzheimer’s disease). We propose downregulation TMEM230 RNASET2 may represent paradigm study age-dependent disorders their glycosylation, signaling.

Язык: Английский

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The role of endoplasmic reticulum stress in type 2 diabetes mellitus mechanisms and impact on islet function

PeerJ, Год журнала: 2025, Номер 13, С. e19192 - e19192

Опубликована: Март 28, 2025

Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder characterized by insulin resistance and dysfunction of islet cells. Endoplasmic reticulum (ER) stress plays crucial role in the pathogenesis progression T2DM, especially function survival β-cells. β-cells are particularly sensitive to ER because they require substantial synthesis secretion energy. In early stages increased demand for exacerbates β-cell stress. Although unfolded protein response (UPR) can temporarily alleviate this stress, prolonged or excessive leads pancreatic cell apoptosis, resulting insufficient secretion. This review explores mechanisms its impact on We discuss how activates UPR signaling pathways regulate folding degradation, but when becomes excessive, these may contribute death. A deeper understanding impacts cells could lead development novel T2DM treatment strategies aimed at improving slowing disease progression.

Язык: Английский

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A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth

PLoS Biology, Год журнала: 2025, Номер 23(4), С. e3003086 - e3003086

Опубликована: Апрель 10, 2025

Endoplasmic-reticulum resident inositol-requiring enzyme 1α (IRE1) supports protein homeostasis via its cytoplasmic kinase-RNase module. Known cancer dependency on IRE1 entails enzymatic activation of the transcription factor XBP1s and regulated RNA decay. We discovered that some cells surprisingly require but not activity. knockdown inhibition or XBP1 disruption attenuated cell cycle progression tumor growth. silencing led to TP53 CDKN1A/p21 in conjunction with increased DNA damage chromosome instability, while decreasing heterochromatin as well histone H3K9me3 methylation. Immunoelectron microscopy detected endogenous at nuclear envelope. Thus, co-opt either enzymatically nonenzymatically, which has significant implications for IRE1’s biological role therapeutic targeting.

Язык: Английский

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Interferon regulatory factor 4 mediates nonenzymatic IRE1 dependency in multiple myeloma cells

PLoS Biology, Год журнала: 2025, Номер 23(4), С. e3003096 - e3003096

Опубликована: Апрель 11, 2025

Multiple myeloma (MM) arises through oncogenic transformation of immunoglobulin-secreting plasma cells. MM often co-opts the central endoplasmic reticulum (ER)-stress mitigator, inositol-requiring enzyme 1 (IRE1), to sustain malignant growth. While certain MMs require enzymatic IRE1-dependent activation transcription factor XBP1s, others display a nonenzymatic IRE1 dependency that is not yet mechanistically understood. Here we identify interferon regulatory 4 (IRF4), which stimulates genes promote immune-cell proliferation, as key conduit for IRE1’s control cell-cycle progression in MM. silencing increased inhibitory S114/S270 phosphorylation on IRF4, disrupting IRF4’s chromatin-binding and transcriptional activity. IRF4 knockdown recapitulated, whereas repletion reversed anti-proliferative phenotype silencing. Furthermore, phospho-deficient, but phospho-mimetic, mutants rescued proliferation under Functional studies revealed engages E2F1 CDC25A promotes CDK2 drive progression. Our results advance mechanistic understanding

Язык: Английский

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ARM-X: an Adaptable Mesenchymal Stromal Cell-based Vaccination Plaftorm Suitable for Solid Tumors

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Апрель 23, 2025

Background: In addition to triggering endosomal escape, the Accum^® platform was recently reported for its ability instill antigen cross-presentation properties in mesenchymal stromal cells (MSCs). Despite promising results obtained with first-generation vaccine using A1 derivative (ARM vaccine), large quantities of cancer antigens were required achieve meaningful therapeutic effects. Given this limitation, additional variants engineered and tested their lower need quantities. A leading variant, AccuTOX^®, selected that purpose. Methods: Several functional studies, including a series assays, conducted SIINFEKL-specific T-cell clone B3Z. Analysis escape effect various anti-oxidant compounds used decipher AccuTOX^® mode action MSCs. The potency AccuTOX^®-reprogramed MSCs (ARM-X) evaluated context vaccination immunocompetent C57BL/6 mice three different pre-established solid tumor models. Various depletion studies also animals identify effector involved response mediated by ARM-X cells. Finally, observed on murine validated human along an immunopeptidome study reflecting these reprogrammed Results: can indeed trigger cross-present antigens, even if pulsed low doses while retaining most innate A1, increased uptake processing, production reactive oxygen species, induction unfolded protein (UPR). When against melanoma, pancreatic colon cancer, administration vaccine, combination anti-PD-1, impairs growth. Mechanistically, relies efferocytosis endogenous phagocytes requires both CD4⁺ CD8⁺ T cells, as leads loss function. Conclusion: Altogether, second-generation represents adaptable multiple tumors. addition, our data clearly allude direct link between AccuTOX^®-mediated UPR activation fact modulated become antigen-presenting via stimulation opens-up new line investigation search agents capable specifically activating pathway convert culture-adapted cellular tool various indications.

Язык: Английский

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