Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion

Science, Год журнала: 2022, Номер 378(6621)

Опубликована: Ноя. 17, 2022

Many human cancers manifest the capability to circumvent attack by adaptive immune system. In this work, we identified a component of evasion that involves frequent up-regulation fragile X mental retardation protein (FMRP) in solid tumors. FMRP represses attack, as revealed cancer cells engineered lack its expression. FMRP-deficient tumors were infiltrated activated T impaired tumor growth and enhanced survival mice. Mechanistically, FMRP's immunosuppression was multifactorial, involving repression chemoattractant C-C motif chemokine ligand 7 (CCL7) concomitant with three immunomodulators-interleukin-33 (IL-33), tumor-secreted S (PROS1), extracellular vesicles. Gene signatures associate network poor prognosis response therapy patients. Collectively, is implicated regulator orchestrates multifaceted barrier antitumor responses.

Язык: Английский

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Ribosomal RNA 2′-O-methylation dynamics impact cell fate decisions

Developmental Cell, Год журнала: 2023, Номер 58(17), С. 1593 - 1609.e9

Опубликована: Июль 19, 2023

Язык: Английский

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Specialized Ribosomes in Health and Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6334 - 6334

Опубликована: Март 28, 2023

Ribosomal heterogeneity exists within cells and between different cell types, at specific developmental stages, occurs in response to environmental stimuli. Mounting evidence supports the existence of specialized ribosomes, or changes ribosome that regulate translation a group transcripts. These alterations have been shown affect affinity ribosomes for certain mRNAs change cotranslational folding nascent polypeptides exit tunnel. The identification requires incorporation ribosomal proteins modifications rRNA and/or protein lead(s) physiologically relevant translation. In this review, we summarize specialization mammals discuss their relevance several human diseases.

Язык: Английский

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Neuronal activity rapidly reprograms dendritic translation via eIF4G2:uORF binding

Nature Neuroscience, Год журнала: 2024, Номер 27(5), С. 822 - 835

Опубликована: Апрель 8, 2024

Abstract Learning and memory require activity-induced changes in dendritic translation, but which mRNAs are involved how they regulated unclear. In this study, to monitor depolarization impacts local biology, we employed a dendritically targeted proximity labeling approach followed by crosslinking immunoprecipitation, ribosome profiling mass spectrometry. Depolarization of primary cortical neurons with KCl or the glutamate agonist DHPG caused rapid reprogramming protein expression, where proteins weakly correlated. For subset pre-localized messages, increased translation upstream open reading frames (uORFs) their downstream coding sequences, enabling localized production long-term potentiation, cell signaling energy metabolism. This activity-dependent was accompanied phosphorylation recruitment non-canonical initiation factor eIF4G2, translated uORFs were sufficient confer depolarization-induced, eIF4G2-dependent translational control. These studies uncovered an unanticipated mechanism uORF control eIF4G2 couples activity remodeling.

Язык: Английский

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FMRP regulates MFF translation to locally direct mitochondrial fission in neurons

Nature Cell Biology, Год журнала: 2024, Номер 26(12), С. 2061 - 2074

Опубликована: Ноя. 15, 2024

Fragile X messenger ribonucleoprotein (FMRP) is a critical regulator of translation, whose dysfunction causes fragile syndrome. FMRP disrupts mitochondrial health in neurons, but it unclear how supports homoeostasis. Here we demonstrate that granules are recruited to the midzone, where they mark fission sites axons and dendrites. Endolysosomal vesicles contribute granule positioning around mitochondria facilitate FMRP-associated via Rab7 GTP hydrolysis. Cryo-electron tomography real-time translation imaging reveal mitochondria-associated ribosome-rich structures serve as local protein synthesis. Specifically, promotes factor (MFF), selectively enabling replicative at midzone. Disrupting function dysregulates MFF perturbs dynamics, resulting increased peripheral an irregular distribution nucleoids. Thus, regulates precise control fission.

Язык: Английский

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Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(23)

Опубликована: Май 30, 2023

Short trinucleotide expansions at the FMR1 locus are associated with late-onset condition fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features from X (associated longer expansions), no clear molecular explanation for these marked differences. One prevailing theory posits that shorter, premutation expansion uniquely causes extreme neurotoxic increases in mRNA (i.e., four to eightfold increases), but evidence support this hypothesis is largely derived analysis of peripheral blood. We applied single-nucleus RNA sequencing postmortem frontal cortex cerebellum 7 individuals matched controls (n = 6) assess cell type–specific neuropathology. found only modest upregulation (~1.3-fold) some glial populations expansions. In cases, we also identified decreased astrocyte proportions cortex. Differential expression gene ontology demonstrated altered neuroregulatory roles glia. Using network analyses, region-specific patterns protein target dysregulation unique notable cortical oligodendrocyte lineage. used pseudotime trajectory determine how development was differences early trajectories cases specifically, implicating developmental perturbations. These findings challenge dogma regarding extremely elevated FXTAS implicate as a critical facet pathophysiology, representing potential therapeutic targets directly human condition.

Язык: Английский

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Proteomics insights into fragile X syndrome: Unraveling molecular mechanisms and therapeutic avenues

Neurobiology of Disease, Год журнала: 2024, Номер 194, С. 106486 - 106486

Опубликована: Март 26, 2024

Fragile X Syndrome (FXS) is a neurodevelopment disorder characterized by cognitive impairment, behavioral challenges, and synaptic abnormalities, with genetic basis linked to mutation in the FMR1 (Fragile Messenger Ribonucleoprotein 1) gene that results deficiency or absence of its protein product, (FMRP). In recent years, mass spectrometry (MS) - based proteomics has emerged as powerful tool uncover complex molecular landscape underlying FXS. This review provides comprehensive overview studies focused on FXS, summarizing key findings an emphasis dysregulated proteins associated These span wide range cellular functions including, but not limited to, plasticity, RNA translation, mitochondrial function. The work conducted these proteomic more holistic understanding pathways involved FXS considerably enhances our knowledge into dysfunction seen

Язык: Английский

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Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complex

Cell Reports, Год журнала: 2023, Номер 42(8), С. 112838 - 112838

Опубликована: Июль 25, 2023

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, but new therapies have been impeded by lack of understanding the pathological mechanisms. Tuberous sclerosis complex (TSC) and fragile X syndrome are associated with alterations in mechanistic target rapamycin (mTOR) messenger ribonucleoprotein 1 (FMRP), which implicated development ASD. Previously, we observed that transcripts FMRP were down-regulated TSC2-deficient neurons. In this study, find turnover dysregulated rodent primary neurons human induced pluripotent stem cell (iPSC)-derived dependent on E3 ubiquitin ligase anaphase-promoting complex. We also demonstrate overexpression can partially rescue hyperexcitability iPSC-derived These data indicate dysregulation represents an important mechanism abnormal neuronal activity TSC illustrate molecular convergence between these two neurogenetic disorders.

Язык: Английский

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Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X syndrome

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(2)

Опубликована: Янв. 3, 2023

Layer 5 (L5) pyramidal neurons receive predictive and sensory inputs in a compartmentalized manner at their apical basal dendrites, respectively. To uncover how integration of is affected autism spectrum disorders (ASD), we used two-photon glutamate uncaging to activate spines the dendrites L5 from mouse model Fragile X syndrome (FXS), most common genetic cause ASD. While subthreshold excitatory integrate linearly wild-type animals, surprisingly those with FXS summate sublinearly, contradicting what would be expected hypersensitivity classically associated We next investigated mechanism underlying this sublinearity by performing knockdown regulatory β4 subunit BK channels, which rescued synaptic integration, result that was corroborated numerical simulations. Taken together, these findings suggest there differential impairment feedforward feedback potentially other forms ASD, as specifically localized subcellular channelopathies. These results challenge traditional view ASD are characterized hypersensitivity, proposing instead hyposensitivity onto cortical neurons.

Язык: Английский

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Navigating a complex dance: the interplay between RNA-binding proteins and T cells in oral epithelial plasticity

Immunometabolism, Год журнала: 2025, Номер 7(1), С. e00054 - e00054

Опубликована: Янв. 1, 2025

The oral epithelium, a dynamic interface constantly facing environmental challenges, relies on intricate molecular pathways to maintain its homeostasis. This comprehensive review delves into the nuanced interplay between T-lymphocytic cells (T cells) and RNA-binding proteins (RBPs) within elucidating their roles in orchestrating immune responses influencing tissue plasticity. By synthesizing current knowledge, we aim unravel intricacies that govern this interplay, with focus potential therapeutic implications for health diseases. Understanding regulatory networks shaped by T RBPs epithelial microenvironment holds promise innovative strategies managing conditions associated dysfunction.

Язык: Английский

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