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1.
Int J Biol Sci ; 18(1): 315-330, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34975335

RESUMO

X-box binding protein 1(XBP1) is a critical component for unfolded protein response (UPR) in ER stress. According to previous studies performed with different XBP1-deficient mice, the XBP1 gene affects mouse cartilage development and causes other related diseases. However, how the complete transcriptome, including mRNA and ncRNAs, affects the function of cartilage and other tissues when XBP1 is deficient in chondrocytes is unclear. In this study, we aimed to screen the differentially expressed (DE) mRNAs, circRNAs, lncRNAs and miRNAs in XBP1 cartilage-specific knockout (CKO) mice using high throughput sequencing and construct the circRNA-miRNA-mRNA and lncRNA-miRNA-mRNA regulatory networks. DE LncRNAs (DE-LncRNAs), circRNAs (DE-circRNAs), miRNAs (DE-miRNAs), and mRNAs [differentially expressed genes (DEGs)] between the cartilage tissue of XBP1 CKO mice and controls were identified, including 441 DE-LncRNAs, 15 DE-circRNAs, 6 DE-miRNAs, and 477 DEGs. Further, 253,235 lncRNA-miRNA-mRNA networks and 1,822 circRNA-miRNA-mRNA networks were constructed based on the correlation between lncRNAs/circRNAs, miRNAs, mRNAs. The whole transcriptome analysis revealed that XBP1 deficiency in cartilage affects the function of cartilage and other different tissues, as well as associated diseases. Overall, our findings may provide potential biomarkers and mechanisms for the diagnosis and treatment of cartilage and other related diseases.


Assuntos
Cartilagem/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Proteína 1 de Ligação a X-Box/deficiência , Animais , Perfilação da Expressão Gênica , Camundongos
2.
PLoS One ; 17(1): e0261789, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35030194

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver diseases in the United States and can progress to cirrhosis, end-stage liver disease and need for liver transplantation. There are limited therapies for NAFLD, in part, due to incomplete understanding of the disease pathogenesis, which involves different cell populations in the liver. Endoplasmic reticulum stress and its adaptative unfolded protein response (UPR) signaling pathway have been implicated in the progression from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). We have previously shown that mice lacking the UPR protein X-box binding protein 1 (XBP1) in the liver demonstrated enhanced liver injury and fibrosis in a high fat sugar (HFS) dietary model of NAFLD. In this study, to better understand the role of liver XBP1 in the pathobiology of NAFLD, we fed hepatocyte XBP1 deficient mice a HFS diet or chow and investigated UPR and other cell signaling pathways in hepatocytes, hepatic stellate cells and immune cells. We demonstrate that loss of XBP1 in hepatocytes increased inflammatory pathway expression and altered expression of the UPR signaling in hepatocytes and was associated with enhanced hepatic stellate cell activation after HFS feeding. We believe that a better understanding of liver cell-specific signaling in the pathogenesis of NASH may allow us to identify new therapeutic targets.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Estresse do Retículo Endoplasmático/imunologia , Fígado , Transdução de Sinais/imunologia , Resposta a Proteínas não Dobradas/imunologia , Proteína 1 de Ligação a X-Box/deficiência , Animais , Estresse do Retículo Endoplasmático/genética , Fígado/imunologia , Fígado/lesões , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/imunologia , Transdução de Sinais/genética , Resposta a Proteínas não Dobradas/genética , Proteína 1 de Ligação a X-Box/imunologia
3.
Exp Neurol ; 339: 113646, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33600817

RESUMO

Spliced X-box binding protein-1 (XBP1s) together with the hexosamine biosynthetic pathway (HBP) and O-GlcNAcylation forms the XBP1s/HBP/O-GlcNAc axis. Our previous studies have provided evidence that activation of this axis is neuroprotective after ischemic stroke and critically, ischemia-induced O-GlcNAcylation is impaired in the aged brain. However, the XBP1s' neuroprotective role and its link to O-GlcNAcylation in stroke, as well as the therapeutic potential of targeting this axis in stroke, have not been well established. Moreover, the mechanisms underlying this age-related impairment of O-GlcNAcylation induction after brain ischemia remain completely unknown. In this study, using transient ischemic stroke models, we first demonstrated that neuron-specific overexpression of Xbp1s improved outcome, and pharmacologically boosting O-GlcNAcylation with thiamet-G reversed worse outcome observed in neuron-specific Xbp1 knockout mice. We further showed that thiamet-G treatment improved long-term functional recovery in both young and aged animals after transient ischemic stroke. Mechanistically, using an analytic approach developed here, we discovered that availability of UDP-GlcNAc was compromised in the aged brain, which may constitute a novel mechanism responsible for the impaired O-GlcNAcylation activation in the aged brain after ischemia. Finally, based on this new mechanistic finding, we evaluated and confirmed the therapeutic effects of glucosamine treatment in young and aged animals using both transient and permanent stroke models. Our data together support that increasing O-GlcNAcylation is a promising strategy in stroke therapy.


Assuntos
Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevenção & controle , Encéfalo/metabolismo , AVC Isquêmico/metabolismo , AVC Isquêmico/prevenção & controle , Neuroproteção/fisiologia , Fatores Etários , Animais , Encéfalo/efeitos dos fármacos , Glucosamina/farmacologia , Glucosamina/uso terapêutico , Glicosilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ratos , Ratos Endogâmicos F344 , Proteína 1 de Ligação a X-Box/deficiência , Proteína 1 de Ligação a X-Box/genética
4.
J Lipid Res ; 60(2): 353-359, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30482806

RESUMO

Refeeding mice after a prolonged fast is a potent stimulus of hepatic lipogenesis, but is also associated with induction of the hepatic unfolded protein response (UPR). The X-box binding protein 1 (Xbp1), a key regulator of the adaptive UPR, transcriptionally activates hepatic lipogenesis genes. We therefore determined whether hepatic Xbp1 mediates the hepatic lipogenic response to refeeding. Mice bearing a hepatocyte-specific deletion of Xbp1 and littermate controls were fasted overnight, followed by refeeding for up to 6 h. Among control mice, refeeding induced hepatic expression of activated Xbp1 and, as expected, induced hepatic expression of genes controlling de novo lipogenesis of fatty acids. Unexpectedly, deletion of hepatic Xbp1 allowed for normal induction of hepatic lipogenesis genes, yet impaired translation of SREBP1c and its targets in response to refeeding. Impaired protein translation was associated with enhanced postprandial activation of the global translational arrest protein, eukaryotic initiation factor 2α, among mice lacking hepatic Xbp1 Deletion of hepatic Xbp1 prevented postprandial induction of genes regulating protein folding and processing and shifted the pattern of postprandial UPR activation to favor proapoptotic signals. We conclude that activation of hepatic Xbp1 in the postprandial states serves the dual roles of restoring postprandial hepatic lipogenesis and proteostasis.


Assuntos
Comportamento Alimentar , Fígado/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Animais , Deleção de Genes , Lipogênese/genética , Camundongos , Proteostase/genética , Ativação Transcricional , Proteína 1 de Ligação a X-Box/deficiência , Proteína 1 de Ligação a X-Box/genética
5.
Nature ; 562(7727): 423-428, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305738

RESUMO

Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function1-4. However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer-an aggressive malignancy that is refractory to standard treatments and current immunotherapies5-8-induces endoplasmic reticulum stress and activates the IRE1α-XBP1 arm of the unfolded protein response9,10 in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1α-XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.


Assuntos
Endorribonucleases/metabolismo , Mitocôndrias/metabolismo , Neoplasias Ovarianas/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Proteína 1 de Ligação a X-Box/metabolismo , Sistemas de Transporte de Aminoácidos Básicos , Animais , Ascite/metabolismo , Respiração Celular , Progressão da Doença , Estresse do Retículo Endoplasmático , Feminino , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Glutamina/metabolismo , Glicosilação , Humanos , Interferon gama/biossíntese , Interferon gama/genética , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias Ovarianas/patologia , Transdução de Sinais , Taxa de Sobrevida , Linfócitos T/metabolismo , Evasão Tumoral/imunologia , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box/biossíntese , Proteína 1 de Ligação a X-Box/deficiência
6.
Blood Adv ; 2(4): 414-427, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29483082

RESUMO

Hematopoietic stem cell transplantation (HCT) is a curative procedure for hematological malignancies, but chronic graft-versus-host disease (cGVHD) remains a major complication after allogeneic HCT. Because donor B cells are essential for cGVHD development and B cells are sensitive to endoplasmic reticulum (ER) stress, we hypothesized that the IRE-1α/XBP-1 pathway is required for B-cell activation and function and for the development of cGVHD. To test this hypothesis, we used conditional knock-out mice deficient of XBP-1 specifically in B cells. Recipients transplanted with donor grafts containing XBP-1-deficient B cells displayed reduced cGVHD compared with controls. Reduction of cGVHD correlated with impaired B-cell functions, including reduced production of anti-double-stranded DNA immunoglobulin G antibodies, CD86, Fas, and GL7 surface expression, and impaired T-cell responses, including reduced interferon-γ production and follicular helper T cells. In a bronchiolitis obliterans cGVHD model, recipients of transplants containing XBP-1-deficient B cells demonstrated improved pulmonary function correlated with reduced donor splenic follicular helper T cells and increased B cells compared with those of wild-type control donor grafts. We then tested if XBP-1 blockade via an IRE-1α inhibitor, B-I09, would attenuate cGVHD and preserve the graft-versus-leukemia (GVL) effect. In a cutaneous cGVHD model, we found that prophylactic administration of B-I09 reduced clinical features of cGVHD, which correlated with reductions in donor T-cell and dendritic cell skin infiltrates. Inhibition of the IRE-1α/XBP-1 pathway also preserved the GVL effect against chronic myelogenous leukemia mediated by allogeneic splenocytes. Collectively, the ER stress response mediated by the IRE-1α/XBP-1 axis is required for cGVHD development but dispensable for GVL activity.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Leucemia , Proteína 1 Reguladora do Ferro/antagonistas & inibidores , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , Animais , Linfócitos B/imunologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Proteína 1 Reguladora do Ferro/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Knockout , Proteína 1 de Ligação a X-Box/deficiência , Proteína 1 de Ligação a X-Box/metabolismo
7.
Circ Res ; 121(3): 270-281, 2017 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-28620068

RESUMO

RATIONALE: Diverse B cell responses and functions may be involved in atherosclerosis. Protective antibody responses, such as those against oxidized lipid epitopes, are thought to mainly derive from T cell-independent innate B cell subsets. In contrast, both pathogenic and protective roles have been associated with T cell-dependent antibodies, and their importance in both humans and mouse models is still unclear. OBJECTIVE: To specifically target antibody production by plasma cells and determine the impact on atherosclerotic plaque development in mice with and without CD4+ T cells. METHODS AND RESULTS: We combined a model of specific antibody deficiency, B cell-specific CD79a-Cre x XBP1 (X-box binding protein-1) floxed mice (XBP1-conditional knockout), with antibody-mediated depletion of CD4+ T cells. Ldlr knockout mice transplanted with XBP1-conditional knockout (or wild-type control littermate) bone marrow were fed western diet for 8 weeks with or without anti-CD4 depletion. All groups had similar levels of serum cholesterol. In Ldlr/XBP1-conditional knockout mice, serum levels of IgG, IgE, and IgM were significantly attenuated, and local antibody deposition in atherosclerotic plaque was absent. Antibody deficiency significantly accelerated atherosclerosis at both the aortic root and aortic arch. T cell and monocyte responses were not modulated, but necrotic core size was greater, even when adjusting for plaque size, and collagen deposition significantly lower. Anti-CD4 depletion in Ldlr/wild-type mice led to a decrease of serum IgG1 and IgG2c but not IgG3, as well as decreased IgM, associated with increased atherosclerosis and necrotic cores, and a decrease in plaque collagen. The combination of antibody deficiency and anti-CD4 depletion has no additive effects on aortic root atherosclerosis. CONCLUSIONS: The endogenous T cell-dependent humoral response can be protective. This has important implications for novel vaccine strategies for atherosclerosis and in understanding the impacts of immunotherapies used in patients at high risk for cardiovascular disease.


Assuntos
Aterosclerose/metabolismo , Linfócitos B/metabolismo , Linfócitos T/metabolismo , Proteína 1 de Ligação a X-Box/deficiência , Animais , Aterosclerose/imunologia , Aterosclerose/patologia , Linfócitos B/imunologia , Imunidade Humoral/fisiologia , Masculino , Camundongos , Camundongos Knockout , Plasmócitos/imunologia , Plasmócitos/metabolismo , Linfócitos T/imunologia , Proteína 1 de Ligação a X-Box/imunologia
8.
Int J Mol Sci ; 18(6)2017 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-28555054

RESUMO

Granulosa cells are crucial for follicular growth, development, and follicular atresia. X-box binding protein 1 (XBP1), a basic region-leucine zipper protein, is widely involved in cell differentiation, proliferation, apoptosis, cellular stress response, and other signaling pathways. In this study, RNA interference, flow cytometry, western blot, real-time PCR, Cell Counting Kit (CCK8), and ELISA were used to investigate the effect of XBP1 on steroidogenesis, apoptosis, cell cycle, and proliferation of mouse granulosa cells. ELISA analysis showed that XBP1 depletion significantly decreased the concentrations of estradiol (E2). Additionally, the expression of estrogen synthesis enzyme Cyp19a1 was sharply downregulated. Moreover, flow cytometry showed that knockdown of XBP1 increased the apoptosis rate and arrests the cell cycle in S-phase in granulosa cells (GCs). Further study confirmed these results. The expression of CCAAT-enhancer-binding protein homologous protein (CHOP), cysteinyl aspartate specific proteases-3 (caspase-3), cleaved caspase-3, and Cyclin E was upregulated, while that of Bcl-2, Cyclin A1, and Cyclin B1 was downregulated. Simultaneously, CCK8 analysis indicated that XBP1 disruption inhibited cell proliferation. In addition, XBP1 knockdown also alters the expression of Has2 and Ptgs2, two essential genes for folliculogenesis. Collectively, these data reveal a novel critical role of XBP1 in folliculogenesis by regulating the cell cycle, apoptosis, and steroid synthesis of mouse granulosa cells.


Assuntos
Apoptose/fisiologia , Ciclo Celular/fisiologia , Estradiol/metabolismo , Células da Granulosa/citologia , Células da Granulosa/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Animais , Apoptose/genética , Ciclo Celular/genética , Proliferação de Células/genética , Proliferação de Células/fisiologia , Feminino , Camundongos , Interferência de RNA/fisiologia , Proteína 1 de Ligação a X-Box/deficiência , Proteína 1 de Ligação a X-Box/genética
9.
Cell Rep ; 14(6): 1382-1394, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26854229

RESUMO

Contextual memory formation relies on the induction of new genes in the hippocampus. A polymorphism in the promoter of the transcription factor XBP1 was identified as a risk factor for Alzheimer's disease and bipolar disorders. XBP1 is a major regulator of the unfolded protein response (UPR), mediating adaptation to endoplasmic reticulum (ER) stress. Using a phenotypic screen, we uncovered an unexpected function of XBP1 in cognition and behavior. Mice lacking XBP1 in the nervous system showed specific impairment of contextual memory formation and long-term potentiation (LTP), whereas neuronal XBP1s overexpression improved performance in memory tasks. Gene expression analysis revealed that XBP1 regulates a group of memory-related genes, highlighting brain-derived neurotrophic factor (BDNF), a key component in memory consolidation. Overexpression of BDNF in the hippocampus reversed the XBP1-deficient phenotype. Our study revealed an unanticipated function of XBP1 in cognitive processes that is apparently unrelated to its role in ER stress.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Hipocampo/metabolismo , Memória/fisiologia , Neurônios/metabolismo , Proteína 1 de Ligação a X-Box/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/genética , Potenciais Evocados/fisiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Hipocampo/citologia , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Knockout , Anotação de Sequência Molecular , Neurônios/citologia , Regiões Promotoras Genéticas , Transdução de Sinais , Resposta a Proteínas não Dobradas/genética , Proteína 1 de Ligação a X-Box/deficiência
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