RESUMEN
Classical swine fever (CSF) is caused by the classical swine fever virus (CSFV), which poses a threat to swine production. The activation of host innate immunity through linker proteins such as tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) is crucial for the induction of the NF-κB pathway. Recent research has revealed the involvement of mitochondrial antiviral-signaling protein (MAVS) in the interaction with TRAF2, 3, 5, and 6 to activate both the NF-κB and IRF3 pathways. This study revealed that CSFV infection led to the upregulation of TRAF1 mRNA and protein levels; moreover, TRAF1 overexpression inhibited CSFV replication, while TRAF1 knockdown promoted replication, highlighting its importance in the host response to CSFV infection. Additionally, the expression of RIG-I, MAVS, TRAF1, IRF1, and ISG15 were detected in PK-15 cells infected with CSFV, revealing that TRAF1 plays a role in regulating IRF1 and ISG15 within the RIG-I pathway. Furthermore, Co-IP, GST pull-down, and IFA analyses demonstrated that TRAF1 interacted with MAVS and co-localized in the cytoplasm during CSFV infection. Ultimately, TRAF1 acted as a novel member of the TRAF family, bound to MAVS as a linker molecule, and functioned as a mediator downstream of MAVS in the RIG-I/MAVS pathway against CSFV replication.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Virus de la Fiebre Porcina Clásica , Factor 1 Regulador del Interferón , Factor 1 Asociado a Receptor de TNF , Regulación hacia Arriba , Animales , Virus de la Fiebre Porcina Clásica/fisiología , Factor 1 Asociado a Receptor de TNF/metabolismo , Factor 1 Asociado a Receptor de TNF/genética , Porcinos , Regulación hacia Arriba/genética , Factor 1 Regulador del Interferón/metabolismo , Factor 1 Regulador del Interferón/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Transducción de Señal , Peste Porcina Clásica/virología , Peste Porcina Clásica/metabolismo , Peste Porcina Clásica/genética , Replicación Viral , Línea Celular , Citocinas/metabolismo , Unión ProteicaRESUMEN
The tumor necrosis factor receptor-associated factor 1 (TRAF1) plays a key role in promoting lymphocyte survival, proliferation, and cytokine production. Recent evidence showed that TRAF1 plays opposing roles in monocytes and macrophages where it controls NF-κB activation and limits pro-inflammatory cytokine production as well as inflammasome-dependent IL-1ß secretion. Importantly, TRAF1 polymorphisms have been strongly linked to an increased risk of rheumatoid arthritis (RA). However, whether and how TRAF1 contributes to RA pathogenesis is not fully understood. Moreover, investigating the role of TRAF1 in driving RA pathogenesis is complicated by its multifaceted and opposing roles in various immune cells. In this study, we subjected wildtype (WT) mice to the collagen antibody-induced arthritis (CAIA) model of RA and injected them intra-articularly with WT- or TRAF1-deficient macrophages. We show that mice injected with TRAF1-deficient macrophages exhibited significantly exacerbated joint inflammation, immune cell infiltration, and tissue damage compared to mice injected with WT macrophages. This study may lay the groundwork for novel therapies for RA that target TRAF1 in macrophages.
Asunto(s)
Artritis Reumatoide , Macrófagos , Factor 1 Asociado a Receptor de TNF , Animales , Factor 1 Asociado a Receptor de TNF/genética , Factor 1 Asociado a Receptor de TNF/metabolismo , Factor 1 Asociado a Receptor de TNF/deficiencia , Artritis Reumatoide/metabolismo , Artritis Reumatoide/genética , Artritis Reumatoide/patología , Macrófagos/metabolismo , Ratones , Artritis Experimental/patología , Artritis Experimental/genética , Artritis Experimental/metabolismo , Artritis Experimental/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Inflamación/genética , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
The imbalance of vascular endothelial cell homeostasis is the key mechanism for the progression of many vascular diseases. RNA modification, particularly N6-Methyladenosine (m6A), plays important function in numerous biological processes. Nevertheless, the regulatory function of m6A RNA methylation in endothelial dysfunction remains insufficiently characterized. In this study, we established that the m6A methyltransferase METTL3 is critical for regulating endothelial function. Functionally, depletion of METTL3 results in decreased endothelial cells proliferation, survival and inflammatory response. Conversely, overexpression of METTL3 elicited the opposite effects. Mechanistically, MeRIP-seq identified that METTL3 catalyzed m6A modification of TRAF1 mRNA and enhanced TRAF1 translation, thereby up-regulation of TRAF1 protein. Over-expression of TRAF1 successfully rescued the inhibition of proliferation and adhesion of endothelial cells due to METTL3 knockdown. Additionally, m6A methylation-mediated TRAF1 expression can be reversed by the demethylase ALKBH5. Knockdown of ALKBH5 upregulated the level of m6A and protein level of TRAF1, and also increased endothelial cells adhesion and inflammatory response. Collectively, our findings suggest that METTL3 regulates vascular endothelium homeostasis through TRAF1 m6A modification, suggesting that targeting the METTL3-m6A-TRAF1 axis may hold therapeutic potential for patients with vascular diseases.
Asunto(s)
Adenosina , Proliferación Celular , Células Endoteliales de la Vena Umbilical Humana , Inflamación , Metiltransferasas , Factor 1 Asociado a Receptor de TNF , Metiltransferasas/metabolismo , Metiltransferasas/genética , Humanos , Metilación , Inflamación/metabolismo , Inflamación/genética , Inflamación/patología , Factor 1 Asociado a Receptor de TNF/metabolismo , Factor 1 Asociado a Receptor de TNF/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/genética , Metilación de ARNRESUMEN
Tumor necrosis factor receptor-associated factor (TRAF) proteins play pivotal roles in a multitude of cellular signaling pathways, encompassing immune response, cell fate determination, development, and thrombosis. Their involvement in these processes hinges largely on their ability to interact directly with diverse receptors via the TRAF domain. Given the limited binding interface, understanding how specific TRAF domains engage with various receptors and how structurally similar binding interfaces of TRAF family members adapt their distinct binding partners has been the subject of extensive structural investigations over several decades. This review presents an in-depth exploration of the current insights into the structural and molecular diversity exhibited by the TRAF domain and TRAF-binding motifs across a range of receptors, with a specific focus on TRAF1.
Asunto(s)
Factor 1 Asociado a Receptor de TNF , Humanos , Factor 1 Asociado a Receptor de TNF/metabolismo , Factor 1 Asociado a Receptor de TNF/química , Factor 1 Asociado a Receptor de TNF/genética , Animales , Unión Proteica , Transducción de Señal , Dominios Proteicos , Modelos MolecularesRESUMEN
INTRODUCTION: Multiple lines of research implicate inflammation-related pathways in the molecular pathology of mood disorders, with our data suggesting a critical role for aberrant cortical tumour necrosis factor α (TNF)-signaling in the molecular pathology of bipolar disorders (BPD) and major depressive disorders (MDD). METHODS: To extend our understanding of changes in TNF-signaling pathways in mood disorders we used Western blotting to measure levels of tumour necrosis factor receptor associated factor 1 (TRAF1) and transmembrane TNF receptor superfamily member 1B (tmTNFRSF1B) in Brodmann's areas (BA) 24 and 46 from people with BPD and MDD. These proteins are key rate-limiting components within TNF-signaling pathways. RESULTS: Compared to controls, there were higher levels of TRAF1 of large effect size (η = 0.19, Cohen's d = 0.97) in BA 24, but not BA 46, from people with BPD. Levels of TRAF1 were not altered in MDD and levels of tmTNFRSF1B were not altered in either disorder. LIMITATIONS: The cases studied had been treated with psychotropic drugs prior to death which is an unresolvable study confound. Cohort sizes are relatively small but not untypical of postmortem CNS studies. CONCLUSIONS: To facilitate post-synaptic signaling, TRAF1 is known to associate with tmTNFRSF1B after that receptor takes its activated conformation which occurs predominantly after it binds to transmembrane TNF (tmTNF). Simultaneously, when tmTNFRSF1B binds to tmTNF reverse signaling through tmTNF is activated. Hence our findings in BA 24 argues that bidirectional TNF-signaling may be an important component of the molecular pathology of BPD.
Asunto(s)
Trastorno Bipolar , Trastorno Depresivo Mayor , Factor 1 Asociado a Receptor de TNF , Humanos , Trastorno Depresivo Mayor/metabolismo , Trastorno Bipolar/metabolismo , Factor 1 Asociado a Receptor de TNF/genética , Factor 1 Asociado a Receptor de TNF/metabolismo , Femenino , Masculino , Adulto , Persona de Mediana Edad , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Estudios de Casos y ControlesRESUMEN
ABSTRACT: Background: Neonatal pneumonia is a common disease in the neonatal period with high mortality. The present work concentrated on the role and mechanism of circular RNA extra spindle pole bodies like 1, separase (circESPL1) in LPS-induced dysfunction of lung fibroblasts. Methods: Reverse transcription-quantitative polymerase chain reaction and Western blot assay were conducted to analyze RNA and protein expression, respectively. Cell viability, proliferation, apoptosis, and inflammation were assessed by Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine assay, flow cytometry, and enzyme-linked immunosorbent assay, respectively. Dual-luciferase reporter assay and RNA immunoprecipitation assay were conducted to verify the intermolecular interactions among circESPL1, miR-146b-3p, and TRAF1. Results: CircESPL1 expression was upregulated in the serum samples of pneumonia patients and LPS-induced lung fibroblasts. CircESPL1 silencing protected lung fibroblasts against LPS-induced dysfunction. CircESPL1 bound to microRNA-146b-3p (miR-146b-3p) in lung fibroblasts. CircESPL1 knockdown-mediated protective effects on LPS-induced lung fibroblasts were largely reversed by the silence of miR-146b-3p. miR-146b-3p directly interacted with the 3' untranslated region of TNF receptor associated factor 1 (TRAF1), and TRAF1 expression was regulated by the circESPL1/miR-146b-3p axis in lung fibroblasts. TRAF1 overexpression largely reversed miR-146b-3p accumulation-mediated protective effects on LPS-induced lung fibroblasts. Conclusion: CircESPL1 knockdown protected lung fibroblasts from LPS-induced injury partly by targeting the miR-146b-3p/TRAF1 axis.
Asunto(s)
MicroARNs , Neumonía , Recién Nacido , Humanos , Factor 1 Asociado a Receptor de TNF/genética , Lipopolisacáridos/toxicidad , Regiones no Traducidas 3' , Apoptosis , Fibroblastos , Pulmón , MicroARNs/genéticaRESUMEN
OBJECTIVE: To investigate the association between loci rs3761847 and rs10818488 of tumor necrosis factor receptor-associated factor 1/complement C5 (TRAF1/C5) gene and the susceptibility to IgAV. METHODS: 100 blood samples of children with IgAV and 100 blood samples of healthy children were collected from the Third Xiangya Hospital of Central South University from June 2017 to June 2019. The target gene fragment was amplified by polymerase chain reaction (PCR), and the single nucleic acid gene polymorphism of the gene loci was detected by PCR sequencing based typing technique. The association between gene polymorphism of each locus and susceptibility to IgAV was analyzed. RESULTS: There were significant differences in both genotype (P < .05) and allele frequencies ï¼P < .05) of rs3761847 of TRAF1/C5 gene between the IgAV group and the control group.Besides, the risks of developing IgAV in children with the TT genotype was 0.495 times and in children with the C allele was 1.627 times of that in children with other genotypes and alleles, respectively (P < .05). For IgAV patients, renal involvement risk in children with CC genotype was 5.859 times of that in children with other genotypes (P < .05). There were no significant differences in genotype (P > .05) and allele frequencies (P > .05) of rs10818488 of TRAF1/C5 gene between the IgAV group and the control group. IgAV patients with TT genotype had a 3.2 times higher risk of renal involvement than those with other genotypes (P < .05). CONCLUSIONS: There is an association between locus rs3761847 of TRAF1/C5 gene single nucleotide polymorphisms and susceptibility to IgAV. The T allele at locus rs3761847 of TRAF1/C5 gene may be a protective factor for IgAV. The C allele at locus rs3761847 and the T allele at locus rs10818488 of TRAF1/C5 gene may be associated with kidney injury in IgAV.
Asunto(s)
Vasculitis por IgA , Niño , Humanos , Factor 1 Asociado a Receptor de TNF/genética , Predisposición Genética a la Enfermedad , Genotipo , Polimorfismo de Nucleótido Simple , Frecuencia de los Genes , Complemento C5/genética , China , Estudios de Casos y ControlesRESUMEN
The yellow catfish (Pelteobagrus fulvidraco) is an economic fish with a large breeding scale, and diseases have led to huge economic losses. Tumor necrosis factor receptor-associated factors (TRAFs) are a class of intracellular signal transduction proteins that play an important role in innate and adaptive immune responses by mediating NF-κB, JNK and MAPK signaling pathways. However, there are few studies on the TRAF gene family in yellow catfish. In this study, the open reading frame (ORF) sequences of TRAF1, TRAF2a, TRAF2b, TRAF3, TRAF4a, TRAF4b, TRAF5, TRAF6 and TRAF7 genes were cloned and identified in yellow catfish. The ORF sequences of the nine TRAF genes of yellow catfish (Pf_TRAF1-7) were 1413-2025 bp in length and encoded 470-674 amino acids. The predicted protein structures of Pf_TRAFs have typically conserved domains compared to mammals. The phylogenetic relationships showed that TRAF genes are conserved during evolution. Gene structure, motifs and syntenic analyses of TRAF genes showed that the exon-intron structure and conserved motifs of TRAF genes are diverse among seven vertebrate species, and the TRAF gene family is relatively conserved evolutionarily. Among them, TRAF1 is more closely related to TRAF2a and TRAF2b, and they may have evolved from a common ancestor. TRAF7 is quite different and distantly related to other TRAFs. Real-time quantitative PCR (qRT-PCR) results showed that all nine Pf_TRAF genes were constitutively expressed in 12 tissues of healthy yellow catfish, with higher mRNA expression levels in the gonad, spleen, brain and gill. After infection with Edwardsiella ictaluri, the expression levels of nine Pf_TRAF mRNAs were significantly changed in the head kidney, spleen, gill and brain tissues of yellow catfish, of which four genes were down-regulated and one gene was up-regulated in the head kidney; four genes were up-regulated and four genes were down-regulated in the spleen; two genes were down-regulated, one gene was up-regulated, and one gene was up-regulated and then down-regulated in the gill; one gene was up-regulated, one gene was down-regulated, and four genes were down-regulated and then up-regulated in the brain. These results indicate that Pf_TRAF genes might be involved in the immune response against bacterial infection. Subcellular localization results showed that all nine Pf_TRAFs were found localized in the cytoplasm, and Pf_TRAF2a, Pf_TRAF3 and Pf_TRAF4a could also be localized in the nucleus, uncovering that the subcellular localization of TRAF protein may be closely related to its structure and function in cellular mechanism. The results of this study suggest that the Pf_TRAF gene family plays important roles in the immune response against pathogen invasion and will provide basic information to further understand the roles of TRAF gene against bacterial infection in yellow catfish.
Asunto(s)
Bagres , Infecciones por Enterobacteriaceae , Enfermedades de los Peces , Animales , Edwardsiella ictaluri/metabolismo , Infecciones por Enterobacteriaceae/genética , Infecciones por Enterobacteriaceae/veterinaria , Bagres/genética , Factor 1 Asociado a Receptor de TNF/genética , Factor 1 Asociado a Receptor de TNF/metabolismo , Filogenia , Factor 3 Asociado a Receptor de TNF/genética , Proteínas de Peces/metabolismo , Mamíferos/metabolismoRESUMEN
Single nucleotide polymorphisms in non-HLA genes are involved in the development of rheumatoid arthritis (RA). SNPS in genes: PADI4 (rs2240340), STAT4 (rs7574865), CD40 (rs4810485), PTPN22 (rs2476601), and TRAF1 (rs3761847) have been described as risk factors for the development of autoimmune diseases, including RA. This study aimed to assess the prevalence of polymorphisms of these genes in the Polish population of patients with rheumatoid arthritis as compared to healthy controls. 324 subjects were included in the study: 153 healthy subjects and 181 patients from the Department of Rheumatology, Medical University of Lodz who fulfilled the criteria of rheumatoid arthritis diagnosis. Genotypes were determined by Taqman SNP Genotyping Assay. rs2476601 (G/A, OR = 2.16, CI = 1.27-3.66; A/A, OR = 10.35, CI = 1.27-84.21), rs2240340 (C/T, OR = 4.35, CI = 2.55-7.42; T/T, OR = 2.80, CI = 1.43-4.10) and rs7574865 (G/T, OR = 1.97, CI = 1.21-3.21; T/T, OR = 3.33, CI = 1.01-11.02) were associated with RA in the Polish population. Rs4810485 was also associated with RA, however after Bonferroni's correction was statistically insignificant. We also found an association between minor alleles of rs2476601, rs2240340, and rs7574865 and RA (OR = 2.32, CI = 1.47-3.66; OR = 2.335, CI = 1.64-3.31; OR = 1.88, CI = 1.27-2.79, respectively). Multilocus analysis revealed an association between CGGGT and rare (below 0.02 frequency) haplotypes (OR = 12.28, CI = 2.65-56.91; OR = 3.23, CI = 1.63-6.39). In the Polish population, polymorphisms of the PADI4, PTPN22, and STAT4 genes have been detected, which are also known risk factors for RA in various other populations.
Asunto(s)
Artritis Reumatoide , Polimorfismo de Nucleótido Simple , Humanos , Factor 1 Asociado a Receptor de TNF/genética , Polonia/epidemiología , Predisposición Genética a la Enfermedad , Artritis Reumatoide/epidemiología , Artritis Reumatoide/genética , Genotipo , Alelos , Estudios de Casos y Controles , Frecuencia de los Genes , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Factor de Transcripción STAT4/genéticaRESUMEN
BACKGROUND: RNA modification plays important roles in many biological processes, such as gene expression control. The aim of this study was to identify single nucleotide polymorphisms related to RNA modification (RNAm-SNPs) for rheumatoid arthritis (RA) as putative functional variants. METHODS: We examined the association of RNAm-SNPs with RA in summary data from a genome-wide association study of 19,234 RA cases and 61,565 controls. We performed eQTL and pQTL analyses for the RNAm-SNPs to find associated gene expression and protein levels. Furthermore, we examined the associations of gene expression and circulating protein levels with RA using two-sample Mendelian randomization analysis methods. RESULTS: A total of 160 RNAm-SNPs related to m6A, m1A, A-to-I, m7G, m5C, m5U and m6Am modifications were identified to be significantly associated with RA. These RNAm-SNPs were located in 62 protein-coding genes, which were significantly enriched in immune-related pathways. RNAm-SNPs in important RA susceptibility genes, such as PADI2, SPRED2, PLCL2, HLA-A, HLA-B, HLA-DRB1, HLA-DPB1, TRAF1 and TXNDC11, were identified. Most of these RNAm-SNPs showed eQTL effects, and the expression levels of 26 of the modifiable genes (e.g., PADI2, TRAF1, HLA-A, HLA-DRB1, HLA-DPB1 and HLA-B) in blood cells were associated with RA. Circulating protein levels, such as CFB, GZMA, HLA-DQA2, IL21, LRPAP1 and TFF3, were affected by RNAm-SNPs and were associated with RA. CONCLUSION: The present study identified RNAm-SNPs in the reported RA susceptibility genes and suggested that RNAm-SNPs may affect RA risk by affecting the expression levels of corresponding genes and proteins.
Asunto(s)
Artritis Reumatoide , Polimorfismo de Nucleótido Simple , Humanos , Cadenas HLA-DRB1/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Factor 1 Asociado a Receptor de TNF/genética , Artritis Reumatoide/genética , Antígenos HLA-A/genética , ARN , Proteínas Portadoras/genética , Proteínas Represoras/genética , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
Secretion of IL-1ß, a potent cytokine that plays a key role in gout pathogenesis, is regulated by inflammasomes. TRAF1 has been linked to heightened risk to inflammatory arthritis. In this article, we show that TRAF1 negatively regulates inflammasome activation to limit caspase-1 and IL-1ß secretion in human and mouse macrophages. TRAF1 reduces linear ubiquitination and subsequent oligomerization of the adapter protein, ASC. i.p. injection of monosodium urate crystals resulted in increased inflammatory cell infiltrates and IL-1ß production in Traf1 knockout mice compared with wild type littermates. In a model of monosodium urate crystal-induced gout, Traf1 knockout mice exhibited more swelling in the knee joints, increased infiltration of inflammatory cells, and higher expression of proinflammatory cytokines. In summary, this study identifies TRAF1 as a key regulator of IL-1ß production and a potential therapeutic target for inflammasome-driven diseases such as gout.
Asunto(s)
Gota , Inflamasomas , Animales , Humanos , Ratones , Proteínas Adaptadoras Transductoras de Señales , Citocinas , Interleucina-1beta , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Factor 1 Asociado a Receptor de TNF/genética , Ácido ÚricoRESUMEN
Cutaneous lupus erythematosus (CLE) has a specific microRNA expression profile. MiR-885-5p has been found to be downregulated in the epidermis of CLE lesions; however, its biological role in the disease has not been studied. In this study, we show that miR-885-5p is markedly reduced in CLE keratinocytes (KCs) with IFN-α and UVB being strong miR-885-5p regulators in vitro. Microarray expression profiling of antiâmiR-885-5pâtransfected KCs identified PSMB5 as a direct target. Specific inhibition of miR-885-5p increased epidermal proliferation by modulating keratin 16 gene K16, BIRC5, TP63, and CDK4 proliferative genes and promoted NF-κB signaling pathway in human primary KCs by increasing IκBα degradation. Silencing PSMB5 rescued the effect of miR-885-5p inhibition, indicating that miR-885-5p regulates proliferation and NF-κB activation by targeting PSMB5 in KCs. In addition, inhibition of miR-885-5p increased the ability of KCs to attract leukocytes in a PSMB5-independent manner. We identified TRAF1 as another direct target, and its silencing reduced leukocyte migration. Collectively, our findings suggest that UVB and IFN-É downregulate miR-885-5p in CLE KCs, leading to epidermal inflammation by NF-κB activity enhancement and proliferation through PSMB5 and immune recruitment through TRAF1. Our data indicate that miR-885-5p is a potential therapeutic target in CLE.
Asunto(s)
Lupus Eritematoso Cutáneo , MicroARNs , Humanos , FN-kappa B/metabolismo , Regulación hacia Abajo , MicroARNs/genética , MicroARNs/metabolismo , Factor 1 Asociado a Receptor de TNF/genética , Factor 1 Asociado a Receptor de TNF/metabolismo , Transducción de Señal/genética , Lupus Eritematoso Cutáneo/genéticaRESUMEN
BACKGROUND: Neonatal pneumonia is a common illness in the neonatal period with a high fatality rate. Accumulating proofs have attested to the crucial role of circular RNAs (circRNAs) in pneumonia. This study was intended to expound on the function of circ_0038467 and the underlying mechanism in lipopolysaccharide (LPS)-stimulated 16HBE cell injury in neonatal pneumonia. METHODS: 16HBE cells were exposed to LPS to establish an in vitro neonatal pneumonia cell model. Quantitative real-time polymerase chain reaction (qRT-PCR) was implemented for detecting the levels of circ_0038467, microRNA-545-3p (miR-545-3p), and tumor necrosis factor receptor-associated factor 1 (TRAF1) in neonatal pneumonia serums and LPS-treated 16HBE cells. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and flow cytometry assays were used to examine cell viability, proliferation, and apoptosis, respectively. The protein abundances of proliferation/apoptosis/inflammation-correlated makers and TRAF1 were tested by Western blot. RNase R and Actinomycin D assays were implemented to determine the features of circ_0038467. The mutual effect between miR-545-3p and circ_0038467 or TRAF1 was affirmed by a dual-luciferase reporter and RNA pull-down assay assays. RESULTS: Circ_0038467 was upregulated in neonatal pneumonia serum specimens and LPS-triggered 16HBE cells. LPS administration restrained 16HBE cell proliferation and promoted apoptosis and inflammation, whereas circ_0038467 silence recovered these influences. Meanwhile, miR-545-3p was targeted by circ_0038467, and circ_0038467 could modulate LPS-treated 16HBE cell injury through absorbing miR-545-3p. Furthermore, circ_0038467 controlled TRAF1 level via segregating miR-545-3p. Moreover, TRAF1 overexpression relieved the suppressive impact of circ_0038467 silence in LPS-triggered 16HBE cell detriment. CONCLUSION: Circ_0038467 knockdown mitigated LPS-exposed 16HBE cell damage through regulating miR-545-3p/PPARA axis.
Asunto(s)
MicroARNs , Neumonía , ARN Circular , Factor 1 Asociado a Receptor de TNF , Humanos , Recién Nacido , Apoptosis , Proliferación Celular , Inflamación , Lipopolisacáridos , MicroARNs/genética , Factor 1 Asociado a Receptor de TNF/genética , ARN Circular/genéticaRESUMEN
INTRODUCTION: A genome-wide association analysis revealed a rheumatoid arthritis (RA)-risk-associated genetic locus on chromosome 9, which contained the tumor necrosis factor receptor-associated factor 1 (TRAF1). However, the detail mechanism by TRAF1 signaled to fibroblast-like synoviocytes (FLSs) apoptosis remains to be fully understood. MATERIALS AND METHODS: Synovial tissue of 10 RA patients and osteoarthritis patients were obtained during joint replacement surgery. We investigated TRAF1 level and FLSs apoptosis percentage in vivo and elucidated the mechanism involved in the regulation of apoptotic process in vitro. RESULTS: We proved the significant increase of TRAF1 level in FLSs of RA patients and demonstrated that TRAF1 level correlated positively with DAS28 score and negatively with FLSs apoptosis. Treatment with siTRAF1 was able to decrease MMPs levels and the phosphorylated forms of JNK/NF-κB in vitro. Moreover, JNK inhibitor could attenuate expression of MMPs and increase percentage of apoptosis in RA-FLSs, while siTRAF1 could not promote apoptosis when RA-FLSs were pretreated with JNK activator. CONCLUSIONS: High levels of TRAF1 in RA synovium play an important role in the synovial hyperplasia of RA by suppressing apoptosis through activating JNK/NF-kB-dependent signaling pathways in response to the engagement of CD40.
Asunto(s)
Artritis Reumatoide , Antígenos CD40/metabolismo , Sinoviocitos , Apoptosis , Artritis Reumatoide/metabolismo , Proliferación Celular , Células Cultivadas , Fibroblastos/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , MAP Quinasa Quinasa 4/metabolismo , FN-kappa B/metabolismo , Membrana Sinovial/patología , Sinoviocitos/metabolismo , Factor 1 Asociado a Receptor de TNF/genética , Factor 1 Asociado a Receptor de TNF/metabolismoRESUMEN
OBJECTIVES: This study aimed to explore the underlying role and mechanism of LINC00313 in osteoarthritis (OA) progression. METHODS: CHON-001 chondrocytes were treated with interleukin (IL)-1ß to induce OA in vitro, and then transfected with LINC00313 overexpression plasmids (pcDNA-LINC00313) or small interfering RNA against tumor necrosis factor (TNF) receptor-associated factor 1 (si-TRAF1). Cell viability, apoptosis, levels of inflammatory cytokines tumor necrosis factor-α (TNF-α), IL-6 and IL-8, and expression of extracellular matrix (ECM) degradation related proteins in CHON-001 cells were determined. TRAF1 promoter methylation were was detected with methylation-specific polymerase chain reaction (MSP) assay. Furthermore, a c-Jun N-terminal kinase (JNK) signaling activator was used to confirm whether the apoptosis signal-regulating kinase 1 (ASK1)/JNK signaling pathway was involved in the function of LINC00313/TRAF1 axis in chondrocytes. In addition, an OA mouse model was established and lentivirus LINC00313 overexpression vector (Lv-LINC00313) was injected, and then inflammatory cytokine levels, ECM protein expression, and pathological changes in cartilage tissues were detected. RESULTS: LINC00313 was downregulated and TRAF1 was upregulated in OA cartilage tissues. LINC00313 overexpression or TRAF1 silencing attenuated IL-1ß-induced viability inhibition, apoptosis, inflammation and ECM degradation in CHON-001 cells. Moreover, LINC00313 inhibited TRAF1 expression through promoting DNA methyltransferase 1 (DNMT1) mediated promoter methylation. TRAF1 overexpression reversed the effects of LINC00313 on IL-1ß-induced chondrocyte injury. LINC00313 overexpression inhibited the ASK1/JNK signaling pathway, and JNK activator reversed the effect. In addition, Lv-LINC00313 treatment alleviated cartilage tissue damage and cartilage matrix degradation in OA mice. CONCLUSIONS: LINC00313 alleviated OA progression through inhibiting TRAF1 expression and the ASK1/JNK signaling pathway.
Asunto(s)
Sistema de Señalización de MAP Quinasas , Osteoartritis , Animales , Apoptosis , ADN/metabolismo , ADN/farmacología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , MAP Quinasa Quinasa Quinasa 5/metabolismo , MAP Quinasa Quinasa Quinasa 5/farmacología , Metilación , Metiltransferasas/metabolismo , Metiltransferasas/farmacología , Ratones , Osteoartritis/genética , Osteoartritis/metabolismo , ARN Interferente Pequeño , Factor 1 Asociado a Receptor de TNF/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Sunitinib resistance can be classified into primary and secondary resistance. While accumulating research has indicated several underlying factors contributing to sunitinib resistance, the precise mechanisms in renal cell carcinoma are still unclear. METHODS: RNA sequencing and m6A sequencing were used to screen for functional genes involved in sunitinib resistance. In vitro and in vivo experiments were carried out and patient samples and clinical information were obtained for clinical analysis. RESULTS: We identified a tumor necrosis factor receptor-associated factor, TRAF1, that was significantly increased in sunitinib-resistant cells, resistant cell-derived xenograft (CDX-R) models and clinical patients with sunitinib resistance. Silencing TRAF1 increased sunitinib-induced apoptotic and antiangiogenic effects. Mechanistically, the upregulated level of TRAF1 in sunitinib-resistant cells was derived from increased TRAF1 RNA stability, which was caused by an increased level of N6-methyladenosine (m6A) in a METTL14-dependent manner. Moreover, in vivo adeno-associated virus 9 (AAV9) -mediated transduction of TRAF1 suppressed the sunitinib-induced apoptotic and antiangiogenic effects in the CDX models, whereas knockdown of TRAF1 effectively resensitized the sunitinib-resistant CDXs to sunitinib treatment. CONCLUSIONS: Overexpression of TRAF1 promotes sunitinib resistance by modulating apoptotic and angiogenic pathways in a METTL14-dependent manner. Targeting TRAF1 and its pathways may be a novel pharmaceutical intervention for sunitinib-treated patients.
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Adenosina , Carcinoma de Células Renales , Neoplasias Renales , Metiltransferasas , Sunitinib , Factor 1 Asociado a Receptor de TNF , Adenosina/análogos & derivados , Inhibidores de la Angiogénesis/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Células Renales/irrigación sanguínea , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Humanos , Neoplasias Renales/irrigación sanguínea , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Metiltransferasas/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Sunitinib/farmacología , Factor 1 Asociado a Receptor de TNF/genética , Factor 1 Asociado a Receptor de TNF/metabolismoRESUMEN
RNA-binding proteins (RBPs) are key regulators of gene expression. RBP dysregulation is reported to play essential roles in tumorigenesis. However, the role of RBPs in urothelial carcinoma of the bladder (UCB) is only starting to be unveiled. Here, we comprehensively assessed the mRNA expression landscape of 104 RBPs from two independent UCB cohorts, Sun Yat-sen University Cancer Center (SYSUCC) and The Cancer Genome Atlas (TCGA). Fragile X-related gene 1 (FXR1) was identified as a novel cancer driver gene in UCB. FXR1 overexpression was found to be related to the poor survival rate in the SYSUCC and TCGA cohorts. Functionally, FXR1 promotes UCB proliferation and tumorigenesis. Mechanistically, FXR1 serves as a platform to recruit CFIm25 and CFIm68, forming a novel 3' processing machinery that functions in sequence-specific poly(A) site recognition. FXR1 affects the 3' processing of Tumor necrosis factor receptor-associated factor 1 (TRAF1) mRNA, which leads to nuclear stabilization. The novel regulatory relationship between FXR1 and TRAF1 can enhance cell proliferation and suppress apoptosis. Our data collectively highlight the novel regulatory role of FXR1 in TRAF1 3' processing as an important determinant of UCB oncogenesis. Our study provides new insight into RBP function and provides a potential therapeutic target for UCB.
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Carcinoma de Células Transicionales , Proteínas de Unión al ARN , Factor 1 Asociado a Receptor de TNF , Neoplasias de la Vejiga Urinaria , Carcinogénesis/genética , Carcinoma de Células Transicionales/genética , Línea Celular Tumoral , Factor de Especificidad de Desdoblamiento y Poliadenilación , Regulación Neoplásica de la Expresión Génica , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Factor 1 Asociado a Receptor de TNF/genética , Factor 1 Asociado a Receptor de TNF/metabolismo , Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Factores de Escisión y Poliadenilación de ARNmRESUMEN
TRAF1 is a pro-survival adaptor molecule in TNFR superfamily (TNFRSF) signaling. TRAF1 is overexpressed in many B cell cancers including refractory chronic lymphocytic leukemia (CLL). Little has been done to assess the role of TRAF1 in human cancer. Here we show that the protein kinase C related kinase Protein Kinase N1 (PKN1) is required to protect TRAF1 from cIAP-mediated degradation during constitutive CD40 signaling in lymphoma. We show that the active phospho-Thr774 form of PKN1 is constitutively expressed in CLL but minimally detected in unstimulated healthy donor B cells. Through a screen of 700 kinase inhibitors, we identified two inhibitors, OTSSP167, and XL-228, that inhibited PKN1 in the nanomolar range and induced dose-dependent loss of TRAF1 in RAJI cells. OTSSP167 or XL-228 treatment of primary patient CLL samples led to a reduction in TRAF1, pNF-κB p65, pS6, pERK, Mcl-1 and Bcl-2 proteins, and induction of activated caspase-3. OTSSP167 synergized with venetoclax in inducing CLL death, correlating with loss of TRAF1, Mcl-1, and Bcl-2. Although correlative, these findings suggest the PKN1-TRAF1 signaling axis as a potential new target for CLL. These findings also suggest the use of the orally available inhibitor OTSSP167 in combination treatment with venetoclax for TRAF1 overexpressing CLL.
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Leucemia Linfocítica Crónica de Células B , Naftiridinas/uso terapéutico , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Naftiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal , Factor 1 Asociado a Receptor de TNF/genéticaRESUMEN
Preterm birth (PTB) is a leading global cause of infant mortality. Risk factors include genetics, lifestyle choices and infection. Understanding the mechanism of PTB could aid the development of novel approaches to prevent PTB. This study aimed to investigate the metabolic biomarkers of PTB in early pregnancy and the association of significant metabolites with participant genotypes. Maternal sera collected at 16 and 20 weeks of gestation, from women who previously experienced PTB (high-risk) and women who did not (low-risk controls), were analysed using 1H nuclear magnetic resonance (NMR) metabolomics and genome-wide screening microarray. ANOVA and probabilistic neural network (PNN) modelling were performed on the spectral bins. Metabolomics genome-wide association (MGWAS) of the spectral bins and genotype data from the same participants was applied to determine potential metabolite-gene pathways. Phenylalanine, acetate and lactate metabolite differences between PTB cases and controls were obtained by ANOVA and PNN showed strong prediction at week 20 (AUC = 0.89). MGWAS identified several metabolite bins with strong genetic associations. Cis-eQTL analysis highlighted TRAF1 (involved in the inflammatory pathway) local to a non-coding SNP associated with lactate at week 20 of gestation. MGWAS of a well-defined cohort of participants highlighted a lactate-TRAF1 relationship that could potentially contribute to PTB.
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Ácido Láctico/sangre , Espectroscopía de Resonancia Magnética , Metaboloma , Metabolómica , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Nacimiento Prematuro/sangre , Nacimiento Prematuro/genética , Factor 1 Asociado a Receptor de TNF/genética , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Edad Gestacional , Humanos , Redes Neurales de la Computación , Fenotipo , Valor Predictivo de las Pruebas , Embarazo , Nacimiento Prematuro/diagnóstico , Estudios Prospectivos , Medición de Riesgo , Factores de RiesgoRESUMEN
Host genetics are important to consider in the role of resistance or susceptibility for developing active pulmonary tuberculosis (TB). Several association studies have reported the role of variants in STAT4 and TRAF1/C5 as risk factors to autoimmune diseases. Nevertheless, more data is needed to elucidate the role of these gene variants in infectious disease. Our data reports for the first time, variant rs10818488 in the TRAF1/C5 gene (found 47% of the population worldwide), is associated with susceptibility (OR = 1.51) to development TB. Multivariate analysis evidenced association between rs10818488 TRAF1/C5 and risk to multibacillary TB (OR = 4.18), confers increased bacteria load in the lung, indicates a decreased ability to control pathogen levels in the lung, and spread of the pathogen to new hosts. We showed that the "loss-of-function" variant in TRAF1/C5 led to susceptibility for TB by decreased production of TNF-α. Our results suggest the role of variant TRAF1/C5 in susceptibility to TB as well as in clinical presentation of multibacillary TB.