RESUMEN
TNF is a potent cytokine known for its involvement in physiology and pathology. In Rheumatoid Arthritis (RA), persistent TNF signals cause aberrant activation of synovial fibroblasts (SFs), the resident cells crucially involved in the inflammatory and destructive responses of the affected synovial membrane. However, the molecular switches that control the pathogenic activation of SFs remain poorly defined. Cyld is a major component of deubiquitination (DUB) machinery regulating the signaling responses towards survival/inflammation and programmed necrosis that induced by cytokines, growth factors and microbial products. Herein, we follow functional genetic approaches to understand how Cyld affects arthritogenic TNF signaling in SFs. We demonstrate that in spontaneous and induced RA models, SF-Cyld DUB deficiency deteriorates arthritic phenotypes due to increased levels of chemokines, adhesion receptors and bone-degrading enzymes generated by mutant SFs. Mechanistically, Cyld serves to restrict the TNF-induced hyperactivation of SFs by limiting Tak1-mediated signaling, and, therefore, leading to supervised NF-κB and JNK activity. However, Cyld is not critically involved in the regulation of TNF-induced death of SFs. Our results identify SF-Cyld as a regulator of TNF-mediated arthritis and inform the signaling landscape underpinning the SF responses.
Asunto(s)
Artritis Reumatoide , Enzima Desubiquitinante CYLD , Fibroblastos , Quinasa I-kappa B , Quinasas Quinasa Quinasa PAM , Transducción de Señal , Membrana Sinovial , Fibroblastos/metabolismo , Fibroblastos/patología , Enzima Desubiquitinante CYLD/metabolismo , Enzima Desubiquitinante CYLD/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Animales , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Ratones , Quinasa I-kappa B/metabolismo , Quinasa I-kappa B/genética , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Artritis Reumatoide/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Humanos , FN-kappa B/metabolismo , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
BACKGROUND: Prostate cancer (PCa) is one of the most common malignant tumors of the male urinary system, and its incidence and mortality rates have been increasing worldwide. Benign prostatic hyperplasia (BPH) represents stromal and epithelial cell proliferation in the prostate in elderly males. Abnormal activation of inflammation-related signalling molecules, such as toll-like receptor 4 (TLR4) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) has been linked to the initiation and progression of various human diseases including PCa and BPH. Cylindromatosis (CYLD) gene alterations are associated with PCa progression. In this study, the contribution of CYLD, JAK2, and TLR4 gene variants to PCa and BPH risks and their associations with prostate-specific antigen (PSA) levels, immunophenotype, and clinical features in Vietnamese men were determined. METHODS: A total of 102 patients with PCa, 65 with BPH, and 114 healthy controls were enrolled. The immunophenotype was analyzed by flow cytometry, cytokine secretion by enzyme-linked immunosorbent assay (ELISA), and gene variants by DNA sequencing. RESULTS: Lower levels of transforming growth factor ß (TGF-ß) and higher numbers of CD13+CD117- and CD56+CD25+ cells were observed in the PCa group than in the BPH group. Genetic analysis of the CYLD gene identified five single nucleotide polymorphisms (SNPs), of which c.2351-47 C>T, c.2351-46A>T, and rs1971432171 T>G had significantly higher frequencies in PCa patients than in the control and BPH groups. Sequencing of the TLR4 gene revealed five nucleotide changes, in which the rs2149356 SNP showed an increased risk for both PCa and BPH and the c.331-206 SNP had a reduced risk for PCa. Importantly, the expansion of activated natural killer (NK) cells and higher levels of PSA were found in PCa patients carrying the CT genotype of the CYLD c.2351-47 compared to those with the wild-type genotype. CONCLUSION: Activation of NK cells in CYLD-sensitive PCa patients was associated with serum PSA release and the CYLD c.2351-47 variant may be a significant risk factor for prostatitis in PCa patients.
Asunto(s)
Enzima Desubiquitinante CYLD , Janus Quinasa 2 , Antígeno Prostático Específico , Hiperplasia Prostática , Neoplasias de la Próstata , Receptor Toll-Like 4 , Humanos , Masculino , Hiperplasia Prostática/genética , Hiperplasia Prostática/sangre , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/sangre , Receptor Toll-Like 4/genética , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Antígeno Prostático Específico/sangre , Anciano , Janus Quinasa 2/genética , Persona de Mediana Edad , Inmunofenotipificación , Genotipo , Polimorfismo de Nucleótido Simple , Estudios de Casos y ControlesRESUMEN
BACKGROUND/AIM: Breast cancer is a leading cause of cancer-related deaths among women. Down-regulation of the tumor suppressor gene Cyld in breast cancer has been linked to a poor prognosis. This study investigated the role of Cyld in breast cancer using conditional mutant mouse models carrying a Cyld mutation, which inactivates the deubiquitinating activity of its protein product CYLD in mammary epithelial cells. MATERIALS AND METHODS: We examined the potential of CYLD inactivation to induce mammary tumors spontaneously or modify the susceptibility of mice to mammary tumorigenesis by DMBA treatment or ErbB2 over-expression. RESULTS: CYLD inactivation significantly increased susceptibility to breast cancer induced by either DMBA treatment or ErbB2 over-expression. Moreover, while CYLD inactivation alone did not lead to spontaneous mammary tumorigenesis, it did contribute to the formation of multifocal hyperplastic lesions in virgin mice of predominantly FVB/NJ background. CONCLUSION: Our study demonstrates the tumor enhancing potential of CYLD inactivation in mammary tumorigenesis in vivo and establishes novel relevant mouse models that can be exploited for developing prognostic and therapeutic protocols.
Asunto(s)
Enzima Desubiquitinante CYLD , Animales , Femenino , Ratones , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/genética , Mutación , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The inflammatory response is tightly regulated to eliminate invading pathogens and avoid excessive production of inflammatory mediators and tissue damage. Caspase-8 is a cysteine protease that is involved in programmed cell death. Here we show the TRIF-RIPK1-Caspase-8 is required for LPS-induced CYLD degradation in macrophages. TRIF functions in the upstream of RIPK1. The homotypic interaction motif of TRIF and the death domain of RIPK1 are essential for Caspase-8 activation. Caspase-8 cleaves CYLD and the D235A mutant is resistant to the protease activity of Caspase-8. TRIF and RIPK1 serve as substrates of Capase-8 in vitro. cFLIP interacts with Caspase-8 to modulate its protease activity on CYLD and cell death. Deficiency in TRIF, Caspase-8 or CYLD can lead to a decrease or increase in the expression of genes encoding inflammatory cytokines. Together, the TRIF-Caspase-8 and CYLD play opposite roles in the regulation of TLR4 signalling.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular , Caspasa 8 , Enzima Desubiquitinante CYLD , Lipopolisacáridos , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Transducción de Señal , Receptor Toll-Like 4 , Caspasa 8/metabolismo , Caspasa 8/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Enzima Desubiquitinante CYLD/metabolismo , Enzima Desubiquitinante CYLD/genética , Animales , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Ratones , Humanos , Regulación de la Expresión Génica , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL , Proteína de Dominio de Muerte Asociada a FasAsunto(s)
Enzima Desubiquitinante CYLD , Neoplasias Cutáneas , Humanos , Enzima Desubiquitinante CYLD/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Femenino , Masculino , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/patología , Índice de Severidad de la Enfermedad , LinajeRESUMEN
TNFα and IFNγ (TNF/IFNγ) synergistically induce caspase-8 activation and cancer cell death. However, the mechanism of IFNγ in promoting TNF-initiated caspase-8 activation in cancer cells is poorly understood. Here, we found that in addition to CASP8, CYLD is transcriptionally upregulated by IFNγ-induced transcription factor IRF1. IRF1-mediated CASP8 and CYLD upregulation additively mediates TNF/IFNγ-induced cancer cell death. Clinically, the expression levels of TNF, IFNγ, CYLD, and CASP8 in melanoma tumors are increased in patients responsive to immune checkpoint blockade (ICB) therapy after anti-PD-1 treatment. Accordingly, our genetic screen revealed that ELAVL1 (HuR) is required for TNF/IFNγ-induced caspase-8 activation. Mechanistically, ELAVL1 binds CASP8 mRNA and extends its stability to sustain caspase-8 expression both in IFNγ-stimulated and in basal conditions. Consequently, ELAVL1 determines death receptors-initiated caspase-8-dependent cell death triggered from stimuli including TNF and TRAIL by regulating basal/stimulated caspase-8 levels. As caspase-8 is a master regulator in cell death and inflammation, these results provide valuable clues for tumor immunotherapy and inflammatory diseases.
Asunto(s)
Inmunoterapia , Factor 1 Regulador del Interferón , Interferón gamma , Melanoma , Humanos , Caspasa 8/genética , Muerte Celular , Proteína 1 Similar a ELAV/genética , Inflamación , Factor 1 Regulador del Interferón/genética , Melanoma/genética , Interferón gamma/genética , Factor de Necrosis Tumoral alfa/genética , Enzima Desubiquitinante CYLD/genética , Animales , RatonesRESUMEN
Abnormal expression of Cylindromatosis (CYLD), a tumor suppressor molecule, plays an important role in tumor development and treatment. In this work, we found that CYLD binds to class I histone deacetylases (HDAC1 and HDAC2) through its N-terminal domain and inhibits HDAC1 activity. RNA sequencing showed that CYLD-HDAC axis regulates cellular antioxidant response via Nrf2 and its target genes. Then we revealed a mechanism that class I HDACs mediate redox abnormalities in CYLD low-expressing tumors. HDACs are central players in the DNA damage signaling. We further confirmed that CYLD regulates radiation-induced DNA damage and repair response through inhibiting class I HDACs. Furthermore, CYLD mediates nasopharyngeal carcinoma cell radiosensitivity through class I HDACs. Thus, we identified the function of the CYLD-HDAC axis in radiotherapy and blocking HDACs by Chidamide can increase the sensitivity of cancer cells and tumors to radiation therapy both in vitro and in vivo. In addition, ChIP and luciferase reporter assays revealed that CYLD could be transcriptionally regulated by zinc finger protein 202 (ZNF202). Our findings offer novel insight into the function of CYLD in tumor and uncover important roles for CYLD-HDAC axis in radiosensitivity, which provide new molecular target and therapeutic strategy for tumor radiotherapy.
Asunto(s)
Inhibidores de Histona Desacetilasas , Neoplasias Nasofaríngeas , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Estrés Oxidativo , Histona Desacetilasas/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Proteínas Represoras/metabolismoRESUMEN
Previous studies have revealed that B cell activation is regulated by various microRNAs(miRNAs). However, the role of microRNA-130b regulating B cell activation and apoptosis is still unclear. In the present study, we first found that the expression of miR-130b was the lowest in Pro/Pre-B cells and the highest in immature B cells. Besides, the expression of miR-130b decreased after activation in B cells. Through the immuno-phenotypic analysis of miR-130b transgenic and knockout mice, we found that miR-130b mainly promoted the proliferation of B cells and inhibited B cell apoptosis. Furthermore, we identified that Cyld, a tumor suppressor gene was the target gene of miR-130b in B cells. Besides, the Cyld-mediated NF-κB signaling was increased in miR-130b overexpressed B cells, which further explains the enhanced proliferation of B cells. In conclusion, we propose that miR-130b promotes B cell proliferation via Cyld-mediated NF-κB signaling, which provides a new theoretical basis for the molecular regulation of B cell activation.
Asunto(s)
MicroARNs , FN-kappa B , Animales , Ratones , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Transducción de Señal/genéticaRESUMEN
N6-Methyladenosine (m6A) mRNA methylation modification is regarded as an important mechanism involved in diverse physiological processes. YT521-B homology (YTH) domain family members are associated with the tumorigenesis of several cancers. However, the role of YTHDC2 in papillary thyroid cancer (PTC) progression remains unknown. Results showed that YTHDC1, YTHDF1, YTHDF2, and YTHDF3 showed no observable difference in thyroid cancer samples. YTHDC2 was significantly downregulated in thyroid cancer samples and cells. YTHDC2 inhibited cell proliferation in PTC cells. YTHDC2 elicited apoptosis in PTC cells, as demonstrated by the elevated expression of pro-apoptotic factors cl-caspase-3/caspase-3 and Bcl-2-associated (Bax), and the reduced anti-apoptotic B cell lymphoma-2 (Bcl-2) expression. There was a positive correlation between YTHDC2 and cylindromatosis (CYLD) expression based on GEPIA database. YTHDC2 increased CYLD expression in PTC cells. CYLD knockdown abolished the effects of YTHDC2 on PTC cell proliferation and apoptosis. Additionally, YTHDC2 inactivated the protein kinase B (Akt) pathway by increasing CYLD in PTC cells. Overall, YTHDC2 inhibited cell proliferation and induced apoptosis in PTC cells by regulating CYLD-mediated inactivation of Akt pathway.
Asunto(s)
Proteínas Proto-Oncogénicas c-akt , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Caspasa 3/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Proliferación Celular/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Apoptosis/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , ARN HelicasasRESUMEN
Tumor suppressor cylindromatosis (CYLD) dysfunction by its downregulation is significantly associated with poor prognosis in patients with glioblastoma (GBM), the most aggressive and malignant type of glioma. However, no effective treatment is currently available for patients with CYLDdownregulated GBM. The aim of the present study was to identify the crucial cell signaling pathways and novel therapeutic targets for CYLD downregulation in GBM cells. CYLD knockdown in GBM cells induced GBM malignant characteristics, such as proliferation, metastasis, and GBM stemlike cell (GSC) formation. Comprehensive proteomic analysis and RNA sequencing data from the tissues of patients with GBM revealed that Wnt/ßcatenin signaling was significantly activated by CYLD knockdown in patients with GBM. Furthermore, a Wnt/ßcatenin signaling inhibitor suppressed all CYLD knockdowninduced malignant characteristics of GBM. Taken together, the results of the present study revealed that Wnt/ßcatenin signaling is responsible for CYLD silencinginduced GBM malignancy; therefore, targeting Wnt/ßcatenin may be effective for the treatment of CYLDnegative patients with GBM with poor prognosis.
Asunto(s)
Glioblastoma , Humanos , Glioblastoma/patología , beta Catenina/genética , Proteómica , Vía de Señalización Wnt/genética , Regulación hacia Abajo , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismoRESUMEN
The CYLD gene is a tumor suppressor, reduced in many cancers. Here, we aimed to investigate CYLD protein level and NF-κß/TNF-α signaling pathway in rectal cancer patients with Lactobacillus acidophilus (L. acidophilus) consumption. One hundred ten patients with non-metastatic rectal cancer were randomly divided into L. acidophilus probiotic (500 mg, three times daily) and placebo groups for 13 weeks. The expression of CYLD, TNF-α, and NF-κB proteins and the genes involved in the NF-κß/TNF-α pathway were evaluated using ELISA and qPCR techniques. The survival rate was measured after five years. Unlike the placebo group, the results showed a significant increase in the expression of CYLD protein and tumor suppressor genes, including FOXP3, ROR-γ, Caspase3, GATA3, T-bet, and a considerable decrease in the expression of NF-Òß and TNF-α proteins and oncogenes, including STAT3, 4, 5, 6, and SMAD 3, in the probiotic group. A higher overall survival rate was seen after L. acidophilus consumption compared to the placebo group (P < 0.05). L. acidophilus consumption can reduce inflammation factors by affecting CYLD protein and its downstream signaling pathways. A schematic plot of probiotic consumption Effects on the CYLD protein in regulating the NF-Ä¸ß signaling pathway in colorectal cancer. NF-Ä¸ß can be activated by canonical and noncanonical pathways, which rely on IκB degradation and p100 processing, respectively. In the canonical NF-κß pathway, dimmers, such as p65/p50, are maintained in the cytoplasm by interacting with an IκBα protein. The binding of a ligand to a cell-surface receptor activates TRAF2, which triggers an IKK complex, containing -α, -ß, -g, which phosphorylates IKK-ß. It then phosphorylates IκB-α, leading to K48-ubiquitination and degradation of this protein. The p65/p50 protein freely enters the nucleus to turn on target genes. The non-canonical pathway is primarily involved in p100/RelB activation. It differs from the classical pathway in that only certain receptor signals activate this pathway. It proceeds through an IKK complex that contains two IKK-α subunits but not NEMO. Several materials including peptidoglycan, phorbol, myristate, acetate, and gram-positive bacteria such as probiotics inhibit NF-κB by inducing CYLD. This protein can block the canonical and noncanonical NF-κß pathways by removing Lys-63 ubiquitinated chains from activated TRAFs, RIP, NEMO, and IKK (α, ß, and γ). Moreover, TNF-α induces apoptosis by binding caspase-3 to FADD.
Asunto(s)
Neoplasias , Probióticos , Humanos , Factor de Necrosis Tumoral alfa , Enzima Desubiquitinante CYLD/genética , Lactobacillus acidophilus , FN-kappa B , Transducción de Señal , Probióticos/farmacología , Probióticos/uso terapéuticoRESUMEN
The lysine 63 deubiquitinase cylindromatosis (CYLD) is expressed at high levels in the brain and is considered to be involved in anxious and depressive behavior, cognitive inflexibility, and autism disorders. Previous research was limited in some brain regions, including the hippocampus, striatum, and amygdala. To better understand whether CYLD plays a role in adaptation to stress and which brain regions are involved, we analyzed the behavior of CYLD-knockout mice in the elevated plus maze (EPM) and light-dark box test (LDT) after acute restraint stress (ARS) and mapped their c-Fos immunoreactivity in brain sections. Here we report that CYLD deficiency leads to an unexpected reaction to ARS in mice, and is accompanied by significant neuronal activation of brain regions including the medial prefrontal cortex (mPFC), dorsal striatum (DS), nucleus accumbens (NAc), and basal lateral amygdala (BLA), but not ventral hippocampus (vHPC). Our findings show that CYLD participates in ARS-induced anxious behavior and that this involves multiple brain regions.
Asunto(s)
Encéfalo , Estrés Psicológico , Ratones , Animales , Ratones Noqueados , Estrés Psicológico/genética , Encéfalo/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ansiedad/genética , Corteza Prefrontal/metabolismo , Enzima Desubiquitinante CYLD/genéticaRESUMEN
CYLD lysine 63 deubiquitinase (CYLD) is a ubiquitin hydrolase with important roles in immunity and cancer. Complete CYLD ablation, truncation and expression of alternate isoforms, including short CYLD, drive distinct phenotypes and offer insights into CYLD function in inflammation, cell death, cell cycle progression and cell transformation. Research in diverse model systems has shown that these are mediated via CYLD regulation of cellular pathways including the NF-κB, Wnt and TGF-ß pathways. Recent biochemical advances and models have offered new insights into the regulation and function of CYLD. In addition, recent discoveries of gain-of-function germline pathogenic CYLD variants in patients with a neurodegenerative phenotype contrast with the more widely known loss-of-function mutations seen in patients with CYLD cutaneous syndrome and with sporadic cancers. Here, we provide a current review of mechanistic insights into CYLD function gained from CYLD animal models, as well as an update on the role of CYLD in human disease.
Asunto(s)
Inflamación , Modelos Biológicos , Animales , Humanos , Muerte Celular , División Celular , Modelos Animales , Enzima Desubiquitinante CYLD/genéticaRESUMEN
BACKGROUND: Cylindroma of the breast is a rare benign neoplasm. Since its first description in 2001, 20 cases have been reported in the literature. METHODS AND RESULTS: We report another case of this rare tumor in a 60-year-old woman with demonstration of the underlying molecular alteration. Histologically, the tumor showed the typical "jigsaw" pattern of a dual population of cells with a triple-negative phenotype. The pathognomonic mutation of the CYLD gene mutation was detected by whole exome sequencing. Cylindromas show morphological overlap with the solid-basaloid variant of adenoid cystic carcinoma, which renders this differential diagnosis difficult. However, distinction of these two lesions is of outmost importance, since cylindromas, in contrast to solid-basaloid variant of adenoid cystic carcinoma, behave in an entirely benign fashion. CONCLUSIONS: Careful evaluation of morphological features such as mitotic figures and cellular atypia is crucial in the diagnostic work-up of triple-negative breast lesions. It is important to keep cylindroma in mind as a pitfall and possible differential diagnosis for the solid-basaloid variant of adenoid cystic carcinoma. Molecular detection of CYLD gene mutation is helpful in cases with ambiguous histology. With this case report, we aim to contribute to a better understanding of mammary cylindroma and facilitate the diagnosis of this rare entity.
Asunto(s)
Carcinoma Adenoide Quístico , Humanos , Mama/patología , Carcinoma Adenoide Quístico/diagnóstico por imagen , Carcinoma Adenoide Quístico/genética , Enzima Desubiquitinante CYLD/genética , Diagnóstico Diferencial , Mutación/genética , Fenotipo , Femenino , Persona de Mediana EdadRESUMEN
Oxidative stress (OS) arises as a consequence of an imbalance between the formation of reactive oxygen species (ROS) and the capacity of antioxidant defense mechanisms to neutralize them. Excessive ROS production can lead to the damage of critical biomolecules, such as lipids, proteins, and DNA, ultimately contributing to the onset and progression of a multitude of diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer's disease, and cancer. Cylindromatosis (CYLD), initially identified as a gene linked to familial cylindromatosis, has a well-established and increasingly well-characterized function in tumor inhibition and anti-inflammatory processes. Nevertheless, burgeoning evidence suggests that CYLD, as a conserved deubiquitination enzyme, also plays a pivotal role in various key signaling pathways and is implicated in the pathogenesis of numerous diseases driven by oxidative stress. In this review, we systematically examine the current research on the function and pathogenesis of CYLD in diseases instigated by oxidative stress. Therapeutic interventions targeting CYLD may hold significant promise for the treatment and management of oxidative stress-induced human diseases.
Asunto(s)
Estrés Oxidativo , Transducción de Señal , Humanos , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Oxidación-ReducciónRESUMEN
Periodontitis is a chronic immune inflammatory disease that can lead to the destruction and loss of the tooth-supporting apparatus. During this process, the balance between bone absorption mediated by osteoclasts and bone formation mediated by osteoblasts is damaged. Consistent with previous studies, we observed that depletion of cylindromatosis (CYLD) resulted in an osteoporotic bone phenotype. However, the effect of CYLD deficiency on periodontitis is undetermined. Here, we investigated whether CYLD affects periodontal tissue homeostasis in experimental periodontitis in Cyld knockout (KO) mice, and we explored the underlying mechanisms. Interestingly, we discovered significant alveolar bone density loss and severely reduced alveolar bone height in Cyld KO mice with experimentally induced periodontitis. We observed increased osteoclast number and activity in both the femurs and alveolar bones, accompanied by the downregulation of osteogenesis genes and upregulation of osteoclastogenesis genes of alveolar bones in ligatured Cyld KO mice. Taken together, our findings demonstrate that the deletion of CYLD in mice plays a vital role in the pathogenesis of periodontal bone loss and suggest that CYLD might exert an ameliorative effect on periodontal inflammatory responses.
Asunto(s)
Pérdida de Hueso Alveolar , Periodontitis , Ratones , Animales , Pérdida de Hueso Alveolar/genética , Osteogénesis , Osteoclastos/patología , Periodontitis/genética , Periodontitis/patología , Huesos/patología , Enzima Desubiquitinante CYLD/genéticaRESUMEN
The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is a protease and scaffold protein essential in propagating B-cell receptor (BCR) signaling to NF-κB. The deubiquitinating enzyme cylindromatosis (CYLD) is a recently discovered MALT1 target that can negatively regulate NF-κB activation. Here, we show that low expression of CYLD is associated with inferior prognosis of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients, and that chronic BCR signaling propagates MALT1-mediated cleavage and, consequently, inactivation and rapid proteasomal degradation of CYLD. Ectopic overexpression of WT CYLD or a MALT1-cleavage resistant mutant of CYLD reduced phosphorylation of IκBα, repressed transcription of canonical NF-κB target genes and impaired growth of BCR-dependent lymphoma cell lines. Furthermore, silencing of CYLD expression rendered BCR-dependent lymphoma cell lines less sensitive to inhibition of NF-κΒ signaling and cell proliferation by BCR pathway inhibitors, e.g., the BTK inhibitor ibrutinib, indicating that these effects are partially mediated by CYLD. Taken together, our findings identify an important role for MALT1-mediated CYLD cleavage in BCR signaling, NF-κB activation and cell proliferation, which provides novel insights into the underlying molecular mechanisms and clinical potential of inhibitors of MALT1 and ubiquitination enzymes as promising therapeutics for DLBCL, MCL and potentially other B-cell malignancies.
Asunto(s)
Enzima Desubiquitinante CYLD , Linfoma de Células B Grandes Difuso , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , FN-kappa B , Humanos , Caspasas/metabolismo , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Linfoma de Células B Grandes Difuso/patología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , FN-kappa B/metabolismo , Receptores de Antígenos de Linfocitos B , Transducción de Señal/fisiologíaRESUMEN
Ubiquitination and deubiquitination of target proteins is an important mechanism for cells to rapidly respond to changes in the external environment. The deubiquitinase, cylindromatosis (CYLD), is a tumor suppressor protein. CYLD from Drosophila melanogaster participates in the antimicrobial immune response. In vertebrates, CYLD also regulates bacterial-induced apoptosis. However, whether CYLD can regulate the bacterial-induced innate immune response in crustaceans is unknown. In the present study, we reported the identification and cloning of CYLD in Chinese mitten crab, Eriocheir sinensis. Quantitative real-time reverse transcription polymerase chain reaction analysis showed that EsCYLD was widely expressed in all the examined tissues and was upregulated in the hemolymph after Vibrio parahaemolyticus challenge. Knockdown of EsCYLD in hemocytes promoted the cytoplasm-to-nucleus translocation of transcription factor Relish under V. parahaemolyticus stimulation and increased the expression of corresponding antimicrobial peptides. In vivo, silencing of EsCYLD promoted the removal of bacteria from the crabs and enhanced their survival. In addition, interfering with EsCYLD expression inhibited apoptosis of crab hemocytes caused by V. parahaemolyticus stimulation. In summary, our findings revealed that EsCYLD negatively regulates the nuclear translocation of Relish to affect the expression of corresponding antimicrobial peptides and regulates the apoptosis of crab hemocytes, thus indirectly participating in the innate immunity of E. sinensis.
Asunto(s)
Apoptosis , Proteínas de Artrópodos , Braquiuros , Enzima Desubiquitinante CYLD , Hemocitos , Inmunidad Innata , Factores de Transcripción , Animales , Secuencia de Aminoácidos , Péptidos Antimicrobianos/metabolismo , Proteínas de Artrópodos/clasificación , Proteínas de Artrópodos/genética , Proteínas de Artrópodos/metabolismo , Secuencia de Bases , Braquiuros/inmunología , Braquiuros/microbiología , Enzima Desubiquitinante CYLD/clasificación , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Hemocitos/enzimología , Inmunidad Innata/genética , Filogenia , Factores de Transcripción/metabolismo , Vibrio parahaemolyticus , Transporte Activo de Núcleo CelularRESUMEN
Osteosarcoma is a common human malignancy with a high mortality rate worldwide. Recent studies have been focused on understanding the involvement of microRNA (miRNAs) in the pathogenesis of osteosarcoma. Therefore, the present study aimed to measure the expression levels of miR-181a, cylindromatosis (CYLD), chromo box homolog 7 (CBX7), B-cell lymphoma 2 (BCL2), and tumor protein p53 in tumor tissue and adjacent normal tissues in patients with osteosarcoma and its relationship with clinicopathological factors. The expression levels of miR-181a, CYLD, CBX7, BCL2, and p53 were measured in 60 patients with osteosarcoma using quantitative real-time polymerase chain reaction. Finally, we compared the relationship between these gene levels and clinicopathological factors in tumor and healthy tissues. Our results showed that the expression levels of miR-181a, BCL2, and p53 were significantly higher in osteosarcoma tissue in comparison with normal tissues (p < .05). On the contrary, CYLD and CBX7 were downregulated in osteosarcoma tumor tissues compared to adjacent healthy tissues (p < .05). In addition, the expression levels of miR-181a in tumor tissues were strongly correlated with patients' age, tumor size, clinical stage, cancer grade, and lymph node metastasis (p < .05). Our findings highlight new insights into understanding the role of miR-181a in the pathogenesis of osteosarcoma. However, further studies are needed to elucidate miRNA as therapeutic targets for osteosarcoma.
Asunto(s)
Neoplasias Óseas , MicroARNs , Osteosarcoma , Humanos , Proteína p53 Supresora de Tumor/genética , Osteosarcoma/patología , MicroARNs/genética , Neoplasias Óseas/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Regulación Neoplásica de la Expresión Génica , Complejo Represivo Polycomb 1/genética , Enzima Desubiquitinante CYLD/genéticaRESUMEN
Toll-like receptor 4 (TLR4) is a key pattern recognition receptor that can be activated by bacterial lipopolysaccharide to elicit inflammatory response. Proper activation of TLR4 is critical for the host defense against microbial infections. Since overactivation of TLR4 causes deleterious effects and inflammatory diseases, its activation needs to be tightly controlled by negative regulatory mechanisms, among which the most pivotal could be deubiquitination of key signaling molecules mediated by deubiquitinating enzymes (DUBs). CYLD is a member of the USP family of DUBs that acts as a critical negative regulator of TLR4-depedent inflammatory responses by deconjugating polyubiquitin chains from signaling molecules, such as TRAF6 and TAK1. Dysregulation of CYLD is implicated in inflammatory diseases. However, how the function of CYLD is regulated during inflammatory response remains largely unclear. Recently, we and other authors have shown that Spata2 functions as an important CYLD partner to regulate enzymatic activity of CYLD and substrate binding by this protein. Here, we show that a Spata2-like protein, Spata2L, can also form a complex with CYLD to inhibit the TLR4-dependent inflammatory response. We found that Spata2L constitutively interacts with CYLD and that the deficiency of Spata2L enhances the LPS-induced NF-κB activation and proinflammatory cytokine gene expression. Mechanistically, Spata2L potentiated CYLD-mediated deubiquitination of TRAF6 and TAK1 likely by promoting CYLD enzymatic activity. These findings identify Spata2L as a novel CYLD regulator, provide new insights into regulatory mechanisms underlying CYLD role in TLR4 signaling, and suggest potential targets for modulating TLR4-induced inflammation.