ABSTRACT
The root endophytic fungus Serendipita indica establishes beneficial symbioses with a broad spectrum of plants and enhances host resilience against biotic and abiotic stresses. However, little is known about the mechanisms underlying S. indica-mediated plant protection. Here, we report S. indica effector (SIE) 141 and its host target CDSP32, a conserved thioredoxin-like protein, and underlying mechanisms for enhancing pathogen resistance and abiotic salt tolerance in Arabidopsis thaliana. SIE141 binding interfered with canonical targeting of CDSP32 to chloroplasts, leading to its re-location into the plant nucleus. This nuclear translocation is essential for both their interaction and resistance function. Furthermore, SIE141 enhanced oxidoreductase activity of CDSP32, leading to CDSP32-mediated monomerization and activation of NON-EXPRESSOR OF PATHOGENESIS-RELATED 1 (NPR1), a key regulator of systemic resistance. Our findings provide functional insights on how S. indica transfers well-known beneficial effects to host plants and indicate CDSP32 as a genetic resource to improve plant resilience to abiotic and biotic stresses.
Subject(s)
Arabidopsis , Salt Stress , Symbiosis , Arabidopsis/microbiology , Arabidopsis/physiology , Arabidopsis/genetics , Basidiomycota/physiology , Oxidoreductases/metabolism , Oxidoreductases/genetics , Cell Nucleus/metabolism , Fungal Proteins/metabolism , Fungal Proteins/genetics , Plastids/metabolism , Arabidopsis Proteins/metabolism , Arabidopsis Proteins/genetics , Plant Diseases/microbiologyABSTRACT
Many carcinomas feature hypoxia, a condition has long been associated with tumor progression and poor prognosis, as well as resistance to chemoradiotherapy. Here, we report that the F-box protein JFK promotes mammary tumor initiation and progression in MMTV-PyMT murine model of spontaneous breast cancer. We find that JFK is inducible under hypoxic conditions, in which hypoxia-inducible factor HIF-1α binds to and transcriptionally activates JFK in breast cancer cells. Consistently, analysis of public clinical datasets reveals that the mRNA level of JFK is positively correlated with that of HIF-1α in breast cancer. We show that JFK deficiency leads to a decrease in HIF-1α-induced glycolysis in breast cancer and sensitizes hypoxic breast cancer cells to ionizing radiation and chemotherapeutic treatment. These results indicate that JFK is an important player in hypoxic response, supporting the pursuit of JFK as a potential therapeutic target for breast cancer intervention.
ABSTRACT
Dysregulation of lipid metabolism could lead to the development of metabolic disorders. We report here that the F-box protein JFK promotes excessive lipid accumulation in adipose tissue and contributes to the development of metabolic syndrome. JFK transgenic mice develop spontaneous obesity, accompanied by dyslipidemia, hyperglycemia, and insulin resistance, phenotypes that are further exacerbated under high-fat diets. In contrast, Jfk knockout mice are lean and resistant to diet-induced metabolic malfunctions. Liver-specific reconstitution of JFK expression in Jfk knockout mice leads to hepatic lipid accumulation resembling human hepatic steatosis and nonalcoholic fatty liver disease. We show that JFK interacts with and destabilizes ING5 through assembly of the SCF complex. Integrative transcriptomic and genomic analysis reveals that the SCFJFK -ING5 axis interferes with AMPK activity and fatty acid ß-oxidation, leading to the suppression of hepatic lipid catabolism. Significantly, JFK is upregulated and AMPKα1 is down-regulated in liver tissues from NAFLD patients. These results reveal that SCFJFK is a bona fide E3 ligase for ING5 and link the SCFJFK -ING5 axis to the development of obesity and metabolic syndrome.
Subject(s)
Insulin Resistance , Metabolic Syndrome , Non-alcoholic Fatty Liver Disease , Animals , Diet, High-Fat/adverse effects , Humans , Lipid Metabolism/genetics , Liver/metabolism , Metabolic Syndrome/genetics , Metabolic Syndrome/metabolism , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Obesity/genetics , Obesity/metabolism , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolismABSTRACT
The microbial reduction of antimonate (Sb(v)) to antimonite (Sb(iii)), which forms insoluble Sb compounds, is a promising approach to remove antimony (Sb) from wastewater. Among the bacterial strains capable of reducing Sb(v) via anaerobic respiration that have been isolated to date, Dechloromonas sp. AR-2 and Propionivibrio sp. AR-3 are promising agents because they can grow aerobically and reduce Sb(v) under both anaerobic and microaerobic conditions. In this study, the effects of temperature, pH, electron donors, and coexisting electron acceptors on Sb(v) reduction and Sb removal by strains AR-2 and AR-3 were investigated to assess the usefulness of the strains in practical Sb treatment scenarios. Efficient Sb(v) reduction and removal by the two strains occurred over a relatively wide temperature range (15-35 °C) and neutral pH (6-7). In contrast, the carbon sources usable by these strains as electron donors for Sb respiration were limited to simple fatty acids such as acetate and lactate. Although strain AR-2 used nitrate and AR-3 used nitrate and arsenate as electron acceptors for anaerobic respiration in addition to Sb(v), the co-presence of other electron acceptors did not inhibit Sb(v) reduction. These results suggest that strains AR-2 and AR-3 can be potentially used in the practical treatment of Sb(v)-containing wastewater. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-02703-0.
ABSTRACT
Antimony (Sb), a toxic metalloid, exists mainly as Sb(V) and Sb(III) in the aquatic environment. Sb(V) displays greater solubility and can be reduced to insoluble Sb(III) compounds by microbial activities under anaerobic conditions, thus affecting the environmental fate of Sb. This study was conducted to evaluate the potential of Sb(V) reduction and removal from the aqueous phase by microbial communities existing in river sediments with and without the impact of Sb mining activities. Among the 14 tested sediment samples, which were collected from an urban river without Sb impact and a river flowing through mining area, microbial communities in two samples could reduce and remove Sb(V) in the presence of high concentrations of sulfate, whereas those in other six samples could reduce Sb(V) even under low sulfate concentrations, indicating the relatively wide distribution of microbial Sb(V) reduction potential in the environment, irrespective of the anthropogenic impact. The Sb(V) reduction and removal abilities under different sulfate levels also suggested the presence of multiple types of Sb(V) reduction and removal pathways, including the direct Sb(V) reduction by anaerobic respiration, indirect (chemical) Sb(V) reduction by sulfide produced by microbial sulfate reduction, and their combination. Furthermore, analysis of microbial communities in two enrichment cultures, which were constructed from sediment samples with Sb(V) reduction ability under the minimum sulfate condition and maintained Sb(V) removal ability during 28-d enrichment process, revealed possible contribution of several microbial taxa such as Azospira, Chlostridium, Dechloromonas, Dendrosporobacter, and Halodesulfovibrio to Sb(V) reduction in sediment microbial communities.
Subject(s)
Microbiota , Rivers , Antimony/analysis , Mining , SulfatesABSTRACT
Microbial antimonate (Sb(V)) reduction is a promising approach to remove Sb(V) from wastewater. However, current knowledge regarding microbial Sb(V) reduction is limited to strictly anaerobic conditions. This study was the first to isolate three facultative-anaerobic Sb(V)-reducing bacterial strains from the sludge collected from a wastewater treatment facility in an antimony products plant. Two of the isolated strains, designated Dechloromonas sp. AR-2 and Propionivibrio sp. AR-3, were characterized based on their Sb(V)-reducing abilities. When cultivated under anaerobic conditions with Sb(V) and acetate as the electron acceptor and donor, respectively, both strains could efficiently reduce 5.0 mM Sb(V), removing most of it from the water phase within 7 d. Along with Sb(V) reduction by the strains, white precipitates, which were likely amorphous Sb(OH)3 solids, were formed with a minor generation of soluble antimonite. Additionally, respiratory Sb(V) reduction by both strains occurred not only under anaerobic but also microaerobic conditions. It was suggested that Sb(V) reduction and the growth abilities of the strains under microaerobic conditions presented a substantial advantage of the use of strains AR-2 and AR-3 for practical applications to Sb(V)-containing wastewater treatment.
ABSTRACT
Hyperactivation of EGFR/PI3K/AKT is a prominent feature of various human cancers. Thus, understanding how this molecular cascade is balanced is of great importance. We report here that the ubiquitin-specific protease USP43 is physically associated with the chromatin remodeling NuRD complex and catalyzes H2BK120 deubiquitination. Functionally this coordinates the NuRD complex to repress a cohort of genes, including EGFR, which are critically involved in cell proliferation and carcinogenesis. We show that USP43 strongly suppresses the growth and metastasis of breast cancer in vivo. Interestingly, USP43 also exists in the cytoplasm, where it is phosphorylated by AKT, enabling its binding to the 14-3-3ß/ε heterodimer and sequestration in the cytoplasm. Significantly, hyperactivation of EGFR/PI3K/AKT in breast cancer is associated with the cytoplasmic retention of USP43 and thus, the inhibition of its transcriptional regulatory function. Moreover, cancer-associated mutations of USP43 affect its subcellular localization and/or epigenetic regulatory functions. Nuclear USP43 is significantly reduced in breast carcinomas and is associated with EGFR accumulation and AKT hyperactivation. A low level of nuclear USP43 correlates with higher histologic grades and poor prognosis. Our study identifies USP43 to be an H2BK120 deubiquitinase and a potential tumor suppressor and reveals a reciprocally inhibitory loop between USP43 and EGFR/PI3K/AKT, whose imbalance drives breast carcinogenesis.
Subject(s)
Breast Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Ubiquitin-Specific Proteases/metabolism , Breast Neoplasms/pathology , Cell Proliferation , ErbB Receptors/metabolism , Female , Humans , Ubiquitin-Specific Proteases/geneticsABSTRACT
BACKGROUND: Melanoma, originated from melanocytes located on the basal membrane of the epithelial tissue, is the most aggressive form of skin cancer that accounts for 75% of skin cancer-related death. Although it is believed that BRAF mutation and the mitogen-activated protein kinase (MAPK) pathway play critical roles in the pathogenesis of melanoma, how the MAPK signaling is regulated in melanoma carcinogenesis is still not fully understood. METHODS: We characterized JMJD6 expression in melanoma tissue array by immunohistochemistry analysis. We used human melanoma A375, 451Lu and SK-MEL-1 cell lines for in vitro proliferation and invasion experiments, and xenograft transplanted mice using murine melanoma B16F10 cells by bioluminescence imaging for in vivo tumor growth and pulmonary metastasis assessments. Endothelial tube formation assay, chicken yolk sac membrane assay and matrigel plug assay were performed to test the effect of JMJD6 on the angiogenic potential in vitro and in vivo. RESULTS: Here we report that the jumonji C domain-containing demethylase/hydroxylase JMJD6 is markedly up-regulated in melanoma. We found that high expression of JMJD6 is closely correlated with advanced clinicopathologic stage, aggressiveness, and poor prognosis of melanoma. RNA-seq showed that knockdown of JMJD6 affects the alternative splicing of a panel of transcripts including that encoding for PAK1, a key component in MAPK signaling pathway. We demonstrated that JMJD6 enhances the MAPK signaling and promotes multiple cellular processes including melanogenesis, proliferation, invasion, and angiogenesis in melanoma cells. Interestingly, JMJD6 is transcriptionally activated by c-Jun, generating a feedforward loop to drive the development and progression of melanoma. CONCLUSIONS: Our results indicate that JMJD6 is critically involved in melanoma carcinogenesis, supporting the pursuit of JMJD6 as a potential biomarker for melanoma aggressiveness and a target for melanoma intervention.
Subject(s)
Alternative Splicing , Jumonji Domain-Containing Histone Demethylases/metabolism , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Melanoma/metabolism , p21-Activated Kinases/genetics , Animals , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , Jumonji Domain-Containing Histone Demethylases/genetics , Luminescent Measurements , Lung Neoplasms/genetics , Lung Neoplasms/pathology , MAP Kinase Signaling System , Melanoma/genetics , Melanoma/pathology , Mice , Neoplasm Invasiveness , Neoplasm Staging , Neoplasm Transplantation , Prognosis , p21-Activated Kinases/metabolismABSTRACT
EGFR is required for animal development, and dysregulation of EGFR is critically implicated in malignant transformation. However, the molecular mechanism underlying the regulation of EGFR expression remains poorly explored. Here we report that the zinc-finger protein ZNF516 is a transcription repressor. ZNF516 is physically associated with the CtBP/LSD1/CoREST complex and transcriptionally represses a cohort of genes including EGFR that are critically involved in cell proliferation and motility. We demonstrate that the ZNF516-CtBP/LSD1/CoREST complex inhibits the proliferation and invasion of breast cancer cells in vitro and suppresses breast cancer growth and metastasis in vivo. Significantly, low expression of ZNF516 is positively associated with advanced pathological staging and poor survival of breast carcinomas. Our data indicate that ZNF516 is a transcription repressor and a potential suppressor of EGFR, adding to the understanding of EGFR-related breast carcinogenesis and supporting the pursuit of ZNF516 as a potential therapeutic target for breast cancer. EGFR is a well-known oncogene; however, the mechanisms regulating its expression are still unclear. Here, analysing genome-wide chromatin associations, the authors show that in breast cancer cells ZNF516 represses EGFR transcription through the interaction with the CtBP/LSD1/CoREST complex.
Subject(s)
Breast Neoplasms/genetics , Chromatin/metabolism , DNA-Binding Proteins/physiology , ErbB Receptors/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Co-Repressor Proteins/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , ErbB Receptors/metabolism , Female , HEK293 Cells , Histone Demethylases/metabolism , Humans , Kaplan-Meier Estimate , Models, Genetic , Neoplasm Invasiveness/genetics , Nerve Tissue Proteins/metabolism , Protein TransportABSTRACT
In this work, magnetic nanoparticles (MNPs) Fe3O4/CeO2 were firstly synthesized using three different preparation methods, including coprecipitation, impregnation oxidation-precipitation and impregnation reduction-precipitation, respectively. The catalytic activities of Fe3O4/CeO2 MNPs, prepared by above three methods, were compared systematically in terms of the degradation of orange G (OG). The impregnation oxidation-precipitation process was economical and maneuverable due to the usage of air, no need of nitrogen protection and higher utilization efficiency of iron. Response surface methodology based on central composite design were used to investigate the individual and interactive effects of three process parameters on the OG degradation, i.e. the initial pH of the solution, the dosage of H2O2 and the initial concentration of OG. Under the optimal conditions of pH 2.5, H2O2 30 mM, OG 50 mg L-1, catalyst 2.0 g L-1 and 35 °C, the degradation percentage of OG was 98.2% within 120 min, which agreed well with the modeling prediction (R2 = 0.9984, and Adj-R2 = 0.9969). And the degradation reaction well followed the first-order kinetic with R2 = 0.9969. The Fe3O4/CeO2-OX MNPs showed high catalytic activity, stability and reusability in the degradation of OG.