Smad ubiquitylation regulatory factor 1(Smurf1)is an important homologous member of E6-AP C-terminus type E3 ubiquitin ligase.Initially,Smurf1 was reportedly involved in the negative regulation of the bone morphogenes...Smad ubiquitylation regulatory factor 1(Smurf1)is an important homologous member of E6-AP C-terminus type E3 ubiquitin ligase.Initially,Smurf1 was reportedly involved in the negative regulation of the bone morphogenesis protein(BMP)pathway.After further research,several studies have confirmed that Smurf1 is widely involved in various biological processes,such as bone homeostasis regulation,cell migration,apoptosis,and planar cell polarity.At the same time,recent studies have provided a deeper understanding of the regulatory mechanisms of Smurf1’s expression,activity,and substrate selectivity.In our review,a brief summary of recent important biological functions and regulatory mechanisms of E3 ubiquitin ligase Smurf1 is proposed.展开更多
The ubiquitin-proteasome system(UPS)dedicates to degrade intracellular proteins to modulate demic homeostasis and functions of organisms.These enzymatic cascades mark and modifies target proteins diversly through cova...The ubiquitin-proteasome system(UPS)dedicates to degrade intracellular proteins to modulate demic homeostasis and functions of organisms.These enzymatic cascades mark and modifies target proteins diversly through covalently binding ubiquitin molecules.In the UPS,E3 ubiquitin ligases are the crucial constituents by the advantage of recognizing and presenting proteins to proteasomes for proteolysis.As the major regulators of protein homeostasis,E3 ligases are indispensable to proper cell manners in diverse systems,and they are well described in physiological bone growth and bone metabolism.Pathologically,classic bone-related diseases such as metabolic bone diseases,arthritis,bone neoplasms and bone metastasis of the tumor,etc.,were also depicted in a UPS-dependent manner.Therefore,skeletal system is versatilely regulated by UPS and it is worthy to summarize the underlying mechanism.Furthermore,based on the current status of treatment,normal or pathological osteogenesis and tumorigenesis elaborated in this review highlight the clinical significance of UPS research.As a strategy possibly remedies the limitations of UPS treatment,emerging PROTAC was described comprehensively to illustrate its potential in clinical application.Altogether,the purpose of this review aims to provide more evidence for exploiting novel therapeutic strategies based on UPS for bone associated diseases.展开更多
A myriad of abiotic stress responses in plants are controlled by abscisic acid(ABA)signaling.ABA receptors can be degraded by both the 26S proteasome pathway and vacuolar degradation pathway after processing via the e...A myriad of abiotic stress responses in plants are controlled by abscisic acid(ABA)signaling.ABA receptors can be degraded by both the 26S proteasome pathway and vacuolar degradation pathway after processing via the endosomal sorting complex required for transport(ESCRT)proteins.Despite being essential for ABA signaling,the upstream regulators of ESCRTs remain unknown.Here,we report that the ESCRT-I component VPS23A is an unstable protein that is degraded via the ubiquitin-proteasome system(UPS).The UEV domain of VPS23A physically interacts with the two PSAP motifs of XBAT35,an E3 ubiquitin ligase,and this interaction results in the deposition of K48 polyubiquitin chains on VPS23A,marking it for degradation by 26S proteasomes.We showed that XBAT35 in plants is a positive regulator of ABA responses that acts via the VPS23A/PYL4 complex,specifically by accelerating VPS23A turnover and thereby increasing accumulation of the ABA receptor PYL4.This work deciphers how an ESCRT component is regulated in plants and deepens our understanding of plant stress responses by illustrating a mechanism whereby crosstalk between the UPS and endosome-vacuole-mediated degradation pathways controls ABA signaling.展开更多
Background:Elucidation of the post-transcriptional modification has led to novel strategies to treat intractable tumors,especially glioblastoma(GBM).The ubiquitin-proteasome system(UPS)mediates a reversible,stringent ...Background:Elucidation of the post-transcriptional modification has led to novel strategies to treat intractable tumors,especially glioblastoma(GBM).The ubiquitin-proteasome system(UPS)mediates a reversible,stringent and stepwise post-translational modification which is closely associated with malignant processes of GBM.To this end,developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease.This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM.Based on the molecular identification,functional characterization,and mechanism investigation,we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM.Methods:We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase.Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT,UBA and WWE domain-containing E3 ubiquitin ligase 1(HUWE1)in GBM.dCas9 synergistic activation mediator system and recombinant adeno-associated virus(rAAV)were used to endogenously overexpress full-length HUWE1 in vitro and in glioma orthotopic xenografts.Results:Low expression of HUWE1 was closely associated with worse prognosis of GBM patients.The ubiquitination and subsequent degradation of N-Myc mediated by HUWE1,leading to the inactivation of downstream Delta-like 1(DLL1)-NOTCH1 signaling pathways,inhibited the proliferation,invasion,and migration of GBM cells in vitro and in vivo.A rAAV dual-vector system for packaging and delivery of dCas9-VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts.Conclusions:The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress GBM progression.Antitumor activity of rAAV dual-vector delivering dCas9-HUWE1 system uncovers a promising therapeutic strategy for GBM.展开更多
Epithelial cancer of the ovary exhibits the highest mortality rate of all gynecological malignancies in women today,since the disease is often diagnosed in advanced stages.While the treatment of cancer with specific c...Epithelial cancer of the ovary exhibits the highest mortality rate of all gynecological malignancies in women today,since the disease is often diagnosed in advanced stages.While the treatment of cancer with specific chemical agents or drugs is the favored treatment regimen,chemotherapy resistance greatly impedes successful ovarian cancer chemotherapy.Thus,chemoresistance becomes one of the most critical clinical issues confronted when treating patients with ovarian cancer.Convincing evidence hints that dysregulation of E3 ubiquitin ligases is a key factor in the development and maintenance of ovarian cancer chemoresistance.This review outlines recent advancement in our understanding of the emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance.We also highlight currently available inhibitors targeting E3 ligase activities and discuss their potential for clinical applications in treating chemoresistant ovarian cancer patients.展开更多
High yield is a major objective for peanut(Arachis hypogaea L.) breeding worldwide. However, fewer yield-related quantitative trait loci(QTL) have been reported in peanut than in other staple food crops such as rice(O...High yield is a major objective for peanut(Arachis hypogaea L.) breeding worldwide. However, fewer yield-related quantitative trait loci(QTL) have been reported in peanut than in other staple food crops such as rice(Oryza sativa), wheat(Triticum aestivum), and maize(Zea mays). This study aimed to identify stable major-effect QTL associated with pod yield per plant, hundred-pod weight for double-seeded pods,hundred-seed weight, shelling percentage, and pod number per plant, allowing us to predict candidate genes by means of transcriptome and genome sequencing. To this end, we used a population of recombinant inbred lines comprising 192 F9:11families derived from a JH6 × KX01-6 cross to construct a highresolution genetic map(1705.7 c M) consisting of 2273 polymorphic SNPs, with 0.75 c M(on average)between adjacent SNPs. We identified two high-confidence, yield-related QTL, qHYF_A08 and qHYF_B06, explaining 5.78%–31.40% of phenotypic variation and with LOD values of 5.10–24.48, in six environments. qHYF_A08 mainly explained the variation in shelling percentage, whereas qHYF_B06explained variation in hundred-pod weight and hundred-seed weight and accounted for 8.77%–31.40%of the variation in effective pod number per plant, pod number per plant, and shelling percentage. We narrowed down qHYF_B06 to an 890-kb interval using an advanced mapping population.Transcriptome and genome analyses revealed that only Arahy.129FS0 and Arahy.3R9A5K in the candidate mapping interval were differentially expressed between JH6 and KX01-6, with substantial structural variations in their promoter and coding regions. Genotypes of 208 peanut accessions determined using a diagnostic CAPS marker suggested that the two haplotypes of Arahy.3R9A5K were highly associated with hundred-seed weight and hundred-pod weight;this diagnostic CAPs marker could therefore be useful for selecting high-yielding lines during peanut breeding. Overall, our results provide valuable information for cloning alleles with favorable effects on peanut yield.展开更多
Animal behaviors and higher-order functions rely on complex neural circuits built by synaptic connections(synapses)to deliver messages among different brain cells.As the major mediator in the nervous system,neurons co...Animal behaviors and higher-order functions rely on complex neural circuits built by synaptic connections(synapses)to deliver messages among different brain cells.As the major mediator in the nervous system,neurons communicate via synapses,which undergo constant structural remodeling with strict regulation.It展开更多
E3 ubiquitin ligases are involved in various physiological processes,and they play pivotal roles in growth and development.In this study,we identified a previously unknown gene in the apple fruit(Malus×domestica)...E3 ubiquitin ligases are involved in various physiological processes,and they play pivotal roles in growth and development.In this study,we identified a previously unknown gene in the apple fruit(Malus×domestica)and named it MdMIEL1.The MdMIEL1 gene encoded a protein that contained a zinc-finger domain at its N-terminus and a RING-finger motif at its C-terminus.To investigate MdMIEL1 functions,we generated transgenic Arabidopsis lines expressing the MdMIEL1 gene under the control of the Cauliflower mosaic virus 35S promoter.Interestingly,ectopic expression of MdMIEL1 in Arabidopsis produced multiple phenotypes,including early germination,early flowering and a lateral root number increase relative to wild-type plants.Further analysis indicated that MdMIEL1 regulated lateral root initiation by increasing auxin accumulation in the roots.In a word,these results suggest that,MdMIEL1 as a novel RING-finger ubiquitin ligase influences plant growth and development,and highlight that MdMIEL1 regulates lateral root growth.展开更多
Objective:The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer target.We aimed to study whether NEDD8(neural precursor cell expressed,developmentall...Objective:The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer target.We aimed to study whether NEDD8(neural precursor cell expressed,developmentally down-regulated 8)might serve as a therapeutic target in esophageal squamous cell carcinoma(ESCC).Methods:The clinical relevance of NEDD8 expression was evaluated by using The Cancer Genome Atlas(TCGA)database and tissue arrays.NEDD8-knockdown ESCC cells generated with the CRISPR/Cas9 system were used to explore the anticancer effects and mechanisms.Quantitative proteomic analysis was used to examine the variations in NEDD8 knockdown-induced biological pathways.The cell cycle and apoptosis were assessed with fluorescence activated cell sorting.A subcutaneous-transplantation mouse tumor model was established to investigate the anticancer potential of NEDD8 silencing in vivo.Results:NEDD8 was upregulated at both the mRNA and protein expression levels in ESCC,and NEDD8 overexpression was associated with poorer overall patient survival(mRNA level:P=0.028,protein level:P=0.026,log-rank test).Downregulation of NEDD8 significantly suppressed tumor growth both in vitro and in vivo.Quantitative proteomic analysis revealed that downregulation of NEDD8 induced cell cycle arrest,DNA damage,and apoptosis in ESCC cells.Mechanistic studies demonstrated that NEDD8 knockdown led to the accumulation of cullin-RING E3 ubiquitin ligases(CRLs)substrates through inactivation of CRLs,thus suppressing the malignant phenotype by inducing cell cycle arrest and apoptosis in ESCC.Rescue experiments demonstrated that the induction of apoptosis after NEDD8 silencing was attenuated by DR5 knockdown.Conclusions:Our study elucidated the anti-ESCC effects and underlying mechanisms of NEDD8 knockdown,and validated NEDD8 as a potential target for ESCC therapy.展开更多
Protein ubiquitination is essential for diverse cellular functions including spermatogenesis.The tripartite motif(TRIM)family proteins,most of which have E3 ubiquitin ligase activity,are highly conserved in mammals.Th...Protein ubiquitination is essential for diverse cellular functions including spermatogenesis.The tripartite motif(TRIM)family proteins,most of which have E3 ubiquitin ligase activity,are highly conserved in mammals.They are involved in important cellular processes such as embryonic development,immunity,and fertility.Our previous studies indicated that Trim69,a testis-specific expressed TRIM family gene,potentially participates in the spermatogenesis by mediating testicular cells apoptosis.In this study,we investigated the biological functions of Trim69 in male mice by established Trim69 knockout mice with CRISPR/Cas9 genomic editing technology.Here,we reported that the male Trim69 knockout mice had normal fertility.The adult knockout mice have shown that the appearance of testes,testis/body weight ratios,testicular histomorphology,and the number and quality of sperm were consistent with wild-type mice.These results indicated that the E3 ubiquitin ligase protein Trim69 was not essential for male mouse fertility,and it might be compensated by other TRIM family members such as Trim58 in Trim69-deficiency testis.This study would help to elucidate the functions of tripartite motif protein family and the regulation of spermatogenesis.展开更多
The deltex family protein DTX3 is believed to possess E3 ubiquitin ligase activity,as it contains a classic RING finger domain.However,its biological role and the underlying mechanism in cancer remain largely elusive....The deltex family protein DTX3 is believed to possess E3 ubiquitin ligase activity,as it contains a classic RING finger domain.However,its biological role and the underlying mechanism in cancer remain largely elusive.Here,we identified DTX3 as a novel mutant p53-interacting protein in ovarian carcinoma.Mechanistically,DTX3 mediated mutant p53 ubiqui-tination and stabilization by perturbing the MDM2-mutant p53 interaction,consequently leading to activation of diverse.mutant p53 target genes.Importantly,a positive correlation between the expression of DTX3 and mutant p53 target genes was further validated in ovarian carcinomas.Ectopic DTX3 promoted,while depletion of DTX3 suppressed,ovarian cancer cell proliferation and invasion.Remarkably,the pro-tumorigenic effect of DTX3 is dependent on mutant p53,because ablation of mutant p53 significantly impaired DTX3-induced gene expression and ovarian cancer cell growth and propagation.Furthermore,DTX3 elevated the expressi on of muta nt p53 target genes and boosted ovarian tumor growth in vivo.Fin ally,DTX3 was amplified and overexpressed in ovarian carci no mas,which is sign ificantly associated with unfavorable prognosis.Altogether,our findings unveil the oncogenic role of DTX3 in ovarian cancer development by bolstering mutant p53 activity.展开更多
Plant U-box(PUB)E3 ubiquitin ligases play important roles in hormone signaling pathways and in response to different abiotic stresses,but little is known about U-box genes in Danshen(root of Salvia miltiorrhiza Bunge)...Plant U-box(PUB)E3 ubiquitin ligases play important roles in hormone signaling pathways and in response to different abiotic stresses,but little is known about U-box genes in Danshen(root of Salvia miltiorrhiza Bunge).Here,we identified and characterized 70 SmPUB genes based on its genome sequence.Phylogenetic analysis of U-box genes from S.miltiorrhiza and Arabidopsis suggested that they can be clustered into seven subgroups(I–VII).Typical U-box domains were found in all identified SmPUB genes through the analysis of conserved motifs.Moreover,qRT-PCR was applied to analyze the relative expression levels of U-box genes in S.miltiorrhiza roots and leaves under PEG-induced water deficit and salt stresses.Results revealed that the SmPUB genes exhibited stronger response to drought than to salt stress.To the best of our knowledge,this report is the first to perform genome-wide identification and analysis of the U-box gene family in S.miltiorrhiza,and the results provide valuable information for better understanding of the function of U-box in S.miltiorrhiza.展开更多
Interferon regulatory factors(IRFs)play pivotal and critical roles in innate and adaptive immune responses;thus,precise and stringent regulation of the stability and activation of IRFs in physiological processes is ne...Interferon regulatory factors(IRFs)play pivotal and critical roles in innate and adaptive immune responses;thus,precise and stringent regulation of the stability and activation of IRFs in physiological processes is necessary.The stability and activities of IRFs are directly or indirectly targeted by endogenous and exogenous proteins in an ubiquitin-dependent manner.However,few reviews have summarized how host E3 ligases/DUBs or viral proteins regulate IRF stability and activity.Additionally,with recent technological developments,details about the ubiquitination of IRFs have been continuously revealed.As knowledge of how these proteins function and interact with IRFs may facilitate a better understanding of the regulation of IRFs in immune responses or other biological processes,we summarized current studies on the direct ubiquitination of IRFs,with an emphasis on how these proteins interact with IRFs and affect their activities,which may provide exciting targets for drug development by regulating the functions of specific E3 ligases.展开更多
Green plants on the earth have evolved intricate mechanisms to acclimatize to and utilize sunlight.In Arabidopsis,light signals are perceived by photoreceptors and transmitted through divergent but overlapping signali...Green plants on the earth have evolved intricate mechanisms to acclimatize to and utilize sunlight.In Arabidopsis,light signals are perceived by photoreceptors and transmitted through divergent but overlapping signaling networks to modulate plant photomorphogenic development.COP1(CONSTITUTIVE PHOTOMORPHOGENIC 1)was first cloned as a central repressor of photomorphogenesis in higher plants and has been extensively studied for over 30 years.It acts as a RING E3 ubiquitin ligase downstream of multiple photoreceptors to target key light-signaling regulators for degradation,primarily as part of large protein complexes.The mammalian counterpart of COP1 is a pluripotent regulator of tumorigenesis and metabolism.A great deal of information on COP1 has been derived from whole-genome sequencing and functional studies in lower green plants,which enables us to illustrate its evolutionary history.Here,we reviewthe current understanding about COP1,with a focus on the conservation and functional diversification of COP1 and its signaling partners in different taxonomic clades.展开更多
The mammalian target of rapamycin(mTOR)critically regulates several essential biological functions,such as cell growth,metabolism,survival,and immune response by forming two important complexes,namely,mTOR complex 1(m...The mammalian target of rapamycin(mTOR)critically regulates several essential biological functions,such as cell growth,metabolism,survival,and immune response by forming two important complexes,namely,mTOR complex 1(mTORC1)and complex 2(mTORC2).mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target.Great efforts have been made to develop efficacious mTOR inhibitors,particularly mTOR kinase inhibitors,which suppress mTORC1 and mTORC2;however,major success has not been achieved.With the strong scientific rationale,the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics.Beyond early findings on induced activation of PI3K/Akt,MEK/ERK,and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy,recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations.These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy.Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.展开更多
The mutation of the Parkin gene is a cause of familial Parkinson’s disease.A growing body of evidence suggests that Parkin also functions as a tumor suppressor.Parkin is an ubiquitin E3 ligase,and plays important rol...The mutation of the Parkin gene is a cause of familial Parkinson’s disease.A growing body of evidence suggests that Parkin also functions as a tumor suppressor.Parkin is an ubiquitin E3 ligase,and plays important roles in a variety of cellular processes implicated in tumorigenesis,including cell cycle,cell proliferation,apoptosis,metastasis,mitophagy and metabolic reprogramming.Here we review the role and mechanism of Parkin in cancer.展开更多
Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the P...Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene,which itself belongs to an E3 ubiquitin ligase.Since the discovery of the Parkin gene in the late 1990s,researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP,the Parkin gene is associated with many diseases,including type 2 diabetes,leprosy,Alzheimer’s,autism,and cancer.Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis.In general,the Parkin gene,a well-established tumor suppressor,is deficient and mutated in a variety of malignancies.Parkin overexpres-sion inhibits tumor cell growth and promotes apoptosis.However,the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood.This article describes the structure,functions,and post-transla-tional modifications of Parkin,and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.展开更多
Tumor necrosis factor receptor-associated factor(TRAF)proteins are conserved in higher eukaryotes and play key roles in transducing cellular signals across different organelles.They are characterized by their C-termin...Tumor necrosis factor receptor-associated factor(TRAF)proteins are conserved in higher eukaryotes and play key roles in transducing cellular signals across different organelles.They are characterized by their C-terminal region(TRAF-C domain)containing seven to eight antiparallelβ-sheets,also known as the meprin and TRAF-C homology(MATH)domain.Over the past few decades,significant progress has been made toward understanding the diverse roles of TRAF proteins in mammals and plants.Compared to other eukaryotic species,the Arabidopsis thaliana and rice(Oryza sativa)genomes encode many more TRAF/MATH domaincontaining proteins;these plant proteins cluster into five classes:TRAF/MATH-only,MATH-BPM,MATH-UBP(ubiquitin protease),Seven in absentia(SINA),and MATH-Filament and MATHPEARLI-4 proteins,suggesting parallel evolution of TRAF proteins in plants.Increasing evidence now indicates that plant TRAF proteins form central signaling networks essential for multiple biological processes,such as vegetative and reproductive development,autophagosome formation,plant immunity,symbiosis,phytohormone signaling,and abiotic stress responses.Here,we summarize recent advances and highlight future prospects for understanding on the molecular mechanisms by which TRAF proteins act in plant development and stress responses.展开更多
Drought is a major threat to alfalfa(Medicago sativa L.)production.The discovery of important alfalfa genes regulating drought response will facilitate breeding for drought-resistant alfalfa cultivars.Here,we report a...Drought is a major threat to alfalfa(Medicago sativa L.)production.The discovery of important alfalfa genes regulating drought response will facilitate breeding for drought-resistant alfalfa cultivars.Here,we report a genome-wide association study of drought resistance in alfalfa.We identified and functionally characterized an MYB-like transcription factor gene(MsMYBH),which increases the drought resistance in alfalfa.Compared with the wild-types,the biomass and forage quality were enhanced in MsMYBH overexpressed plants.Combined RNA-seq,proteomics and chromatin immunoprecipitation analysis showed that MsMYBH can directly bind to the promoters of MsMCP1,MsMCP2,MsPRX1A and MsCARCAB to improve their expression.The outcomes of such interactions include better water balance,high photosynthetic efficiency and scavenge excess H_(2)O_(2)in response to drought.Furthermore,an E3 ubiquitin ligase(MsWAV3)was found to induce MsMYBH degradation under long-term drought,via the 26S proteasome pathway.Furthermore,variable-number tandem repeats in MsMYBH promoter were characterized among a collection of germplasms,and the variation is associated with promoter activity.Collectively,our findings shed light on the functions of MsMYBH and provide a pivotal gene that could be leveraged for breeding drought-resistant alfalfa.This discovery also offers new insights into the mechanisms of drought resistance in alfalfa.展开更多
基金supported by the Natural Science Foundation of Hubei Province(No.2021CFB155)China Postdoctoral Science Foundation(No.2021M701338)Part of the work was supported by Postdoctoral Creative Research Positions of Hubei Province of China(No.2021).
文摘Smad ubiquitylation regulatory factor 1(Smurf1)is an important homologous member of E6-AP C-terminus type E3 ubiquitin ligase.Initially,Smurf1 was reportedly involved in the negative regulation of the bone morphogenesis protein(BMP)pathway.After further research,several studies have confirmed that Smurf1 is widely involved in various biological processes,such as bone homeostasis regulation,cell migration,apoptosis,and planar cell polarity.At the same time,recent studies have provided a deeper understanding of the regulatory mechanisms of Smurf1’s expression,activity,and substrate selectivity.In our review,a brief summary of recent important biological functions and regulatory mechanisms of E3 ubiquitin ligase Smurf1 is proposed.
基金supported,in part,by the National Natural Science Foundation of China Grants(82022047,81972100)National Key Research and Development Program of China Grants(2019YFA0906001)Guangdong Provincial Science and Technology Innovation Council Grant(2017B030301018,China)。
文摘The ubiquitin-proteasome system(UPS)dedicates to degrade intracellular proteins to modulate demic homeostasis and functions of organisms.These enzymatic cascades mark and modifies target proteins diversly through covalently binding ubiquitin molecules.In the UPS,E3 ubiquitin ligases are the crucial constituents by the advantage of recognizing and presenting proteins to proteasomes for proteolysis.As the major regulators of protein homeostasis,E3 ligases are indispensable to proper cell manners in diverse systems,and they are well described in physiological bone growth and bone metabolism.Pathologically,classic bone-related diseases such as metabolic bone diseases,arthritis,bone neoplasms and bone metastasis of the tumor,etc.,were also depicted in a UPS-dependent manner.Therefore,skeletal system is versatilely regulated by UPS and it is worthy to summarize the underlying mechanism.Furthermore,based on the current status of treatment,normal or pathological osteogenesis and tumorigenesis elaborated in this review highlight the clinical significance of UPS research.As a strategy possibly remedies the limitations of UPS treatment,emerging PROTAC was described comprehensively to illustrate its potential in clinical application.Altogether,the purpose of this review aims to provide more evidence for exploiting novel therapeutic strategies based on UPS for bone associated diseases.
基金grant 2016YFA0500500 from the National Key R&D Program of Chinagrant 31800228 from the National Natural Science Foundation of China.
文摘A myriad of abiotic stress responses in plants are controlled by abscisic acid(ABA)signaling.ABA receptors can be degraded by both the 26S proteasome pathway and vacuolar degradation pathway after processing via the endosomal sorting complex required for transport(ESCRT)proteins.Despite being essential for ABA signaling,the upstream regulators of ESCRTs remain unknown.Here,we report that the ESCRT-I component VPS23A is an unstable protein that is degraded via the ubiquitin-proteasome system(UPS).The UEV domain of VPS23A physically interacts with the two PSAP motifs of XBAT35,an E3 ubiquitin ligase,and this interaction results in the deposition of K48 polyubiquitin chains on VPS23A,marking it for degradation by 26S proteasomes.We showed that XBAT35 in plants is a positive regulator of ABA responses that acts via the VPS23A/PYL4 complex,specifically by accelerating VPS23A turnover and thereby increasing accumulation of the ABA receptor PYL4.This work deciphers how an ESCRT component is regulated in plants and deepens our understanding of plant stress responses by illustrating a mechanism whereby crosstalk between the UPS and endosome-vacuole-mediated degradation pathways controls ABA signaling.
基金from National Key R&D Program of China(2016YFA0101200 to XWB)the National Natural Science Foundation of China(81602196 to TL)+1 种基金the Special Grant for Chongqing Postdoctoral Researcher Research Project(xmT2017001 to TL)the Postdoctoral Support Program for Innovative Talent(BX201600022 to TL)'Open Project of Key Laboratory of Tumor Immunopathology of Ministry of Education(2020jsz603 to YY).
文摘Background:Elucidation of the post-transcriptional modification has led to novel strategies to treat intractable tumors,especially glioblastoma(GBM).The ubiquitin-proteasome system(UPS)mediates a reversible,stringent and stepwise post-translational modification which is closely associated with malignant processes of GBM.To this end,developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease.This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM.Based on the molecular identification,functional characterization,and mechanism investigation,we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM.Methods:We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase.Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT,UBA and WWE domain-containing E3 ubiquitin ligase 1(HUWE1)in GBM.dCas9 synergistic activation mediator system and recombinant adeno-associated virus(rAAV)were used to endogenously overexpress full-length HUWE1 in vitro and in glioma orthotopic xenografts.Results:Low expression of HUWE1 was closely associated with worse prognosis of GBM patients.The ubiquitination and subsequent degradation of N-Myc mediated by HUWE1,leading to the inactivation of downstream Delta-like 1(DLL1)-NOTCH1 signaling pathways,inhibited the proliferation,invasion,and migration of GBM cells in vitro and in vivo.A rAAV dual-vector system for packaging and delivery of dCas9-VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts.Conclusions:The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress GBM progression.Antitumor activity of rAAV dual-vector delivering dCas9-HUWE1 system uncovers a promising therapeutic strategy for GBM.
基金the National Natural Science Foundation of China(31972884,81903083)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(81821002)+1 种基金National Clinical Research Center for Geriatrics(Z20201007)1·3·5 Project for Disciplines of Excellence,West China Hospital(ZYGD18003),Sichuan University.
文摘Epithelial cancer of the ovary exhibits the highest mortality rate of all gynecological malignancies in women today,since the disease is often diagnosed in advanced stages.While the treatment of cancer with specific chemical agents or drugs is the favored treatment regimen,chemotherapy resistance greatly impedes successful ovarian cancer chemotherapy.Thus,chemoresistance becomes one of the most critical clinical issues confronted when treating patients with ovarian cancer.Convincing evidence hints that dysregulation of E3 ubiquitin ligases is a key factor in the development and maintenance of ovarian cancer chemoresistance.This review outlines recent advancement in our understanding of the emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance.We also highlight currently available inhibitors targeting E3 ligase activities and discuss their potential for clinical applications in treating chemoresistant ovarian cancer patients.
基金jointly supported by the Earmarked Fund for CARS-13the Modern Agricultural Industrial Technology System of Hebei Province (HBCT2018090101 and HBCT2018090201)+3 种基金the Science and Technology Innovation Team of Modern Peanut Seed Industry (21326316D)the Technology Innovation Special Project(2022KJCXZX-LYS-11)the Basic Research Funds of Hebei Academy of Agriculture and Forestry Sciences (2021060201)the Talents Construction Project of Science and Technology Innovation,Hebei Academy of Agriculture and Forestry Sciences (C22R0311)。
文摘High yield is a major objective for peanut(Arachis hypogaea L.) breeding worldwide. However, fewer yield-related quantitative trait loci(QTL) have been reported in peanut than in other staple food crops such as rice(Oryza sativa), wheat(Triticum aestivum), and maize(Zea mays). This study aimed to identify stable major-effect QTL associated with pod yield per plant, hundred-pod weight for double-seeded pods,hundred-seed weight, shelling percentage, and pod number per plant, allowing us to predict candidate genes by means of transcriptome and genome sequencing. To this end, we used a population of recombinant inbred lines comprising 192 F9:11families derived from a JH6 × KX01-6 cross to construct a highresolution genetic map(1705.7 c M) consisting of 2273 polymorphic SNPs, with 0.75 c M(on average)between adjacent SNPs. We identified two high-confidence, yield-related QTL, qHYF_A08 and qHYF_B06, explaining 5.78%–31.40% of phenotypic variation and with LOD values of 5.10–24.48, in six environments. qHYF_A08 mainly explained the variation in shelling percentage, whereas qHYF_B06explained variation in hundred-pod weight and hundred-seed weight and accounted for 8.77%–31.40%of the variation in effective pod number per plant, pod number per plant, and shelling percentage. We narrowed down qHYF_B06 to an 890-kb interval using an advanced mapping population.Transcriptome and genome analyses revealed that only Arahy.129FS0 and Arahy.3R9A5K in the candidate mapping interval were differentially expressed between JH6 and KX01-6, with substantial structural variations in their promoter and coding regions. Genotypes of 208 peanut accessions determined using a diagnostic CAPS marker suggested that the two haplotypes of Arahy.3R9A5K were highly associated with hundred-seed weight and hundred-pod weight;this diagnostic CAPs marker could therefore be useful for selecting high-yielding lines during peanut breeding. Overall, our results provide valuable information for cloning alleles with favorable effects on peanut yield.
基金supported by the grants from the National Basic Research Program of China (973 Program)(No.2013CB945602)the National Natural Science Foundation of China(No.31270825 and 31171043)
文摘Animal behaviors and higher-order functions rely on complex neural circuits built by synaptic connections(synapses)to deliver messages among different brain cells.As the major mediator in the nervous system,neurons communicate via synapses,which undergo constant structural remodeling with strict regulation.It
基金supported by National Natural Science Foundation of China (31272142, 31325024, 31471854)Ministry of Education of China (IRT15R42)
文摘E3 ubiquitin ligases are involved in various physiological processes,and they play pivotal roles in growth and development.In this study,we identified a previously unknown gene in the apple fruit(Malus×domestica)and named it MdMIEL1.The MdMIEL1 gene encoded a protein that contained a zinc-finger domain at its N-terminus and a RING-finger motif at its C-terminus.To investigate MdMIEL1 functions,we generated transgenic Arabidopsis lines expressing the MdMIEL1 gene under the control of the Cauliflower mosaic virus 35S promoter.Interestingly,ectopic expression of MdMIEL1 in Arabidopsis produced multiple phenotypes,including early germination,early flowering and a lateral root number increase relative to wild-type plants.Further analysis indicated that MdMIEL1 regulated lateral root initiation by increasing auxin accumulation in the roots.In a word,these results suggest that,MdMIEL1 as a novel RING-finger ubiquitin ligase influences plant growth and development,and highlight that MdMIEL1 regulates lateral root growth.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81602072,81902380,81820108022,and 81625018)Innovation Program of Shanghai Municipal Education Commission(Grant No.2019-01-07-00-10-E00056)+5 种基金Program of Shanghai Academic/Technology Research Leader(Grant No.18XD1403800)National High Technology Research and Development Program of China(Grant No.2015AA021107-019)Scientific Research Project of Shanghai Science and Technology Commission(Grant No.18411960600)Shanghai Technological Innovation Action Projects(Grant No.18411950800)Shanghai‘Rising Stars of Medical Talent’Youth Development Program,Outstanding Youth Medical Talents,2018the Shanghai Sailing Program(Grant No.17YF1405000).
文摘Objective:The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer target.We aimed to study whether NEDD8(neural precursor cell expressed,developmentally down-regulated 8)might serve as a therapeutic target in esophageal squamous cell carcinoma(ESCC).Methods:The clinical relevance of NEDD8 expression was evaluated by using The Cancer Genome Atlas(TCGA)database and tissue arrays.NEDD8-knockdown ESCC cells generated with the CRISPR/Cas9 system were used to explore the anticancer effects and mechanisms.Quantitative proteomic analysis was used to examine the variations in NEDD8 knockdown-induced biological pathways.The cell cycle and apoptosis were assessed with fluorescence activated cell sorting.A subcutaneous-transplantation mouse tumor model was established to investigate the anticancer potential of NEDD8 silencing in vivo.Results:NEDD8 was upregulated at both the mRNA and protein expression levels in ESCC,and NEDD8 overexpression was associated with poorer overall patient survival(mRNA level:P=0.028,protein level:P=0.026,log-rank test).Downregulation of NEDD8 significantly suppressed tumor growth both in vitro and in vivo.Quantitative proteomic analysis revealed that downregulation of NEDD8 induced cell cycle arrest,DNA damage,and apoptosis in ESCC cells.Mechanistic studies demonstrated that NEDD8 knockdown led to the accumulation of cullin-RING E3 ubiquitin ligases(CRLs)substrates through inactivation of CRLs,thus suppressing the malignant phenotype by inducing cell cycle arrest and apoptosis in ESCC.Rescue experiments demonstrated that the induction of apoptosis after NEDD8 silencing was attenuated by DR5 knockdown.Conclusions:Our study elucidated the anti-ESCC effects and underlying mechanisms of NEDD8 knockdown,and validated NEDD8 as a potential target for ESCC therapy.
基金supported by the National Key Research and Development Program of China(No.2018YFC1003503-2,No.2017YFA0103803,and No.2016YFA0500903)the National Natural Science Foundation of China(No.31890784)。
文摘Protein ubiquitination is essential for diverse cellular functions including spermatogenesis.The tripartite motif(TRIM)family proteins,most of which have E3 ubiquitin ligase activity,are highly conserved in mammals.They are involved in important cellular processes such as embryonic development,immunity,and fertility.Our previous studies indicated that Trim69,a testis-specific expressed TRIM family gene,potentially participates in the spermatogenesis by mediating testicular cells apoptosis.In this study,we investigated the biological functions of Trim69 in male mice by established Trim69 knockout mice with CRISPR/Cas9 genomic editing technology.Here,we reported that the male Trim69 knockout mice had normal fertility.The adult knockout mice have shown that the appearance of testes,testis/body weight ratios,testicular histomorphology,and the number and quality of sperm were consistent with wild-type mice.These results indicated that the E3 ubiquitin ligase protein Trim69 was not essential for male mouse fertility,and it might be compensated by other TRIM family members such as Trim58 in Trim69-deficiency testis.This study would help to elucidate the functions of tripartite motif protein family and the regulation of spermatogenesis.
基金This study was supported by the National Natural Science Foundation of China(No.81672566,81874053,81972431,and 81702352)the Basic and Clinical Translational Research Fundi ng from Fudan University Sha nghai Cancer Center.
文摘The deltex family protein DTX3 is believed to possess E3 ubiquitin ligase activity,as it contains a classic RING finger domain.However,its biological role and the underlying mechanism in cancer remain largely elusive.Here,we identified DTX3 as a novel mutant p53-interacting protein in ovarian carcinoma.Mechanistically,DTX3 mediated mutant p53 ubiqui-tination and stabilization by perturbing the MDM2-mutant p53 interaction,consequently leading to activation of diverse.mutant p53 target genes.Importantly,a positive correlation between the expression of DTX3 and mutant p53 target genes was further validated in ovarian carcinomas.Ectopic DTX3 promoted,while depletion of DTX3 suppressed,ovarian cancer cell proliferation and invasion.Remarkably,the pro-tumorigenic effect of DTX3 is dependent on mutant p53,because ablation of mutant p53 significantly impaired DTX3-induced gene expression and ovarian cancer cell growth and propagation.Furthermore,DTX3 elevated the expressi on of muta nt p53 target genes and boosted ovarian tumor growth in vivo.Fin ally,DTX3 was amplified and overexpressed in ovarian carci no mas,which is sign ificantly associated with unfavorable prognosis.Altogether,our findings unveil the oncogenic role of DTX3 in ovarian cancer development by bolstering mutant p53 activity.
基金This work was supported by the National Natural Science Foundation of China(31871694,31800255)the Fundamental Research Funds of Zhejiang Sci-Tech University(2020Q022,14042216-Y).
文摘Plant U-box(PUB)E3 ubiquitin ligases play important roles in hormone signaling pathways and in response to different abiotic stresses,but little is known about U-box genes in Danshen(root of Salvia miltiorrhiza Bunge).Here,we identified and characterized 70 SmPUB genes based on its genome sequence.Phylogenetic analysis of U-box genes from S.miltiorrhiza and Arabidopsis suggested that they can be clustered into seven subgroups(I–VII).Typical U-box domains were found in all identified SmPUB genes through the analysis of conserved motifs.Moreover,qRT-PCR was applied to analyze the relative expression levels of U-box genes in S.miltiorrhiza roots and leaves under PEG-induced water deficit and salt stresses.Results revealed that the SmPUB genes exhibited stronger response to drought than to salt stress.To the best of our knowledge,this report is the first to perform genome-wide identification and analysis of the U-box gene family in S.miltiorrhiza,and the results provide valuable information for better understanding of the function of U-box in S.miltiorrhiza.
基金supported by the National Key Research and Development Program of China(2018YFA0800503 and 2018YFD0500100)an excellent young scientist foundation of NSFC(31822017)+2 种基金Zhejiang Provincial Natural Science Foundation of China(LR19C080001)the National Natural Science Foundation of China(81572651 and 81771675)the Fundamental Research Funds for the Central Universities。
文摘Interferon regulatory factors(IRFs)play pivotal and critical roles in innate and adaptive immune responses;thus,precise and stringent regulation of the stability and activation of IRFs in physiological processes is necessary.The stability and activities of IRFs are directly or indirectly targeted by endogenous and exogenous proteins in an ubiquitin-dependent manner.However,few reviews have summarized how host E3 ligases/DUBs or viral proteins regulate IRF stability and activity.Additionally,with recent technological developments,details about the ubiquitination of IRFs have been continuously revealed.As knowledge of how these proteins function and interact with IRFs may facilitate a better understanding of the regulation of IRFs in immune responses or other biological processes,we summarized current studies on the direct ubiquitination of IRFs,with an emphasis on how these proteins interact with IRFs and affect their activities,which may provide exciting targets for drug development by regulating the functions of specific E3 ligases.
基金supported by grants from National Key R&D Program of China(2017YFA0503800)National Natural Science Foundation of China(31330048,31621001)+3 种基金Peking-Tsinghua Center for Life SciencesPeking UniversitySouthern University of Science and TechnologyXiamen University.
文摘Green plants on the earth have evolved intricate mechanisms to acclimatize to and utilize sunlight.In Arabidopsis,light signals are perceived by photoreceptors and transmitted through divergent but overlapping signaling networks to modulate plant photomorphogenic development.COP1(CONSTITUTIVE PHOTOMORPHOGENIC 1)was first cloned as a central repressor of photomorphogenesis in higher plants and has been extensively studied for over 30 years.It acts as a RING E3 ubiquitin ligase downstream of multiple photoreceptors to target key light-signaling regulators for degradation,primarily as part of large protein complexes.The mammalian counterpart of COP1 is a pluripotent regulator of tumorigenesis and metabolism.A great deal of information on COP1 has been derived from whole-genome sequencing and functional studies in lower green plants,which enables us to illustrate its evolutionary history.Here,we reviewthe current understanding about COP1,with a focus on the conservation and functional diversification of COP1 and its signaling partners in different taxonomic clades.
文摘The mammalian target of rapamycin(mTOR)critically regulates several essential biological functions,such as cell growth,metabolism,survival,and immune response by forming two important complexes,namely,mTOR complex 1(mTORC1)and complex 2(mTORC2).mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target.Great efforts have been made to develop efficacious mTOR inhibitors,particularly mTOR kinase inhibitors,which suppress mTORC1 and mTORC2;however,major success has not been achieved.With the strong scientific rationale,the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics.Beyond early findings on induced activation of PI3K/Akt,MEK/ERK,and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy,recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations.These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy.Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.
基金supported by grants to Z.F.from the NIH(R01CA227912)Rutgers Cancer Institute of New Jersey Pilot Award,and by grants to W.H.from the NIH(R01CA160558,R01CA203965)Ellison Medical Foundation.
文摘The mutation of the Parkin gene is a cause of familial Parkinson’s disease.A growing body of evidence suggests that Parkin also functions as a tumor suppressor.Parkin is an ubiquitin E3 ligase,and plays important roles in a variety of cellular processes implicated in tumorigenesis,including cell cycle,cell proliferation,apoptosis,metastasis,mitophagy and metabolic reprogramming.Here we review the role and mechanism of Parkin in cancer.
基金This work was supported by the National Natural Science Foundation of China(81622005)Beijing Natural Science Foundation(7172213).
文摘Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene,which itself belongs to an E3 ubiquitin ligase.Since the discovery of the Parkin gene in the late 1990s,researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP,the Parkin gene is associated with many diseases,including type 2 diabetes,leprosy,Alzheimer’s,autism,and cancer.Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis.In general,the Parkin gene,a well-established tumor suppressor,is deficient and mutated in a variety of malignancies.Parkin overexpres-sion inhibits tumor cell growth and promotes apoptosis.However,the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood.This article describes the structure,functions,and post-transla-tional modifications of Parkin,and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.
基金supported by the Key Realm R&D Program of Guangdong Province(Project 2020B0202090001)the National Natural Science Foundation of China(projects 31725004 and 31800217)+1 种基金the Natural Science Foundation of Guangdong Province(Project 2018A030313210)China Postdoctoral Science Foundation(Project 2021M693667)。
文摘Tumor necrosis factor receptor-associated factor(TRAF)proteins are conserved in higher eukaryotes and play key roles in transducing cellular signals across different organelles.They are characterized by their C-terminal region(TRAF-C domain)containing seven to eight antiparallelβ-sheets,also known as the meprin and TRAF-C homology(MATH)domain.Over the past few decades,significant progress has been made toward understanding the diverse roles of TRAF proteins in mammals and plants.Compared to other eukaryotic species,the Arabidopsis thaliana and rice(Oryza sativa)genomes encode many more TRAF/MATH domaincontaining proteins;these plant proteins cluster into five classes:TRAF/MATH-only,MATH-BPM,MATH-UBP(ubiquitin protease),Seven in absentia(SINA),and MATH-Filament and MATHPEARLI-4 proteins,suggesting parallel evolution of TRAF proteins in plants.Increasing evidence now indicates that plant TRAF proteins form central signaling networks essential for multiple biological processes,such as vegetative and reproductive development,autophagosome formation,plant immunity,symbiosis,phytohormone signaling,and abiotic stress responses.Here,we summarize recent advances and highlight future prospects for understanding on the molecular mechanisms by which TRAF proteins act in plant development and stress responses.
基金the project funding granted by the Sci-Tech Innovation 2030 of China(2023ZD040600302)the National Natural Science Foundation of China(31761143013)the National Center for Forestry and Grassland Genetic Resources(2005DKA21003)。
文摘Drought is a major threat to alfalfa(Medicago sativa L.)production.The discovery of important alfalfa genes regulating drought response will facilitate breeding for drought-resistant alfalfa cultivars.Here,we report a genome-wide association study of drought resistance in alfalfa.We identified and functionally characterized an MYB-like transcription factor gene(MsMYBH),which increases the drought resistance in alfalfa.Compared with the wild-types,the biomass and forage quality were enhanced in MsMYBH overexpressed plants.Combined RNA-seq,proteomics and chromatin immunoprecipitation analysis showed that MsMYBH can directly bind to the promoters of MsMCP1,MsMCP2,MsPRX1A and MsCARCAB to improve their expression.The outcomes of such interactions include better water balance,high photosynthetic efficiency and scavenge excess H_(2)O_(2)in response to drought.Furthermore,an E3 ubiquitin ligase(MsWAV3)was found to induce MsMYBH degradation under long-term drought,via the 26S proteasome pathway.Furthermore,variable-number tandem repeats in MsMYBH promoter were characterized among a collection of germplasms,and the variation is associated with promoter activity.Collectively,our findings shed light on the functions of MsMYBH and provide a pivotal gene that could be leveraged for breeding drought-resistant alfalfa.This discovery also offers new insights into the mechanisms of drought resistance in alfalfa.
