The COVID-19 pandemic,caused by the newly emerged coronavirus SARS-CoV-2,has resulted in unprecedented global health challenges,including millions of infections and deaths.While the direct effects of the virus are cri...The COVID-19 pandemic,caused by the newly emerged coronavirus SARS-CoV-2,has resulted in unprecedented global health challenges,including millions of infections and deaths.While the direct effects of the virus are critical,the interplay between SARS-CoV-2 and cellular host factors significantly impacts the replication cycle of the virus and the clinical severity of COVID-19.This review provides a comprehensive analysis of hostpathogen interactions,focusing on the functional roles and regulatory mechanisms of SARS-CoV-2 viral proteins.We systematically review the literature to detail how SARS-CoV-2 engages with host cellular machinery,with a specific emphasis on their modulation by E3 ubiquitin ligases.By dissecting these intricate interactions and the impact of E3 ligases on SARS-CoV-2 infection,we aimto uncover novel therapeutic opportunities and strategies to effectively combat COVID-19.展开更多
The ubiquitin-proteasome system involves three types of enzymes(E1,E2,and E3)that promote protein ubiquitination and degradation.Among these,the E3 ubiquitin ligase mediates substrate specificity.In rice,over 1500 E3 ...The ubiquitin-proteasome system involves three types of enzymes(E1,E2,and E3)that promote protein ubiquitination and degradation.Among these,the E3 ubiquitin ligase mediates substrate specificity.In rice,over 1500 E3 enzymes have been identified,playing diverse roles in growth,developmental processes,and responses to biotic and abiotic stresses.In recent years,significant progress has been made,with some breakthroughs in regulating disease resistance.Here,we summarize the roles of rice E3 ubiquitin ligases in responding to biotic and abiotic stresses,as well as their functions in regulating key agronomic traits such as seed size.Additionally,future research directions are discussed.This review aims to facilitate further studies on E3 ubiquitin ligases in rice.展开更多
Macrophages,existed in almost all organs of the body,are responsible for detecting tissue injury,pathogens,playing a key role in host defense against a variety of invading pathogens triggering inflammatory responses.E...Macrophages,existed in almost all organs of the body,are responsible for detecting tissue injury,pathogens,playing a key role in host defense against a variety of invading pathogens triggering inflammatory responses.Emerging evidence suggests that macrophage-mediated immune responses are efficiently regulated by the ubiquitination modification,which is responsible for normal immune responses.However,numerous studies indicates that the aberrant activation or inhibition of macrophage-mediated immune responses occurs in inflammation,mainly caused by dysregulated ubiquitination modification due to E3 ubiquitin ligases mutations or abnormal expression.Notably,E3 ubiquitin ligases,responsible for recognizing the substrates,are key enzymes in the ubiquitin proteasome system(UPS)composed of ubiquitin(Ub),ubiquitin-activating E1 enzymes,ubiquitin-conjugating E2 enzymes,E3 ubiquitin ligases,26S proteasome,and deubiquitinating enzymes.Intriguingly,several E3 ubiquitin ligases are involved in the regulation of some common signal pathways in macrophage-mediated inflammation,including Toll-like receptors(TLRs),nucleotide-binding oligomerization domain(NOD)-like receptors(NLRs),RIG-I-like receptors(RLRs),C-type lectin receptors(CLRs)and the receptor for advanced glycation end products(RAGE).Herein,we summarized the physiological and pathological roles of E3 ligases in macrophage-mediated inflammation,as well as the inhibitors and agonists targeting E3 ligases in macrophage mediated inflammation,providing the new ideas for targeted therapies in macrophage-mediated inflammation caused aberrant function of E3 ligases.展开更多
Many biological processes such as cell proliferation, differentiation, and cell death depend precisely on the timely synthesis and degradation of key regulatory proteins. While protein synthesis can be regulated at mu...Many biological processes such as cell proliferation, differentiation, and cell death depend precisely on the timely synthesis and degradation of key regulatory proteins. While protein synthesis can be regulated at multiple levels, protein degradation is mainly controlled by the ubiquitin-proteasome system （UPS）, which consists of two distinct steps： （1） ubiquitylation of targeted protein by E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase, and （2） subsequent degradation by the 26S proteasome. Among all E3 ubiquitin ligases, the SCF （SKP1-CUL1-F-box protein） E3 ligases are the largest family and are responsible for the turnover of many key regulatory proteins. Aberrant regulation of SCF E3 ligases is associated with various human diseases, such as cancers, including skin cancer. In this review, we provide a comprehensive overview of all currently published data to define a promoting role of SCF E3 ligases in the development of skin cancer. The future directions in this area of research are also discussed with an ultimate goal to develop small molecule inhibitors of SCF E3 ligases as a novel approach for the treatment of human skin cancer. Furthermore, altered components or substrates of SCF E3 ligases may also be developed as the biomarkers for early diagnosis or predicting prognosis.展开更多
E3 ubiquitin ligases are a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome.Therefore,E3 ubiquitin ligases play an essential role in a...E3 ubiquitin ligases are a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome.Therefore,E3 ubiquitin ligases play an essential role in a variety of biological processes including cell cycle regulation,proliferation and apoptosis.E3 ubiquitin ligases are often found overexpressed in human cancers,including lung cancer,and their deregulation has been shown to contribute to cancer development.However,the lack of specific inhibitors in clinical trials is a major issue in targeting E3 ubiquitin ligases with currently only one E3 ubiquitin ligase inhibitor being tested in the clinical setting.In this review,we focus on E3 ubiquitin ligases that have been found deregulated in lung cancer.Furthermore,we discuss the processes in which they are involved and evaluate them as potential anti-cancer targets.By better understanding the mechanisms by which E3 ubiquitin ligases regulate biological processes and their exact role in carcinogenesis,we can improve the development of specific E3 ubiquitin ligase inhibitors and pave the way for novel treatment strategies for cancer patients.展开更多
E3 ubiquitin ligases have an important role in carcinogenesis and include a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome.So far,E3...E3 ubiquitin ligases have an important role in carcinogenesis and include a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome.So far,E3 ubiquitin ligases have been reported to have a role in a variety of biological processes including cell cycle regulation,cell proliferation,and apoptosis.Recently,several kinds of E3 ubiquitin ligases were demonstrated to be generally highly expressed in gastric cancer(GC) tissues and to contribute to carcinogenesis.In this review,we summarize thecurrent knowledge and information about the clinical significance of E3 ubiquitin ligases in GC.Bortezomib,a proteasome inhibitor,encouraged the evaluation of other components of the ubiquitin proteasome system for pharmaceutical intervention.The clinical value of novel treatment strategies targeting aberrant E3 ubiquitin ligases for GC are discussed in the review.展开更多
To defend against pathogen attacks,plants have evolved a sophisticated immune system comprising pathogen-associated molecular pattern(PAMP)-triggered immunity(PTI)and effector-triggered immunity(ETI).Upon recognizing ...To defend against pathogen attacks,plants have evolved a sophisticated immune system comprising pathogen-associated molecular pattern(PAMP)-triggered immunity(PTI)and effector-triggered immunity(ETI).Upon recognizing invading pathogens,plant cells rapidly initiate a series of immune signaling events,including a burst of reactive oxygen species(ROS),activation of mitogen-activated protein kinase(MAPK)cascades,calcium flux,phytohormone signaling,and post-translational modifications(PTMs)of target proteins.Since immunity activation is energetically costly and often associated with growth,development.展开更多
The ubiquitin-proteasome system(UPS) serves as a highly complicated yet conserved pathway that plays a pivotal role in plant growth and development,stress responses,and defense against pathogens.UPS operates through a...The ubiquitin-proteasome system(UPS) serves as a highly complicated yet conserved pathway that plays a pivotal role in plant growth and development,stress responses,and defense against pathogens.UPS operates through a cascade of enzymatic reactions.The ubiquitin-activating enzyme(E1) activates ubiquitin in an ATP-dependent manner,which is then transferred to the ubiquitin-conjugating enzyme(E2).展开更多
Immune-related receptor-like kinases(RLKs) and receptor-like cytoplasmic kinases(RLCKs) enable plant cells to rapidly transduce and amplify immune signals at an early stage of pathogen attack,which is essential for pl...Immune-related receptor-like kinases(RLKs) and receptor-like cytoplasmic kinases(RLCKs) enable plant cells to rapidly transduce and amplify immune signals at an early stage of pathogen attack,which is essential for plant survival,and these immune kinases must be tightly controlled to prevent aberrant activation.The U-box type E3 ubiquitin ligase SPL11(Os PUB11) has been shown to trigger the ubiquitination and degradation of the S-locus RLK SDS2 to attenuate immunity in rice.展开更多
To combat pathogen attacks, plants have developed a highly advanced immune system, which requires tight regulation to initiate robust defense responses while simultaneously preventing autoimmunity. The ubiquitin-prote...To combat pathogen attacks, plants have developed a highly advanced immune system, which requires tight regulation to initiate robust defense responses while simultaneously preventing autoimmunity. The ubiquitin-proteasome system (UPS), which is responsible for degrading excess or misfolded proteins, has vital roles in ensuring strong and effective immune responses. E3 ligases, as key UPS components, play extensively documented roles in rice immunity by modulating the ubiquitination and degradation of downstream substrates involved in various immune signaling pathways. Here, we summarize the crucial roles of rice E3 ligases in both pathogen/microbe/damage-associated molecular pattern-triggered immunity and effector-triggered immunity, highlight the molecular mechanisms by which E3 ligases function in rice immune signaling, and emphasize the functions of E3 ligases as targets of pathogen effectors for pathogenesis. We also discuss potential strategies for application of immunity-associated E3 ligases in breeding of disease-resistant rice varieties without growth penalty. This review provides a comprehensive and updated understanding of the sophisticated and interconnected regulatory functions of E3 ligases in rice immunity and in balancing immunity with growth and development.展开更多
Since its discovery in the late 1970s, the ubiquitin proteasome pathway appears to be omnipresent in many research fields. Although originally discovered in animals, the pathway has a very central role in plants, whic...Since its discovery in the late 1970s, the ubiquitin proteasome pathway appears to be omnipresent in many research fields. Although originally discovered in animals, the pathway has a very central role in plants, which may be correlated to their sessile lifestyle. E3 ligases function as flexible and highly diverse key regulators within the path- way by targeting substrate proteins for ubiquitylation, and often proteolytic degradation via the 26S proteasome. This review provides a concise overview on the most common classes of E3 ligases so far described in plants, and emphasizes recent findings regarding these interesting and flexible enzymes and their diverse functions in plant biology.展开更多
The mechanism regulating proteasomal activity under proteotoxic stress conditions remains unclear.Here,we showed that arsenite-induced proteotoxic stress resulted in upregulation of Arabidopsis homologous PUB22 and PU...The mechanism regulating proteasomal activity under proteotoxic stress conditions remains unclear.Here,we showed that arsenite-induced proteotoxic stress resulted in upregulation of Arabidopsis homologous PUB22 and PUB23 U-boxE3 ubiquitin ligases and that pub22 pub23 double mutants displayed arsenite-insensitive seed germination and root growth phenotypes.PUB22/PUB23 downregulated 26 S proteasome activity by promoting the dissociation of the 19 S regulatory particle from the holo-proteasome complex,resulting in intracellular accumulation of UbG76 VGFP,an artificial substrate of the proteasome complex,and insoluble poly-ubiquitinated proteins.These results suggest that PUB22/PUB23 play a critical role in arsenite-induced proteotoxic stress response via negative regulation of 26 S proteasome integrity.展开更多
Banana fruit ripening is a highly regulatory process involving various layers consisting of transcriptional regulation,epigenetic factor,and post-translational modification.Previously,we reported that MaERF11 cooperat...Banana fruit ripening is a highly regulatory process involving various layers consisting of transcriptional regulation,epigenetic factor,and post-translational modification.Previously,we reported that MaERF11 cooperated with MaHDA1 to precisely regulate the transcription of ripening-associated genes via histone deacetylation.However,whether MaERF11 is subjected to post-translational modification during banana ripening is largely unknown.In this study,we found that MaERF11 targeted a subset of starch degradation-related genes using the DNA affinity purification sequence(DAP-Seq)approach.Electrophoretic mobility shift assay(EMSA)and dual-luciferase reporter assay(DLR)demonstrated that MaERF11 could specifically bind and repress the expression of the starch degradation-related genes MaAMY3,MaBAM2 and MaGWD1.Further analyses of yeast two-hybrid(Y2H),bimolecular fluorescence complementation(BiFC)and Luciferase complementation imaging(LCI)assays indicated that MaERF11 interacted with the ubiquitin E3 ligase MaRFA1,and this interaction weakened the MaERF11-mediated transcriptional repression capacity.Collectively,our results suggest an additional regulatory layer in which MaERF11 regulates banana fruit ripening and expands the regulatory network in fruit ripening at the post-translational modification level.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
Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulp...Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell(NPC)death and IVDD,but the underlying mechanisms remain unclear.Although the effects of Drp1 phosphorylation in IVDD have been studied,it is currently unknown if small ubiquitin-like modifications(SUMOylation)of Drp1 regulate IVDD.This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase(MAPL),a mitochondrial SUMO E3 ligase,during IVDD progression.The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing.展开更多
The development of maize(Zea mays)kernels is a complex physiological process regulated by numerous genes in a spatially and temporally coordinated manner.However,many regulatory genes involved in this process remain u...The development of maize(Zea mays)kernels is a complex physiological process regulated by numerous genes in a spatially and temporally coordinated manner.However,many regulatory genes involved in this process remain unidentified.In this study,we identified ZmZFP2,a gene encoding a C4HC3-type RING zinc finger protein,which regulates kernel size and weight.This discovery was based on suppression subtractive hybridization from maize endosperm in our previous research.We further investigated the role of ZmZFP2 in regulating kernel development.The zmzfp2-ems mutant exhibited significantly reduced kernel size and weight,accompanied by fewer endosperm cells and altered starch and protein accumulation.CRISPR/Cas9-mediated knockouts and overexpression lines confirmed that ZmZFP2 positively regulates kernel size and weight,with overexpression leading to increased kernel size and weight.Transcriptome analysis revealed that ZmZFP2 regulates genes involved in zeatin biosynthesis,starch metabolism,and protein processing,further supporting its role in kernel development.Additionally,ZmZFP2 was shown to interact with the transcription factor ZmEREB98,implicating it in the gene regulatory network during grain filling.Together,these findings demonstrate that ZmZFP2 is a key regulator of maize kernel size and weight,functioning through its E3 ubiquitin ligase activity and interactions with various metabolic pathways.This study provides novel insights into the genetic regulation of kernel development and presents potential strategies for improving maize yield and quality.展开更多
BACKGROUND Thin endometrium,leading cause of recurrent implantation failure and infertility,has been found to respond to exosomes.AIM To investigate the efficacy of exosomes in addressing the issue of thin endometrium...BACKGROUND Thin endometrium,leading cause of recurrent implantation failure and infertility,has been found to respond to exosomes.AIM To investigate the efficacy of exosomes in addressing the issue of thin endometrium.METHODS RNA sequencing and reverse transcription-quantitative polymerase chain reaction were employed to identify differentially expressed microRNAs(miRNAs)in human umbilical cord mesenchymal stem cell(hucMSC)treated with exosomes enriched with endometrial cell-derived components.Additionally,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to highlight significant enrichment in specific biological pathways,molecular functions,and cellular components.Transwell and wound healing assays were performed to assess migratory potential,and western blotting was detected protein level.RESULTS A total of 53 differentially expressed miRNAs were identified in hucMSC treated with exosomes enriched with endometrial cell-derived components,comprising 27 upregulated and 26 downregulated miRNAs,which includes miR-137-3p.Enhanced migratory potential was observed in the Transwell and wound healing assays,and western blotting confirmed the epithelial differentiation of hucMSC and the increased p-signal transducer and activator of transcription 3.These effects were attributed to the upregulation of miR-137-3p.CONCLUSION miR-137-3p in exosomes from hypoxia-affected endometrial epithelial cell stimulates the signal transducer and activator of transcription 3 signaling pathway,enhancing the migration and differentiation of hucMSC into endometrial epithelial cell.展开更多
This article comments on the study by Zhang et al,which proposed that exosomes derived from hypoxia-injured endometrial epithelial cells promote human umbilical cord mesenchymal stem cell migration and differentiation...This article comments on the study by Zhang et al,which proposed that exosomes derived from hypoxia-injured endometrial epithelial cells promote human umbilical cord mesenchymal stem cell migration and differentiation into endo-metrial epithelial cells via exosomal miR-137-3p.The authors demonstrated that miR-137-3p targets ubiquitin protein ligase E3C and activates signal transducer and activator of transcription 3 signaling,thereby driving epithelial lineage transition.While this study expands our understanding of exosome-mediated intercellular communication in endometrial repair,several key gaps remain.Notably,microRNA(miRNA)profiling was performed in human umbilical cord mesenchymal stem cells post-exosome treatment,not in the exosomes derived from hypoxia-injured endometrial epithelial cell themselves,leaving open whether miR-137-3p is directly transferred or indirectly induced.In addition,data on exosome characterization were unavailable,and the rationale for selecting miR-137-3p over other differentially expressed miRNAs was not well justified.Future studies should include direct exosomal miRNA content analysis,in vivo validation,and deeper mechanistic exploration of the ubiquitin protein ligase E3C-signal transducer and activator of transcription 3 ubiquitination axis to establish the clinical and biological relevance of this pathway.展开更多
This study by Zhang et al elucidates the role of exosome miR-137-3p targeting ubiquitin protein ligase E3C to activate signal transducer and activator of transcription 3 under hypoxia conditions,thereby promoting the ...This study by Zhang et al elucidates the role of exosome miR-137-3p targeting ubiquitin protein ligase E3C to activate signal transducer and activator of transcription 3 under hypoxia conditions,thereby promoting the migration and differentiation of human umbilical cord mesenchymal stem cells to endometrial epithelial cells.It emphasizes that exosomal miR-137-3p/ubiquitin protein ligase E3C/signal transducer and activator of transcription 3 axis is a promising pathway for endometrial regeneration.This article introduced the therapeutic potential of exosomal microRNAs in regenerative medicine while underscoring the need for standardized protocols in optimizing exosome delivery and validating molecular pathways for clinical translation.展开更多
文摘The COVID-19 pandemic,caused by the newly emerged coronavirus SARS-CoV-2,has resulted in unprecedented global health challenges,including millions of infections and deaths.While the direct effects of the virus are critical,the interplay between SARS-CoV-2 and cellular host factors significantly impacts the replication cycle of the virus and the clinical severity of COVID-19.This review provides a comprehensive analysis of hostpathogen interactions,focusing on the functional roles and regulatory mechanisms of SARS-CoV-2 viral proteins.We systematically review the literature to detail how SARS-CoV-2 engages with host cellular machinery,with a specific emphasis on their modulation by E3 ubiquitin ligases.By dissecting these intricate interactions and the impact of E3 ligases on SARS-CoV-2 infection,we aimto uncover novel therapeutic opportunities and strategies to effectively combat COVID-19.
基金supported by the National Natural Science Foundation of China(Grant No.32071922)the Henan Province Science and Technology Joint Fund,China(Grant No.242301420134).
文摘The ubiquitin-proteasome system involves three types of enzymes(E1,E2,and E3)that promote protein ubiquitination and degradation.Among these,the E3 ubiquitin ligase mediates substrate specificity.In rice,over 1500 E3 enzymes have been identified,playing diverse roles in growth,developmental processes,and responses to biotic and abiotic stresses.In recent years,significant progress has been made,with some breakthroughs in regulating disease resistance.Here,we summarize the roles of rice E3 ubiquitin ligases in responding to biotic and abiotic stresses,as well as their functions in regulating key agronomic traits such as seed size.Additionally,future research directions are discussed.This review aims to facilitate further studies on E3 ubiquitin ligases in rice.
文摘Macrophages,existed in almost all organs of the body,are responsible for detecting tissue injury,pathogens,playing a key role in host defense against a variety of invading pathogens triggering inflammatory responses.Emerging evidence suggests that macrophage-mediated immune responses are efficiently regulated by the ubiquitination modification,which is responsible for normal immune responses.However,numerous studies indicates that the aberrant activation or inhibition of macrophage-mediated immune responses occurs in inflammation,mainly caused by dysregulated ubiquitination modification due to E3 ubiquitin ligases mutations or abnormal expression.Notably,E3 ubiquitin ligases,responsible for recognizing the substrates,are key enzymes in the ubiquitin proteasome system(UPS)composed of ubiquitin(Ub),ubiquitin-activating E1 enzymes,ubiquitin-conjugating E2 enzymes,E3 ubiquitin ligases,26S proteasome,and deubiquitinating enzymes.Intriguingly,several E3 ubiquitin ligases are involved in the regulation of some common signal pathways in macrophage-mediated inflammation,including Toll-like receptors(TLRs),nucleotide-binding oligomerization domain(NOD)-like receptors(NLRs),RIG-I-like receptors(RLRs),C-type lectin receptors(CLRs)and the receptor for advanced glycation end products(RAGE).Herein,we summarized the physiological and pathological roles of E3 ligases in macrophage-mediated inflammation,as well as the inhibitors and agonists targeting E3 ligases in macrophage mediated inflammation,providing the new ideas for targeted therapies in macrophage-mediated inflammation caused aberrant function of E3 ligases.
基金supported by the National Cancer Institute grants (Nos. CA118762, CA156744, CA170995 and CA171277) to Y.Sthe National Institute of General Medical Sciences grant (No. GM094777) to W.W
文摘Many biological processes such as cell proliferation, differentiation, and cell death depend precisely on the timely synthesis and degradation of key regulatory proteins. While protein synthesis can be regulated at multiple levels, protein degradation is mainly controlled by the ubiquitin-proteasome system （UPS）, which consists of two distinct steps： （1） ubiquitylation of targeted protein by E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase, and （2） subsequent degradation by the 26S proteasome. Among all E3 ubiquitin ligases, the SCF （SKP1-CUL1-F-box protein） E3 ligases are the largest family and are responsible for the turnover of many key regulatory proteins. Aberrant regulation of SCF E3 ligases is associated with various human diseases, such as cancers, including skin cancer. In this review, we provide a comprehensive overview of all currently published data to define a promoting role of SCF E3 ligases in the development of skin cancer. The future directions in this area of research are also discussed with an ultimate goal to develop small molecule inhibitors of SCF E3 ligases as a novel approach for the treatment of human skin cancer. Furthermore, altered components or substrates of SCF E3 ligases may also be developed as the biomarkers for early diagnosis or predicting prognosis.
文摘E3 ubiquitin ligases are a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome.Therefore,E3 ubiquitin ligases play an essential role in a variety of biological processes including cell cycle regulation,proliferation and apoptosis.E3 ubiquitin ligases are often found overexpressed in human cancers,including lung cancer,and their deregulation has been shown to contribute to cancer development.However,the lack of specific inhibitors in clinical trials is a major issue in targeting E3 ubiquitin ligases with currently only one E3 ubiquitin ligase inhibitor being tested in the clinical setting.In this review,we focus on E3 ubiquitin ligases that have been found deregulated in lung cancer.Furthermore,we discuss the processes in which they are involved and evaluate them as potential anti-cancer targets.By better understanding the mechanisms by which E3 ubiquitin ligases regulate biological processes and their exact role in carcinogenesis,we can improve the development of specific E3 ubiquitin ligase inhibitors and pave the way for novel treatment strategies for cancer patients.
文摘E3 ubiquitin ligases have an important role in carcinogenesis and include a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome.So far,E3 ubiquitin ligases have been reported to have a role in a variety of biological processes including cell cycle regulation,cell proliferation,and apoptosis.Recently,several kinds of E3 ubiquitin ligases were demonstrated to be generally highly expressed in gastric cancer(GC) tissues and to contribute to carcinogenesis.In this review,we summarize thecurrent knowledge and information about the clinical significance of E3 ubiquitin ligases in GC.Bortezomib,a proteasome inhibitor,encouraged the evaluation of other components of the ubiquitin proteasome system for pharmaceutical intervention.The clinical value of novel treatment strategies targeting aberrant E3 ubiquitin ligases for GC are discussed in the review.
基金National Natural Science Foundation of China(No.32072403 and No.31871945)for financial support。
文摘To defend against pathogen attacks,plants have evolved a sophisticated immune system comprising pathogen-associated molecular pattern(PAMP)-triggered immunity(PTI)and effector-triggered immunity(ETI).Upon recognizing invading pathogens,plant cells rapidly initiate a series of immune signaling events,including a burst of reactive oxygen species(ROS),activation of mitogen-activated protein kinase(MAPK)cascades,calcium flux,phytohormone signaling,and post-translational modifications(PTMs)of target proteins.Since immunity activation is energetically costly and often associated with growth,development.
基金supported by the National Key Research and Development Program of China (2023YFC2604500,2024YFD1200600)the National Natural Science Foundation of China (32472566)。
文摘The ubiquitin-proteasome system(UPS) serves as a highly complicated yet conserved pathway that plays a pivotal role in plant growth and development,stress responses,and defense against pathogens.UPS operates through a cascade of enzymatic reactions.The ubiquitin-activating enzyme(E1) activates ubiquitin in an ATP-dependent manner,which is then transferred to the ubiquitin-conjugating enzyme(E2).
基金supported by the Innovation Program of Chinese Academy of Agricultural Sciences (CAAS-CSCB202301) to Y.N.the National Natural Science Foundation of China (U24A20388) to R.W.
文摘Immune-related receptor-like kinases(RLKs) and receptor-like cytoplasmic kinases(RLCKs) enable plant cells to rapidly transduce and amplify immune signals at an early stage of pathogen attack,which is essential for plant survival,and these immune kinases must be tightly controlled to prevent aberrant activation.The U-box type E3 ubiquitin ligase SPL11(Os PUB11) has been shown to trigger the ubiquitination and degradation of the S-locus RLK SDS2 to attenuate immunity in rice.
基金National Natural Science Foundation of China(no.32072403 and no.31871945).
文摘To combat pathogen attacks, plants have developed a highly advanced immune system, which requires tight regulation to initiate robust defense responses while simultaneously preventing autoimmunity. The ubiquitin-proteasome system (UPS), which is responsible for degrading excess or misfolded proteins, has vital roles in ensuring strong and effective immune responses. E3 ligases, as key UPS components, play extensively documented roles in rice immunity by modulating the ubiquitination and degradation of downstream substrates involved in various immune signaling pathways. Here, we summarize the crucial roles of rice E3 ligases in both pathogen/microbe/damage-associated molecular pattern-triggered immunity and effector-triggered immunity, highlight the molecular mechanisms by which E3 ligases function in rice immune signaling, and emphasize the functions of E3 ligases as targets of pathogen effectors for pathogenesis. We also discuss potential strategies for application of immunity-associated E3 ligases in breeding of disease-resistant rice varieties without growth penalty. This review provides a comprehensive and updated understanding of the sophisticated and interconnected regulatory functions of E3 ligases in rice immunity and in balancing immunity with growth and development.
基金This work was supported by the National Science Foundation （NSF grant MCB-1020673 to H.H.）,We would like to thank Sutton Mooney for critical reading and NSF for support （NSF grant MCB-1020673 to H.H.）. No conflict of interest declared.
文摘Since its discovery in the late 1970s, the ubiquitin proteasome pathway appears to be omnipresent in many research fields. Although originally discovered in animals, the pathway has a very central role in plants, which may be correlated to their sessile lifestyle. E3 ligases function as flexible and highly diverse key regulators within the path- way by targeting substrate proteins for ubiquitylation, and often proteolytic degradation via the 26S proteasome. This review provides a concise overview on the most common classes of E3 ligases so far described in plants, and emphasizes recent findings regarding these interesting and flexible enzymes and their diverse functions in plant biology.
基金supported by grants from the National Research Foundation(Mid-Career Researcher Program Project No.2017R1A2B2006750 and Basic Science Research Program Project No.2018R1A6A1A03025607),Republic of Korea,to Woo T.Kim。
文摘The mechanism regulating proteasomal activity under proteotoxic stress conditions remains unclear.Here,we showed that arsenite-induced proteotoxic stress resulted in upregulation of Arabidopsis homologous PUB22 and PUB23 U-boxE3 ubiquitin ligases and that pub22 pub23 double mutants displayed arsenite-insensitive seed germination and root growth phenotypes.PUB22/PUB23 downregulated 26 S proteasome activity by promoting the dissociation of the 19 S regulatory particle from the holo-proteasome complex,resulting in intracellular accumulation of UbG76 VGFP,an artificial substrate of the proteasome complex,and insoluble poly-ubiquitinated proteins.These results suggest that PUB22/PUB23 play a critical role in arsenite-induced proteotoxic stress response via negative regulation of 26 S proteasome integrity.
基金financially supported by the National Natural Science Foundation of China(Grant Nos.31830071,32202561)the earmarked fund for CARS(Grant No.CARS-31)。
文摘Banana fruit ripening is a highly regulatory process involving various layers consisting of transcriptional regulation,epigenetic factor,and post-translational modification.Previously,we reported that MaERF11 cooperated with MaHDA1 to precisely regulate the transcription of ripening-associated genes via histone deacetylation.However,whether MaERF11 is subjected to post-translational modification during banana ripening is largely unknown.In this study,we found that MaERF11 targeted a subset of starch degradation-related genes using the DNA affinity purification sequence(DAP-Seq)approach.Electrophoretic mobility shift assay(EMSA)and dual-luciferase reporter assay(DLR)demonstrated that MaERF11 could specifically bind and repress the expression of the starch degradation-related genes MaAMY3,MaBAM2 and MaGWD1.Further analyses of yeast two-hybrid(Y2H),bimolecular fluorescence complementation(BiFC)and Luciferase complementation imaging(LCI)assays indicated that MaERF11 interacted with the ubiquitin E3 ligase MaRFA1,and this interaction weakened the MaERF11-mediated transcriptional repression capacity.Collectively,our results suggest an additional regulatory layer in which MaERF11 regulates banana fruit ripening and expands the regulatory network in fruit ripening at the post-translational modification level.
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supported by National Natural Science Foundation of China(82272549,82472505,and 82472498)National key Research and Development plan,Ministry of Science and Technology of the People’s Republic of China(2022YFC2407203)+2 种基金the Young Health Talents of Shanghai Municipal Health Commission,China(2022YQ011)China Medical Education Association(3030537245)The Youth Talent Project of Huashan Hospital(30302164006).
文摘Intervertebral disc degeneration(IVDD)is the primary contributor to a range of spinal diseases.Dynamin-related protein 1(Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell(NPC)death and IVDD,but the underlying mechanisms remain unclear.Although the effects of Drp1 phosphorylation in IVDD have been studied,it is currently unknown if small ubiquitin-like modifications(SUMOylation)of Drp1 regulate IVDD.This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase(MAPL),a mitochondrial SUMO E3 ligase,during IVDD progression.The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing.
基金supported by the National Natural Science Foundation of China(31971962,31771812,and 32272129 to Yuling Li)Zhongyuan Scholars in Henan Province(22400510003 to Yuling Li)+3 种基金the Major Public Welfare Projects of Henan Province(201300111100 to Yuling Li)Tackle Program of Agricultural Seed in Henan Province(2022010201 to Yuling Li)Technical System of Maize Industry in Henan Province(HARS62922-02-S to Yuling Li)Key Scientific Research Projects for Higher Education of Henan Province(19zx001 to Yuling Li).
文摘The development of maize(Zea mays)kernels is a complex physiological process regulated by numerous genes in a spatially and temporally coordinated manner.However,many regulatory genes involved in this process remain unidentified.In this study,we identified ZmZFP2,a gene encoding a C4HC3-type RING zinc finger protein,which regulates kernel size and weight.This discovery was based on suppression subtractive hybridization from maize endosperm in our previous research.We further investigated the role of ZmZFP2 in regulating kernel development.The zmzfp2-ems mutant exhibited significantly reduced kernel size and weight,accompanied by fewer endosperm cells and altered starch and protein accumulation.CRISPR/Cas9-mediated knockouts and overexpression lines confirmed that ZmZFP2 positively regulates kernel size and weight,with overexpression leading to increased kernel size and weight.Transcriptome analysis revealed that ZmZFP2 regulates genes involved in zeatin biosynthesis,starch metabolism,and protein processing,further supporting its role in kernel development.Additionally,ZmZFP2 was shown to interact with the transcription factor ZmEREB98,implicating it in the gene regulatory network during grain filling.Together,these findings demonstrate that ZmZFP2 is a key regulator of maize kernel size and weight,functioning through its E3 ubiquitin ligase activity and interactions with various metabolic pathways.This study provides novel insights into the genetic regulation of kernel development and presents potential strategies for improving maize yield and quality.
基金Supported by the National High Level Hospital Clinical Research Funding,No.2022-PUMCH-B-080 and No.2022-PUMCH-C-064.
文摘BACKGROUND Thin endometrium,leading cause of recurrent implantation failure and infertility,has been found to respond to exosomes.AIM To investigate the efficacy of exosomes in addressing the issue of thin endometrium.METHODS RNA sequencing and reverse transcription-quantitative polymerase chain reaction were employed to identify differentially expressed microRNAs(miRNAs)in human umbilical cord mesenchymal stem cell(hucMSC)treated with exosomes enriched with endometrial cell-derived components.Additionally,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to highlight significant enrichment in specific biological pathways,molecular functions,and cellular components.Transwell and wound healing assays were performed to assess migratory potential,and western blotting was detected protein level.RESULTS A total of 53 differentially expressed miRNAs were identified in hucMSC treated with exosomes enriched with endometrial cell-derived components,comprising 27 upregulated and 26 downregulated miRNAs,which includes miR-137-3p.Enhanced migratory potential was observed in the Transwell and wound healing assays,and western blotting confirmed the epithelial differentiation of hucMSC and the increased p-signal transducer and activator of transcription 3.These effects were attributed to the upregulation of miR-137-3p.CONCLUSION miR-137-3p in exosomes from hypoxia-affected endometrial epithelial cell stimulates the signal transducer and activator of transcription 3 signaling pathway,enhancing the migration and differentiation of hucMSC into endometrial epithelial cell.
基金Supported by the General Program of the Natural Science Foundation of Guangdong Province,No.2025A1515011163.
文摘This article comments on the study by Zhang et al,which proposed that exosomes derived from hypoxia-injured endometrial epithelial cells promote human umbilical cord mesenchymal stem cell migration and differentiation into endo-metrial epithelial cells via exosomal miR-137-3p.The authors demonstrated that miR-137-3p targets ubiquitin protein ligase E3C and activates signal transducer and activator of transcription 3 signaling,thereby driving epithelial lineage transition.While this study expands our understanding of exosome-mediated intercellular communication in endometrial repair,several key gaps remain.Notably,microRNA(miRNA)profiling was performed in human umbilical cord mesenchymal stem cells post-exosome treatment,not in the exosomes derived from hypoxia-injured endometrial epithelial cell themselves,leaving open whether miR-137-3p is directly transferred or indirectly induced.In addition,data on exosome characterization were unavailable,and the rationale for selecting miR-137-3p over other differentially expressed miRNAs was not well justified.Future studies should include direct exosomal miRNA content analysis,in vivo validation,and deeper mechanistic exploration of the ubiquitin protein ligase E3C-signal transducer and activator of transcription 3 ubiquitination axis to establish the clinical and biological relevance of this pathway.
文摘This study by Zhang et al elucidates the role of exosome miR-137-3p targeting ubiquitin protein ligase E3C to activate signal transducer and activator of transcription 3 under hypoxia conditions,thereby promoting the migration and differentiation of human umbilical cord mesenchymal stem cells to endometrial epithelial cells.It emphasizes that exosomal miR-137-3p/ubiquitin protein ligase E3C/signal transducer and activator of transcription 3 axis is a promising pathway for endometrial regeneration.This article introduced the therapeutic potential of exosomal microRNAs in regenerative medicine while underscoring the need for standardized protocols in optimizing exosome delivery and validating molecular pathways for clinical translation.
