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
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
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
Rice panicle architecture affects grain number per panicle and therefore determines grain yield.The receptor-like kinase OsER1 regulates panicle development by perceiving extracellular small peptide ligands;however,ho...Rice panicle architecture affects grain number per panicle and therefore determines grain yield.The receptor-like kinase OsER1 regulates panicle development by perceiving extracellular small peptide ligands;however,how activated OsER1 fine-tunes panicle morphogenesis remains unclear.This study reveals that members of the conserved SEVEN IN ABSENTIA OF RICE(SINAR)E3 ubiquitin ligase family regulate rice spikelet number in either synergistic or antagonistic manners by modulating the ubiquitination and stability of OsER1.Notably,SINAR1 and SINAR6 reduce the ubiquitination activity of SINAR2/3/4/5 through heterodimer formation,acting as a molecular brake to protect OsER1 from vacuolar degradation.These findings identify SINAR1 and SINAR6 as key components of a negative feedback mechanism that ensures optimal OsER1 signaling and shapes panicle architecture.Targeted suppression of SINAR1 and SINAR6 markedly enhances grain yield by promoting OsER1 degradation,demonstrating that attenuation of OsER1-mediated developmental signaling-while maintaining its function-optimizes rice panicle architecture without compromising spikelet fertility.Together,our findings reveal an antagonistic,ligase-mediated regulatory mechanism that maintains receptor homeostasis and provide a strategy to enhance rice yield through manipulation of dichotomous SINA E3 ligases.展开更多
Radiotherapy resistance remains a major clinical challenge in colorectal cancer(CRC)treatment.Our study reveals that the regulation of nuclear E3 ubiquitin ligase maintains K48-ubiquitin levels that correlate with CRC...Radiotherapy resistance remains a major clinical challenge in colorectal cancer(CRC)treatment.Our study reveals that the regulation of nuclear E3 ubiquitin ligase maintains K48-ubiquitin levels that correlate with CRC radiotherapy sensitivity.We identify NPRL2 as the central mediator of this process.Following radiation,NPRL2 rapidly translocates to the nucleus,where it directly binds to the catalytic domains of key E3 ubiquitin ligases,including HERC2 and RNF8,and functionally inactivates them.This NPRL2-mediated inhibition of E3 ligase activity prevents the degradation of critical DNA repair proteins.Importantly,clinical analyses demonstrate that nuclear NPRL2 plays a role in sustaining radioresistance.Mechanistic investigations reveal that radiation-induced AMPK activation initiates this process by phosphorylating WDR24,which promotes NPRL2 dissociation from the GATOR1 complex and facilitates its nuclear translocation.Therapeutic targeting through AMPK inhibition effectively blocks NPRL2 nuclear accumulation,leading to impaired DNA damage repair and significant radiosensitization of CRC cells in both in vitro and in vivo models.These findings not only elucidate the AMPK/WDR24/NPRL2 signaling axis as a fundamental regulator of DNA repair machinery in CRC,but also provide compelling evidence for its potential as a novel therapeutic target to overcome radioresistance and improve radiotherapy efficacy in CRC patients.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
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
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
Auxin regulates plant growth by integrating transport and signaling.Polar auxin transport establishes auxin gradients essential for development,with PIN-FORMED(PIN)efflux carriers generating directionality and AUXIN1/...Auxin regulates plant growth by integrating transport and signaling.Polar auxin transport establishes auxin gradients essential for development,with PIN-FORMED(PIN)efflux carriers generating directionality and AUXIN1/LIKE-AUX1(AUX1/LAX)influx carriers ensuring efficient uptake.Canonical signaling begins when auxin binds TRANSPORT INHIBITOR RESPONSE 1/AUXIN SIGNALING F-BOX PROTEIN(TIR1/AFB)receptors,the F-box component of the SKP1-CULLIN1-F-box(SCF)E3 ubiquitin ligase complex(Gray et al.,2001).Auxin promotes recruitment and degradation of AUXIN/INDOLE-3-ACETIC ACID(AUX/IAA)repressors,thereby releasing AUXIN RESPONSE FACTOR(ARF)to activate transcription(Gray et al.,2001).Recent discoveries have expended this model.Cryo-electron microscopy(cryo-EM)structures of AUX1 clarified its proton(H+)-coupled import(Yang et al.,2025),and TIR1 was shown to function as an adenylate cyclase(AC),producing c AMP to activate transcription(Chen et al.,2025).Synthetic promoter studies further revealed a bi-layer ARF/cis-element code shaping cel type-specific gene expression(Martin-Arevalil o et al.,2025).展开更多
Ubiquitination of proteins is one of the critical regulatory mechanisms in eukaryotes. In higher plants, protein ubiquitination plays an essential role in many biological processes, including hormone signaling, photom...Ubiquitination of proteins is one of the critical regulatory mechanisms in eukaryotes. In higher plants, protein ubiquitination plays an essential role in many biological processes, including hormone signaling, photomorphogenesis, and pathogen defense. However, the roles of protein ubiquitination in the repro- ductive process are not clear. In this study, we identified four plant-specific RING-finger genes designated Aberrant_Pollen Development 1_ （APD1） to APD4, as regulators of pollen mitosis II （PMII） in Arabidopsis thaliana （L.）. The apdl apd2 double mutant showed a significantly increased percentage of bicellular-like pollen at the mature pollen stage. Further downregulation of the APD3 and APD4 transcripts in apdl apd2 by RNA interference （RNAi） resulted in more severe abnormal bicellular-like pollen phenotypes than in apdl apd2, suggesting that cell division was defective in male gametogenesis. All of the four genes were expressed in multiple stages at different levels during male gametophyte development. Confocal analysis using green florescence fusion proteins （GFP） GFP-APD1 and GFP-APD2 showed that APDs are associated with intracellular membranes. Furthermore, APD2 had E2-dependent E3 ligase activity in vitro, and five APD2-interacting proteins were identified. Our results suggest that these four genes may be involved, redundantly, in regulating the PMII process during male gametogenesis.展开更多
Controlled stability of proteins is a highly efficient mechanism to direct diverse processes in living cells. A key regulatory system for protein stability is given by the ubiquitin proteasome pathway, which uses E3 l...Controlled stability of proteins is a highly efficient mechanism to direct diverse processes in living cells. A key regulatory system for protein stability is given by the ubiquitin proteasome pathway, which uses E3 ligases to mark specific proteins for degradation. In this work, MYB56 is identified as a novel target of a CULLIN3 （CUL3）-based E3 ligase. Its stability depends on the presence of MATH-BTB/POZ （BPM） proteins, which function as substrate adaptors to the E3 ligase. Genetic studies have indicated that MYB56 is a negative regulator of flowering, while BPMs positively affect this developmental program. The interaction between BPMs and MYB56 occurs at the promoter of FLOWERING LOCUS T （FT）, a key regulator in initiating flowering in Arabidopsis, and results in instability of MYB56. Overall the work establishes MYB transcription factors as substrates of BPM proteins, and provides novel information on components that participate in controlling flowering time in plants.展开更多
Protein ubiquitination is an important means of posttranslational modification which plays an essential role in the regulation of various aspects of leukocyte development and function. The specificity of ubiquitin tag...Protein ubiquitination is an important means of posttranslational modification which plays an essential role in the regulation of various aspects of leukocyte development and function. The specificity of ubiquitin tagging to a protein substrate is determined by E3 ubiquitin ligases via defined E3-substrate interactions. In this review, we will focus on two E3 ligases, VHL and Itch, to discuss the latest progress in understanding their roles in the differentiation and function of CD4+ T helper cell subsets, the stability of regulatory T cells, effector function of CD8+ T cells, as well as the development and maturation of innate lymphoid cells. The biological implications of these E3 ubiquitin ligases will be highlighted in the context of normal and dysregulated immune responses including the control of homeostasis, inflammation, auto-immune responses and anti-tumor immunity. Further elucidation of the ubiquitin system in immune cells will help in the design of new therapeutic interventions for human immunological diseases and cancer.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
Accumulating evidence has revealed that the ubiquitin proteasome system plays fundamental roles in the regulation of diverse cellular activities in eukaryotes.The ubiquitin protein ligases(E3s)are central to the prote...Accumulating evidence has revealed that the ubiquitin proteasome system plays fundamental roles in the regulation of diverse cellular activities in eukaryotes.The ubiquitin protein ligases(E3s)are central to the proteasome system because of their ability to determine its substrate specificity.Several studies have demonstrated the essential role of a group of ER(endoplasmic reticulum)-localized E3s in the positive or negative regulation of cell homeostasis.Most ER-related E3s are conserved between plants and mammals,and a few plant-specific components have been reported.In this review,we summarize the functions of ERrelated E3s in plant growth,ER-associated protein degradation and ER-phagy,abiotic and biotic stress responses,and hormone signaling.Furthermore,we highlight several questions that remain to be addressed and suggest directions for further research on ER-related E3 ubiquitin ligases.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.
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.
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 Key Research and Development Program of China(2022YFD1200102)the National Natural Science Foundation of China(32388201)+1 种基金the Biological Breeding-National Science and Technology Major Project(2023ZD0406801)the CAS-Croucher Funding Scheme for Joint Laboratories,and the State Key Laboratory of Plant Trait Design.
文摘Rice panicle architecture affects grain number per panicle and therefore determines grain yield.The receptor-like kinase OsER1 regulates panicle development by perceiving extracellular small peptide ligands;however,how activated OsER1 fine-tunes panicle morphogenesis remains unclear.This study reveals that members of the conserved SEVEN IN ABSENTIA OF RICE(SINAR)E3 ubiquitin ligase family regulate rice spikelet number in either synergistic or antagonistic manners by modulating the ubiquitination and stability of OsER1.Notably,SINAR1 and SINAR6 reduce the ubiquitination activity of SINAR2/3/4/5 through heterodimer formation,acting as a molecular brake to protect OsER1 from vacuolar degradation.These findings identify SINAR1 and SINAR6 as key components of a negative feedback mechanism that ensures optimal OsER1 signaling and shapes panicle architecture.Targeted suppression of SINAR1 and SINAR6 markedly enhances grain yield by promoting OsER1 degradation,demonstrating that attenuation of OsER1-mediated developmental signaling-while maintaining its function-optimizes rice panicle architecture without compromising spikelet fertility.Together,our findings reveal an antagonistic,ligase-mediated regulatory mechanism that maintains receptor homeostasis and provide a strategy to enhance rice yield through manipulation of dichotomous SINA E3 ligases.
基金supported by the National Natural Science Foundation of China(NSFC)(No.82373209 to Xuecen Wang,82272743 to Xin Yue,82373203 to Yong Chen and 82373379 to Ran-yi Liu)Funding by Science and Technology Projects in Guangzhou(No.2024A04J4633 to Xuecen Wang and 2025A04J0177 to Xin Yue,China)from the Science and Technology Projects of Guangzhou+1 种基金the Kelin Rising Star Talent Program from The First Affiliated Hospital(No.R08039 to Xuecen Wang,China)the Basic Scientific Research Operation of Sun Yat-sen University(No.24qnpy335 to Xuecen Wang,China).
文摘Radiotherapy resistance remains a major clinical challenge in colorectal cancer(CRC)treatment.Our study reveals that the regulation of nuclear E3 ubiquitin ligase maintains K48-ubiquitin levels that correlate with CRC radiotherapy sensitivity.We identify NPRL2 as the central mediator of this process.Following radiation,NPRL2 rapidly translocates to the nucleus,where it directly binds to the catalytic domains of key E3 ubiquitin ligases,including HERC2 and RNF8,and functionally inactivates them.This NPRL2-mediated inhibition of E3 ligase activity prevents the degradation of critical DNA repair proteins.Importantly,clinical analyses demonstrate that nuclear NPRL2 plays a role in sustaining radioresistance.Mechanistic investigations reveal that radiation-induced AMPK activation initiates this process by phosphorylating WDR24,which promotes NPRL2 dissociation from the GATOR1 complex and facilitates its nuclear translocation.Therapeutic targeting through AMPK inhibition effectively blocks NPRL2 nuclear accumulation,leading to impaired DNA damage repair and significant radiosensitization of CRC cells in both in vitro and in vivo models.These findings not only elucidate the AMPK/WDR24/NPRL2 signaling axis as a fundamental regulator of DNA repair machinery in CRC,but also provide compelling evidence for its potential as a novel therapeutic target to overcome radioresistance and improve radiotherapy efficacy in CRC patients.
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Young Scientists Fund of the National Natural Science Foundation of China(61572004,L.L.,32202496,H.H.)。
文摘Auxin regulates plant growth by integrating transport and signaling.Polar auxin transport establishes auxin gradients essential for development,with PIN-FORMED(PIN)efflux carriers generating directionality and AUXIN1/LIKE-AUX1(AUX1/LAX)influx carriers ensuring efficient uptake.Canonical signaling begins when auxin binds TRANSPORT INHIBITOR RESPONSE 1/AUXIN SIGNALING F-BOX PROTEIN(TIR1/AFB)receptors,the F-box component of the SKP1-CULLIN1-F-box(SCF)E3 ubiquitin ligase complex(Gray et al.,2001).Auxin promotes recruitment and degradation of AUXIN/INDOLE-3-ACETIC ACID(AUX/IAA)repressors,thereby releasing AUXIN RESPONSE FACTOR(ARF)to activate transcription(Gray et al.,2001).Recent discoveries have expended this model.Cryo-electron microscopy(cryo-EM)structures of AUX1 clarified its proton(H+)-coupled import(Yang et al.,2025),and TIR1 was shown to function as an adenylate cyclase(AC),producing c AMP to activate transcription(Chen et al.,2025).Synthetic promoter studies further revealed a bi-layer ARF/cis-element code shaping cel type-specific gene expression(Martin-Arevalil o et al.,2025).
基金supported by the National Key Basic Research Program of the People's Republic of China(2011CB915402)the National Science Foundation of China(30970270to JJL)
文摘Ubiquitination of proteins is one of the critical regulatory mechanisms in eukaryotes. In higher plants, protein ubiquitination plays an essential role in many biological processes, including hormone signaling, photomorphogenesis, and pathogen defense. However, the roles of protein ubiquitination in the repro- ductive process are not clear. In this study, we identified four plant-specific RING-finger genes designated Aberrant_Pollen Development 1_ （APD1） to APD4, as regulators of pollen mitosis II （PMII） in Arabidopsis thaliana （L.）. The apdl apd2 double mutant showed a significantly increased percentage of bicellular-like pollen at the mature pollen stage. Further downregulation of the APD3 and APD4 transcripts in apdl apd2 by RNA interference （RNAi） resulted in more severe abnormal bicellular-like pollen phenotypes than in apdl apd2, suggesting that cell division was defective in male gametogenesis. All of the four genes were expressed in multiple stages at different levels during male gametophyte development. Confocal analysis using green florescence fusion proteins （GFP） GFP-APD1 and GFP-APD2 showed that APDs are associated with intracellular membranes. Furthermore, APD2 had E2-dependent E3 ligase activity in vitro, and five APD2-interacting proteins were identified. Our results suggest that these four genes may be involved, redundantly, in regulating the PMII process during male gametogenesis.
文摘Controlled stability of proteins is a highly efficient mechanism to direct diverse processes in living cells. A key regulatory system for protein stability is given by the ubiquitin proteasome pathway, which uses E3 ligases to mark specific proteins for degradation. In this work, MYB56 is identified as a novel target of a CULLIN3 （CUL3）-based E3 ligase. Its stability depends on the presence of MATH-BTB/POZ （BPM） proteins, which function as substrate adaptors to the E3 ligase. Genetic studies have indicated that MYB56 is a negative regulator of flowering, while BPMs positively affect this developmental program. The interaction between BPMs and MYB56 occurs at the promoter of FLOWERING LOCUS T （FT）, a key regulator in initiating flowering in Arabidopsis, and results in instability of MYB56. Overall the work establishes MYB transcription factors as substrates of BPM proteins, and provides novel information on components that participate in controlling flowering time in plants.
文摘Protein ubiquitination is an important means of posttranslational modification which plays an essential role in the regulation of various aspects of leukocyte development and function. The specificity of ubiquitin tagging to a protein substrate is determined by E3 ubiquitin ligases via defined E3-substrate interactions. In this review, we will focus on two E3 ligases, VHL and Itch, to discuss the latest progress in understanding their roles in the differentiation and function of CD4+ T helper cell subsets, the stability of regulatory T cells, effector function of CD8+ T cells, as well as the development and maturation of innate lymphoid cells. The biological implications of these E3 ubiquitin ligases will be highlighted in the context of normal and dysregulated immune responses including the control of homeostasis, inflammation, auto-immune responses and anti-tumor immunity. Further elucidation of the ubiquitin system in immune cells will help in the design of new therapeutic interventions for human immunological diseases and cancer.
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supported by National Natural Science Foundation of China grant 31972862by Transgenic Research Project(2018ZX08009-11B-002).
文摘Accumulating evidence has revealed that the ubiquitin proteasome system plays fundamental roles in the regulation of diverse cellular activities in eukaryotes.The ubiquitin protein ligases(E3s)are central to the proteasome system because of their ability to determine its substrate specificity.Several studies have demonstrated the essential role of a group of ER(endoplasmic reticulum)-localized E3s in the positive or negative regulation of cell homeostasis.Most ER-related E3s are conserved between plants and mammals,and a few plant-specific components have been reported.In this review,we summarize the functions of ERrelated E3s in plant growth,ER-associated protein degradation and ER-phagy,abiotic and biotic stress responses,and hormone signaling.Furthermore,we highlight several questions that remain to be addressed and suggest directions for further research on ER-related E3 ubiquitin ligases.
