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To combat pathogen attacks, plants have developed a highly advanced immune system, which requires tight regulation to initiate robust defense responses while preventing autoimmunity simultaneously. The ubiquitin-proteasome system (UPS), responsible for degrading excess or misfolded proteins, exerts vital roles in ensuring strong and effective immune responses. E3 ligases, as key UPS components, have been extensively documented in rice immunity through 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 of E3 ligases 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 the immunity-associated E3 ligases in breeding disease-resistant rice varieties without growth penalty. This review thus provides comprehensive and updated understanding on the sophisticated and interconnected regulatory functions of E3 ligases in rice immunity and its balancing with growth and development.
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The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.
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Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Ubiquitina-Proteína Ligasas , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismo , Humanos , Relación Estructura-Actividad , Estructura Molecular , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis químicaRESUMEN
Cellular responses to external stress allow microorganisms to adapt to a vast array of environmental conditions, including infection sites. The molecular mechanisms behind these responses are studied to gain insight into microbial pathogenesis, which could lead to new antimicrobial therapies. Here, we explore a role for arrestin protein-mediated ubiquitination in stress response and pathogenesis in the pathogenic fungus Cryptococcus neoformans. In a previous study, we identified four arrestin-like proteins in C. neoformans and found that one of these is required for efficient membrane synthesis, likely by directing interaction between fatty acid synthases and the Rsp5 E3 ubiquitin ligase. Here, we further explore Cn Rsp5 function and determine that this single Ub ligase is absolutely required for pathogenesis and survival in the presence of cellular stress. Additionally, we show that a second arrestin-like protein, Ali2, similarly facilitates interaction between Rsp5 and some of its protein targets. Of the four postulated C. neoformans arrestin-like proteins, Ali2 appears to contribute the most to C. neoformans pathogenesis, likely by directing Rsp5 to pathogenesis-related ubiquitination targets. A proteomics-based differential ubiquitination screen revealed that several known cell surface proteins are ubiquitinated by Rsp5 and a subset also requires Ali2 for their ubiquitination. Rsp5-mediated ubiquitination alters the stability and the localization of these proteins. A loss of Rsp5-mediated ubiquitination results in cell wall defects that increase susceptibility to external stresses. These findings support a model in which arrestin-like proteins guide Rsp5 to ubiquitinate specific target proteins, some of which are required for survival during stress. IMPORTANCE: Microbial proteins involved in human infectious diseases often need to be modified by specific chemical additions to be fully functional. Here, we explore the role of a particular protein modification, ubiquitination, in infections due to the human fungal pathogen Cryptococcus neoformans. We identified a complex of proteins responsible for adding ubiquitin groups to fungal proteins, and this complex is required for virulence. These proteins are fungal specific and might be targets for novel anti-infection therapy.
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Purpose: Colorectal cancer is the third most common cause of cancer death worldwide. We probed the correlations between E3 ubiquitin ligase (E3)-related genes (ERGs) and colon cancer prognosis and immune responses. Methods: Gene expression profiles and clinical data of patients with colon cancer were acquired from the TCGA, GTEx, GSE17537 and GSE29621 databases. ERGs were identified by coexpression analysis. WGCNA and differential expression analysis were subsequently conducted. Consensus clustering identified two molecular clusters. Differential analysis of the two clusters and Cox regression were then conducted. A prognostic model was constructed based on 10 machine learning algorithms and 92 algorithm combinations. The CIBERSORT, ssGSEA and TIMER algorithms were used to estimate immune infiltration. The OncoPredict algorithm and The Cancer Immunome Atlas (TCIA) predicted susceptibility to chemotherapeutic and targeted drugs and immunotherapy sensitivity. CCK-8, scratch-wound and RTâPCR assays were subsequently conducted. Results: Two ERG-associated clusters were identified. The prognosis and immune function of patients in cluster A were superior to those of patients in cluster B. We constructed a prognostic model with perfect predictive capability and validated it in internal and external colon cancer datasets. We discovered significant discrepancies in immune infiltration and immune checkpoints between different risk groups. The group with high-risk had a reduced half-maximal inhibitory concentration (IC50) for some routine antitumor drugs and reduced susceptibility to immunotherapy. In vitro experiments demonstrated that the ectopic expression of PRELP inhibited the migration and proliferation of CRC cells. Conclusions: In summary, we identified novel molecular subtypes and developed a prognostic model, which will help a lot in the advancement of better forecasting and therapeutic approaches.
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Cotton is one of the world's most important economic crops. Verticillium wilt is a devastating cotton disease caused by Verticillium dahliae, significantly impacting cotton yield and quality. E3 ubiquitin ligases are essential components of the ubiquitin-mediated 26S proteasome system, responsible for recognizing ubiquitinated target proteins and promoting their degradation, which play a crucial regulatory role in plant immune responses. In this study, on the basis of the confirmation of differential expression of GhDIRP1, a RING-type E3 ubiquitin ligase encoding gene, in two cotton varieties resistant (Zhongzhimian 2) or susceptible (Jimian 11) to V. dahliae, we demonstrated that GhDIRP1 is a negative regulator of V. dahliae resistance because silencing GhDIRP1 in cotton and heterogeneously overexpressing the gene in Arabidopsis enhanced and compromised resistance to V. dahliae, respectively. The GhDIRP1-mediated immune response seemed to be realized through multiple physiological pathways, including hormone signaling, reactive oxygen species, and lignin biosynthesis. Based on the sequences of GhDIRP1 isolated from Zhongzhimian 2 and Jimian 11, we found that GhDIRP1 had identical coding but different promoter sequences in the two varieties, with the promoter of Zhongzhimian 2 being more active than that of Jimian 11 because the former drove a stronger expression of GUS and LUC reporter genes. The results link the ubiquitination pathway to multiple physiological pathways acting in the cotton immune response and provide a candidate gene for breeding cotton varieties resistant to V. dahliae.
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This study aims to investigate the role of RNF149 and tetraspanin CD63 in lipopolysaccharide/Toll-like receptor 4 (LPS/TLR4) signal transduction. TNF-α was assessed using enzyme-linked immunosorbent assay. The distribution of TLR4 was examined through flow cytometry after CD63 knockdown. Real-time polymerase chain reaction was used to analyze the expression of the target genes RNF149 and CD63 under different conditions. Western blotting was employed to detect gene expression, while immunoprecipitation and confocal microscopy were used to evaluate protein interactions. Transcriptome array data from stimulated monocytes (GSE7547) was obtained from GEO and subjected to bioinformatic analysis. It is suggested that CD63 may serve as a substrate of RNF149, with RNF149 capable of directly interacting with CD63. RNF149 degrades CD63 through covalent modification of CD63 at lysine 29 of the ubiquitin monomer, leading to the formation of a multiubiquitin chain. Both RNF149 and CD63 interact with TLR4, with CD63 promoting LPS/TLR4 signaling and RNF149 inhibits it. CD63 does not impact the distribution of TLR4 on the cell surface and does not directly interact with TIRAP, IRAK4, or TRAF6, but does interact with Myd88.RNF149 plays a negative regulatory role in LPS/TLR4 signal transduction by mediating ubiquitination-induced CD63 degradation.
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Targeted protein degradation is an emergent and rapidly evolving therapeutic strategy. In particular, biologics-based targeted degradation modalities (bioPROTACs) are relatively under explored compared to small molecules. Here, we investigate how target affinity, cellular localization, and valency of bioPROTACs impact efficacy of targeted degradation of the oncogenic phosphatase src-homology 2 containing protein tyrosine phosphatase-2 (SHP2). We identify bivalent recruitment of SHP2 by bioPROTACs as a broadly applicable strategy to improve potency. Moreover, we demonstrate that SHP2-targeted bioPROTACs can effectively counteract gain-of-function SHP2 mutants present in cancer, which are otherwise challenging to selectively target with small molecule constructs. Overall, this study demonstrates the utility of bioPROTACs for challenging targets, and further explicates design principles for therapeutic bioPROTACs.
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Degrons are minimal protein features that are sufficient to target proteins for degradation. In most cases, degrons allow recognition by components of the cytosolic ubiquitin proteasome system. Currently, all of the identified degrons only function within the cytosol. Using Saccharomyces cerevisiae, we identified the first short linear sequences that function as degrons from the endoplasmic reticulum (ER) lumen. We show that when these degrons are transferred to proteins, they facilitate proteasomal degradation through the ERAD system. These degrons enable degradation of both luminal and integral membrane ER proteins, expanding the types of proteins that can be targeted for degradation in budding yeast and mammalian tissue culture. This discovery provides a framework to target proteins for degradation from the previously unreachable ER lumen and builds toward therapeutic approaches that exploit the highly-conserved ERAD system.
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In plants, vegetative growth is controlled by synergistic and/or antagonistic effects of many regulatory factors. Here, the authors demonstrate that the ubiquitin ligase seven in absentia1 (SINA1) mammalian BTF2-like transcription factors, Drosophila synapse-associated proteins, and yeast DOS2-like proteins (BSD1) function as a regulatory module to control vegetative growth in tomato via regulation of the production of plant growth hormone gibberellin (GA). SINA1 negatively regulates the protein level of BSD1 through ubiquitin-proteasome-mediated degradation, and the transgenic tomato over-expressing SINA1 (SINA1-OX) resembles the dwarfism phenotype of the BSD1-knockout (BSD1-KO) tomato plant. BSD1 directly activates expression of the BSD1-regulated gene 1 (BRG1) via binding to a novel core BBS (standing for BSD1 binding site) binding motif in the BRG1 promoter. Knockout of BRG1 (BRG1-KO) in tomato also results in a dwarfism phenotype, suggesting BRG1 plays a positive role in vegetative growth as BSD1 does. Significantly, GA contents are attenuated in transgenic SINA1-OX, BSD1-KO, and BRG1-KO plants exhibiting dwarfism phenotype and exogenous application of bioactive GA3 restores their vegetative growth. Moreover, BRG1 is required for the expression of multiple GA biosynthesis genes and BSD1 activates three GA biosynthesis genes promoting GA production. Thus, this study suggests that the SINA1-BSD1 module controls vegetative growth via direct and indirect regulation of GA biosynthesis in tomato.
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Malaria is a mosquito-borne infectious disease caused by unicellular eukaryotic parasites of the Plasmodium genus. Protein ubiquitination by E3 ligases is a critical post-translational modification required for various cellular processes during the lifecycle of Plasmodium parasites. However, little is known about the repertoire and function of these enzymes in Plasmodium. Here, we show that Plasmodium expresses a conserved cullin RING E3 ligase (CRL) complex that is functionally related to CRL4 in other eukaryotes. In P. falciparum asexual blood stages, a cullin-4 scaffold interacts with the RING protein RBX1, the adaptor protein DDB1, and a set of putative receptor proteins that may determine substrate specificity for ubiquitination. These receptor proteins contain WD40-repeat domains and include WD-repeat protein important for gametogenesis 1 (WIG1). This CRL4-related complex is also expressed in P. berghei gametocytes, with WIG1 being the only putative receptor detected in both the schizont and gametocyte stages. WIG1 disruption leads to a complete block in microgamete formation. Proteomic analyses indicate that WIG1 disruption alters proteostasis of ciliary proteins and components of the DNA replication machinery during gametocytogenesis. Further analysis by ultrastructure expansion microscopy (U-ExM) indicates that WIG1-dependent depletion of ciliary proteins is associated with impaired the formation of the microtubule organization centers that coordinate mitosis with axoneme formation and altered DNA replication during microgametogenesis. This work identifies a CRL4-related ubiquitin ligase in Plasmodium that is critical for the formation of microgametes by regulating proteostasis of ciliary and DNA replication proteins.IMPORTANCEPlasmodium parasites undergo fascinating lifecycles with multiple developmental steps, converting into morphologically distinct forms in both their mammalian and mosquito hosts. Protein ubiquitination by ubiquitin ligases emerges as an important post-translational modification required to control multiple developmental stages in Plasmodium. Here, we identify a cullin RING E3 ubiquitin ligase (CRL) complex expressed in the replicating asexual blood stages and in the gametocyte stages that mediate transmission to the mosquito. WIG1, a putative substrate recognition protein of this ligase complex, is essential for the maturation of microgametocytes into microgametes upon ingestion by a mosquito. More specifically, WIG1 is required for proteostasis of ciliary proteins and components of the DNA replication machinery during gametocytogenesis. This requirement is linked to DNA replication and microtubule organization center formation, both critical to the development of flagellated microgametes.
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Protein homeostasis depends on many fundamental processes including mRNA synthesis, translation, post-translational modifications, and proteolysis. In the late 70s and early 80s the discovery that the small 76 amino acid protein ubiquitin could be attached to target proteins via a multi-stage process involving ubiquitin-activating enzymes, ubiquitin conjugating enzymes, and ubiquitin ligases, revealed an exciting new post-translational mechanism to regulate protein degradation. This cellular system was uncovered using biochemical methods by Avram Hershko, who would later won the Nobel prize for this discovery; however, the biological functions of ubiquitin ligases remained unknown for many years. It was initially described that ubiquitin modifies proteins at one or more lysine residues and once a long ubiquitin chain was assembled, proteins were degraded by the proteasome. Now we know that proteins can be mono-, multimono-, homotypic poly-, or heterotypic poly-ubiquitylated, each of which confers a specific signal that goes beyond protein degradation regulating additional key cellular functions such as signal transduction, protein localization, recognition of damaged proteins, etc.
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Tumor suppressor genes play critical roles in normal tissue homeostasis, and their dysregulation underlies human diseases including cancer. Besides human genetics, model organisms such as Drosophila have been instrumental in discovering tumor suppressor pathways that were subsequently shown to be highly relevant in human cancer. Here we show that hyperplastic disc (Hyd), one of the first tumor suppressors isolated genetically in Drosophila and encoding an E3 ubiquitin ligase with hitherto unknown substrates, and Lines (Lin), best known for its role in embryonic segmentation, define an obligatory tumor suppressor protein complex (Hyd-Lin) that targets the zinc finger-containing oncoprotein Bowl for ubiquitin-mediated degradation, with Lin functioning as a substrate adaptor to recruit Bowl to Hyd for ubiquitination. Interestingly, the activity of the Hyd-Lin complex is directly inhibited by a micropeptide encoded by another zinc finger gene, drumstick (drm), which functions as a pseudosubstrate by displacing Bowl from the Hyd-Lin complex, thus stabilizing Bowl. We further identify the epigenetic regulator Polycomb repressive complex1 (PRC1) as a critical upstream regulator of the Hyd-Lin-Bowl pathway by directly repressing the transcription of the micropeptide drm Consistent with these molecular studies, we show that genetic inactivation of Hyd, Lin, or PRC1 resulted in Bowl-dependent hyperplastic tissue overgrowth in vivo. We also provide evidence that the mammalian homologs of Hyd (UBR5, known to be recurrently dysregulated in various human cancers), Lin (LINS1), and Bowl (OSR1/2) constitute an analogous protein degradation pathway in human cells, and that OSR2 promotes prostate cancer tumorigenesis. Altogether, these findings define a previously unrecognized tumor suppressor pathway that links epigenetic program to regulated protein degradation in tissue growth control and tumorigenesis.
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Carcinogénesis , Proteínas de Drosophila , Proteolisis , Ubiquitina-Proteína Ligasas , Animales , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Carcinogénesis/genética , Humanos , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/embriología , Genes Supresores de Tumor , Ubiquitinación , Proteínas del Grupo Polycomb/metabolismo , Proteínas del Grupo Polycomb/genética , Complejo Represivo Polycomb 1/metabolismo , Complejo Represivo Polycomb 1/genéticaRESUMEN
The Ralstonia solanacearum species complex causes bacterial wilt in a variety of crops. Tomato cultivar Hawaii 7996 is a widely used resistance resource; however, the resistance is evaded by virulent strains, with the underlying mechanisms still unknown. Here, we report that the phylotype â ¡ strain ES5-1 can overcome Hawaii 7996 resistance. RipV2, a type â ¢ effector specific to phylotype â ¡ strains, is vital in overcoming tomato resistance. RipV2, which encodes an E3 ubiquitin ligase, suppresses immune responses and Toll/interleukin-1 receptor/resistance nucleotide-binding/leucine-rich repeat (NLR) (TNL)-mediated cell death. Tomato helper NLR N requirement gene 1 (NRG1), enhanced disease susceptibility 1 (EDS1), and senescence-associated gene 101b (SAG101b) are identified as RipV2 target proteins. RipV2 is essential for ES5-1 virulence in Hawaii 7996 but not in SlNRG1-silenced tomato, demonstrating SlNRG1 to be an RipV2 virulence target. Our results dissect the mechanisms of RipV2 in disrupting immunity and highlight the importance of converged immune components in conferring bacterial wilt resistance.
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Resistencia a la Enfermedad , Enfermedades de las Plantas , Ralstonia solanacearum , Solanum lycopersicum , Ubiquitinación , Ralstonia solanacearum/patogenicidad , Ralstonia solanacearum/metabolismo , Solanum lycopersicum/microbiología , Solanum lycopersicum/inmunología , Solanum lycopersicum/metabolismo , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/inmunología , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas NLR/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteolisis , VirulenciaRESUMEN
Ubiquitination is an evolutionary, ancient system of post-translational modification of proteins that occurs through a cascade involving ubiquitin activation, transfer, and conjugation. The maturation of this system has followed two main pathways. The first is the conservation of a universal structural fold of ubiquitin and ubiquitin-like proteins, which are present in both Archaea and Bacteria, as well as in multicellular Eukaryotes. The second is the rise of the complexity of the superfamily of ligases, which conjugate ubiquitin-like proteins to substrates, in terms of an increase in the number of enzyme variants, greater variation in structural organization, and the diversification of their catalytic domains. Here, we examine the diversity of the ubiquitination system among different organisms, assessing the variety and conservation of the key domains of the ubiquitination enzymes and ubiquitin itself. Our data show that E2 ubiquitin-conjugating enzymes of metazoan phyla are highly conservative, whereas the homology of E3 ubiquitin ligases with human orthologues gradually decreases depending on "molecular clock" timing and evolutionary distance. Surprisingly, Chordata and Echinodermata, which diverged over 0.5 billion years ago during the Cambrian explosion, share almost the same homology with humans in the amino acid sequences of E3 ligases but not in their adaptor proteins. These observations may suggest that, firstly, the E2 superfamily already existed in its current form in the last common metazoan ancestor and was generally not affected by purifying selection in metazoans. Secondly, it may indicate convergent evolution of the ubiquitination system and highlight E3 adaptor proteins as the "upper deck" of the ubiquitination system, which plays a crucial role in chordate evolution.
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Evolución Molecular , Transducción de Señal , Enzimas Ubiquitina-Conjugadoras , Ubiquitina , Ubiquitinación , Humanos , Ubiquitina/metabolismo , Animales , Enzimas Ubiquitina-Conjugadoras/metabolismo , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/química , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/química , Procesamiento Proteico-Postraduccional , FilogeniaRESUMEN
The SEVEN IN ABSENTIA (SINA) E3 ubiquitin ligase is widely involved in drought and salt stress in plants. However, the biological function of the SINA proteins in cotton is still unknown. This study aimed to reveal the function of GhSINAT5 through biochemical, genetic and molecular approaches. GhSINAT5 is expressed in several tissues of cotton plants, including roots, stems, leaves and cotyledons, and its expression levels are significantly affected by polyethylene glycol, abscisic acid and sodium chloride. When GhSINAT5 was silenced in cotton plants, drought and salinity stress occurred, and the length, area and volume of the roots significantly decreased. Under drought stress, the levels of proline, superoxide dismutase, peroxidase and catalase in the GhSINAT5-silenced cotton plants were significantly lower than those in the non-silenced control plants, whereas the levels of hydrogen peroxide and malondialdehyde were greater. Moreover, the expression of stress-related genes in silenced plants under drought stress suggested that GhSINAT5 may play a positive role in the plant response to drought and salt stress by regulating these stress response-related genes. These findings not only deepen our understanding of the mechanisms of drought resistance in cotton but also provide potential targets for future improvements in crop stress resistance through genetic engineering.
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Sequías , Regulación de la Expresión Génica de las Plantas , Gossypium , Proteínas de Plantas , Tolerancia a la Sal , Gossypium/genética , Gossypium/metabolismo , Gossypium/fisiología , Tolerancia a la Sal/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Silenciador del Gen , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Estrés Fisiológico/genética , Plantas Modificadas Genéticamente/genética , Resistencia a la SequíaRESUMEN
The CBL (Casitas B-lineage lymphoma) family, as a class of ubiquitin ligases, can regulate signal transduction and activate receptor tyrosine kinases through various tyrosine kinase-dependent pathways. There are three members of the family: c-CBL, CBL-b, and CBL-c. Numerous studies have demonstrated the important role of CBL in various cellular pathways, particularly those involved in the occurrence and progression of cancer, hematopoietic development, and regulation of T cell receptors. Therefore, the purpose of this review is to comprehensively summarize the function and regulatory role of CBL family proteins in different human tumors, as well as the progress of drug research targeting CBL family, so as to provide a broader clinical measurement strategy for the treatment of tumors.
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Restricting the localization of evolutionarily conserved histone H3 variant CENP-A to the centromere is essential to prevent chromosomal instability (CIN), an important hallmark of cancers. Overexpressed CENP-A mislocalizes to non-centromeric regions and contributes to CIN in yeast, flies, and human cells. Centromeric localization of CENP-A is facilitated by the interaction of Mis18ß with CENP-A specific chaperone HJURP. Cellular levels of Mis18ß are regulated by ß-transducin repeat containing protein (ß-TrCP), an F-box protein of SCF (Skp1, Cullin, F-box) E3-ubiquitin ligase complex. Here, we show that defects in ß-TrCP-mediated proteolysis of Mis18ß contributes to the mislocalization of endogenous CENP-A and CIN in a triple-negative breast cancer (TNBC) cell line, MDA-MB-231. CENP-A mislocalization in ß-TrCP depleted cells is dependent on high levels of Mis18ß as depletion of Mis18ß suppresses mislocalization of CENP-A in these cells. Consistent with these results, endogenous CENP-A is mislocalized in cells overexpressing Mis18ß alone. In summary, our results show that ß-TrCP-mediated degradation of Mis18ß prevents mislocalization of CENP-A and CIN. We propose that deregulated expression of Mis18ß may be one of the key mechanisms that contributes to chromosome segregation defects in cancers.
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Breast cancer (BC) is the most common malignant tumor worldwide. Despite enormous progress made in the past decades, the underlying mechanisms of BC remain further illustrated. Recently, TRIM family proteins proved to be engaged in BC progression through regulating various aspects. Here we reviewed the structures and basic functions of TRIM family members and first classified them into three groups according to canonical polyubiquitination forms that they could mediate: K48- only, K63- only, and both K48- and K63-linked ubiquitination. Afterwards, we focused on the specific biological functions and mechanisms of TRIMs in BCs, including tumorigenesis and invasiveness, drug sensitivity, tumor immune microenvironment (TIME), cell cycle, and metabolic reprogramming. We also explored the potential of TRIMs as novel biomarkers for predicting prognosis and future therapeutic targets in BC.
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Neoplasias de la Mama , Proteínas de Motivos Tripartitos , Ubiquitinación , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Femenino , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Microambiente Tumoral , Biomarcadores de Tumor/metabolismo , Pronóstico , Regulación Neoplásica de la Expresión Génica , AnimalesRESUMEN
The ubiquitin-proteasome system (UPS) plays crucial roles in cellular processes including plant growth, development, and stress responses. In this study, we report that a pair of E3 ubiquitin ligases, AvrPiz-t-interaction protein 6 (APIP6) and IPA1-interaction protein 1 (IPI1), intricately target early flowering3 (ELF3) paralogous proteins to control rice immunity and flowering. APIP6 forms homo-oligomers or hetero-oligomers with IPI1. Both proteins interact with OsELF3-2, promoting its degradation to positively control resistance against the rice blast fungus (Magnaporthe oryzae). Intriguingly, overexpression of IPI1 in Nipponbare caused significantly late-flowering phenotypes similar to the oself3-1 mutant. Except for late flowering, oself3-1 enhances resistance against M. oryzae. IPI1 also interacts with and promotes the degradation of OsELF3-1, a paralog of OsELF3-2. Notably, IPI1 and APIP6 synergistically modulate OsELF3s degradation, finely tuning blast disease resistance by targeting OsELF3-2, while IPI1 controls both disease resistance and flowering by targeting OsELF3-1. This study unravels multiple functions for a pair of E3 ligases in rice.
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E3 ubiquitin ligases (UBLs), as enzymes capable of specifically recognizing target proteins in the process of protein ubiquitination, play crucial roles in regulating responses to abiotic stresses such as drought, salt, and temperature. Abscisic acid (ABA), a plant endogenous hormone, is essential to regulating plant growth, development, disease resistance, and defense against abiotic stresses, and acts through a complex ABA signaling pathway. Hormone signaling transduction relies on protein regulation, and E3 ubiquitin ligases play important parts in regulating the ABA pathway. Therefore, this paper reviews the ubiquitin-proteasome-mediated protein degradation pathway, ABA-related signaling pathways, and the regulation of ABA-signaling-pathway-related genes by E3 ubiquitin ligases, aiming to provide references for further exploration of the relevant research on how plant E3 ubiquitin ligases regulate the ABA pathway.