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The pathogen Agrobacterium tumefaciens is known for causing crown gall tumours in plants. However, it has also been harnessed as a valuable tool for plant genetic transformation. Apart from the T-DNA, Agrobacterium also delivers at least five virulence proteins into the host plant cells, which are required for an efficient infection. One of these virulence proteins is VirD5. F-box proteins, encoded in the host plant genome or the Ti plasmid, and the ubiquitin/26S proteasome system (UPS) also play an important role in facilitating Agrobacterium infection. Our study identified two Arabidopsis F-box proteins, D5BF1 and D5BF2, that bind VirD5 and facilitate its degradation via the UPS. Additionally, we found that Agrobacterium partially suppresses the expression of D5BF1 and D5BF2. Lastly, stable transformation and tumorigenesis efficiency assays revealed that D5BF1 and D5BF2 negatively regulate the Agrobacterium infection process, showing that the plant F-box proteins and UPS play a role in defending against Agrobacterium infection.

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The lignocellulosic feedstock of woody bamboo shows promising potential as an alternative to conventional wood, attributed to its excellent properties. The content and distribution of lignin serve as the foundation of these properties. While the regulation of lignin biosynthesis in bamboo has been extensively studied at the transcriptional level, its posttranslational control has remained poorly understood. This study provides a ubiquitinome dataset for moso bamboo (Phyllostachys edulis), identifying 13015 ubiquitinated sites in 4849 unique proteins. We further identified Kelch repeat F-boxprotein 9 (PeKFB9) that plays a negative role in lignin biosynthesis. Heterologous expression of PeKFB9 resulted in reduced accumulation of lignin and decreased phenylalanine ammonia-lyase (PAL) activities. Both in vitro and in vivo assays identified interaction between PeKFB9 and PePAL10. Further examination revealed that SCFPeKFB9 mediated the ubiquitination and degradation of PePAL10 via the 26S proteasome pathway. Moreover, PebZIP28667 could bind to the PePAL10 promoter to significantly inhibit its transcription, and ubiquitination of PebZIP28667 weakened this inhibition. Collectively, our findings reveal a PeKFB9-PePAL10/PebZIP28667-PePAL10 module that acts as a negative regulator of lignin biosynthesis. This study advances our understanding of posttranslational regulation in plant lignification, which will facilitate the improvement of the properties of bamboo wood and the breeding of varieties.

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Phenylpropanoids, a class of specialized metabolites, play crucial roles in plant growth and stress adaptation and include diverse phenolic compounds such as flavonoids. Phenylalanine ammonia-lyase (PAL) and chalcone synthase (CHS) are essential enzymes functioning at the entry points of general phenylpropanoid biosynthesis and flavonoid biosynthesis, respectively. In Arabidopsis, PAL and CHS are turned over through ubiquitination-dependent proteasomal degradation. Specific kelch domain-containing F-Box (KFB) proteins as components of ubiquitin E3 ligase directly interact with PAL or CHS, leading to polyubiquitinated PAL and CHS, which in turn influences phenylpropanoid and flavonoid production. Although phenylpropanoids are vital for tomato nutritional value and stress responses, the post-translational regulation of PAL and CHS in tomato remains unknown. We identified 31 putative KFB-encoding genes in the tomato genome. Our homology analysis and phylogenetic study predicted four PAL-interacting SlKFBs, while SlKFB18 was identified as the sole candidate for the CHS-interacting KFB. Consistent with their homolog function, the predicted four PAL-interacting SlKFBs function in PAL degradation. Surprisingly, SlKFB18 did not interact with tomato CHS and the overexpression or knocking out of SlKFB18 did not affect phenylpropanoid contents in tomato transgenic lines, suggesting its irreverence with flavonoid metabolism. Our study successfully discovered the post-translational regulatory machinery of PALs in tomato while highlighting the limitation of relying solely on a homology-based approach to predict interacting partners of F-box proteins.

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The molecular mechanisms that govern the metabolic commitment to reproduction, which often occurs at the expense of somatic reserves, remain poorly understood. We identified the Caenorhabditis elegans F-box protein FBXL-5 as a negative regulator of maternal provisioning of vitellogenin lipoproteins, which mediate the transfer of intestinal lipids to the germline. Mutations in fbxl-5 partially suppress the vitellogenesis defects observed in the heterochronic mutants lin-4 and lin-29, both of which ectopically express fbxl-5 at the adult developmental stage. FBXL-5 functions in the intestine to negatively regulate expression of the vitellogenin genes; and consistently, intestine-specific over-expression of FBXL-5 is sufficient to inhibit vitellogenesis, restrict lipid accumulation, and shorten lifespan. Our epistasis analyses suggest that fbxl-5 functions in concert with cul-6, a cullin gene, and the Skp1-related gene skr-3 to regulate vitellogenesis. Additionally, fbxl-5 acts genetically upstream of rict-1, which encodes the core mTORC2 protein Rictor, to govern vitellogenesis. Together, our results reveal an unexpected role for a SCF ubiquitin-ligase complex in controlling intestinal lipid homeostasis by engaging mTORC2 signaling.

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Ankyrin repeat is a 33-amino acid motif commonly observed in eukaryotes and, to a lesser extent, in prokaryotes and archaea and rarely in viruses. This motif plays a crucial role in regulating various cellular processes like the cell cycle, transcription, cell signaling, and inflammatory responses through interactions between proteins. Poxviruses exhibit a distinctive feature of containing multiple ankyrin repeat proteins within their genomes. All the genera of poxviruses possess these proteins except molluscipox virus, crocodylidpox virus, and red squirrel poxvirus. An intriguing characteristic has generated notable interest in studying the functions of these proteins within poxvirus biology. Within poxviruses, ankyrin repeat proteins exhibit a distinct configuration, featuring ankyrin repeats in the N-terminal region and a cellular F-box homolog in the C-terminal region, which enables interactions with the cellular Skp, Cullin, F-box containing ubiquitin ligase complex. Through the examination of experimental evidences and discussions from current literature, this review elucidates the organization and role of ankyrin repeat proteins in poxviruses. Various research studies have highlighted the significant importance of these proteins in poxviral pathogenesis and, acting as factors that enhance virulence. Consequently, they represent viable targets for developing genetically altered viruses with decreased virulence, thus displaying potential as candidates for vaccines and antiviral therapeutic development contributing to safer and more effective strategies against poxviral infections.

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Tea plant (Camellia sinensis [L.]) is one of the most important crops in China, and tea branch is an important agronomic trait that determines the yield of tea plant. In previous work focused on GWAS that detecting GWAS signals related to plant architecture through whole genome re-sequencing of ancient tea plants, a gene locus TEA 029928 significantly related to plant type was found. Sequence alignment results showed that this gene belonged to the F-box family. We named it CsBRC. CsBRC-GFP fusion proteins were mainly localized in the plasma membrane. By comparing the phenotypes of CsBRC transgenic tobacco and WT tobacco, it was found that the number of branches of transgenic tobacco was significantly higher than that of wild-type tobacco. Through RNA-seq analysis, it was found that CsBRC affects the branching development of plants by regulating the expression of genes related to brassinosteroid synthesis pathway in plants. In addition, overexpression of CsBRC in rice could increase tiller number, grain length and width, and 1,000-grain weight.

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Merkel cell polyomavirus (MCPyV) is a double-stranded tumor virus that is the main causative agent of Merkel cell carcinoma (MCC). The MCPyV large T antigen (LT), an essential viral DNA replication protein, maintains viral persistence by interacting with host Skp1-Cullin 1-F-box (SCF) E3 ubiquitin ligase complexes, which subsequently induces LT's proteasomal degradation, restricting MCPyV DNA replication. SCF E3 ubiquitin ligases require their substrates to be phosphorylated to bind them, utilizing phosphorylated serine residues as docking sites. The MCPyV LT unique region (MUR) is highly phosphorylated and plays a role in multiple host protein interactions, including SCF E3 ubiquitin ligases. Therefore, this domain highly governs LT stability. Though much work has been conducted to identify host factors that restrict MCPyV LT protein expression, the kinase(s) that cooperates with the SCF E3 ligase remains unknown. Here, we demonstrate that casein kinase 1 alpha (CK1α) negatively regulates MCPyV LT stability and LT-mediated replication by modulating interactions with the SCF ß-TrCP. Specifically, we show that numerous CK1 isoforms (α, δ, ε) localize in close proximity to MCPyV LT through in situ proximity ligation assays (PLA) and CK1α overexpression mainly resulted in decreased MCPyV LT protein expression. Inhibition of CK1α using short hairpin RNA (shRNA) and treatment of a CK1α inhibitor or an mTOR inhibitor, TORKinib, resulted in decreased ß-TrCP interaction with LT, increased LT expression, and enhanced MCPyV replication. The expression level of the CSNK1A1 gene transcripts is higher in MCPyV-positive MCC, suggesting a vital role of CK1α in limiting MCPyV replication required for establishing persistent infection. IMPORTANCE: Merkel cell polyomavirus (MCPyV) large tumor antigen is a polyphosphoprotein and the phosphorylation event is required to modulate various functions of LT, including viral replication. Therefore, cellular kinase pathways are indispensable for governing MCPyV polyomavirus infection and life cycle in coordinating with the immunosuppression environment at disease onset. Understanding the regulation mechanisms of MCPyV replication by viral and cellular factors will guide proper prevention strategies with targeted inhibitors for MCPyV-associated Merkel cell carcinoma (MCC) patients, who currently lack therapies.

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Gastric cancer (GC) is a prevalent malignancy characterized by significant morbidity and mortality, yet its underlying pathogenesis remains elusive. The etiology of GC is multifaceted, involving the activation of oncogenes and the inactivation of antioncogenes. The ubiquitin-proteasome system (UPS), responsible for protein degradation and the regulation of physiological and pathological processes, emerges as a pivotal player in GC development. Specifically, the F-box protein (FBP), an integral component of the SKP1-Cullin1-F-box protein (SCF) E3 ligase complex within the UPS, has garnered attention for its prominent role in carcinogenesis, tumor progression, and drug resistance. Dysregulation of several FBPs has recently been observed in GC, underscoring their significance in disease progression. This comprehensive review aims to elucidate the distinctive characteristics of FBPs involved in GC, encompassing their impact on cell proliferation, apoptosis, invasive metastasis, and chemoresistance. Furthermore, we delve into the emerging role of FBPs as downstream target proteins of non-coding RNAs(ncRNAs) in the regulation of gastric carcinogenesis, outlining the potential utility of FBPs as direct therapeutic targets or advanced therapies for GC.

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F-box proteins play essential roles in various cellular processes of spermatogenesis by means of ubiquitylation and subsequent target protein degradation. They are the substrate-recognition subunits of SKP1-cullin 1-F-box protein (SCF) E3 ligase complexes. Dysregulation of F­box protein­mediated proteolysis could lead to male infertility in humans and mice. The emerging studies revealed the physiological function, pathological evidence, and biochemical substrates of F-box proteins in the development of male germ cells, which urging us to review the current understanding of how F­box proteins contribute to spermatogenesis. More functional and mechanistic study will be helpful to define the roles of F-box protein in spermatogenesis, which will pave the way for the logical design of F-box protein-targeted diagnosis and therapies for male infertility, as the spermatogenic role of many F-box proteins remains elusive.

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F-box protein is a subunit of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex, which plays a critical role in regulating different pathways in plant immunity. In this study, we identified the rice (Oryza sativa) F-box protein OsFBX156, which targets the heat shock protein 70 (OsHSP71.1) to regulate resistance to the rice blast fungus Magnaporthe oryzae. Overexpression of OsFBX156 or knockout of OsHSP71.1 in rice resulted in the elevation of pathogenesis-related (PR) genes and an induction burst of reactive oxygen species (ROS) after flg22 and chitin treatments, thereby enhancing resistance to M. oryzae. Furthermore, OsFBX156 can promote the degradation of OsHSP71.1 through the 26S proteasome pathway. This study sheds lights on a novel mechanism wherein the F-box protein OsFBX156 targets OsHSP71.1 for degradation to promote ROS production and PR gene expression, thereby positively regulating rice innate immunity.

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Complete panicle exsertion (CPE) is an economically important quantitative trait that contributes to grain yield in rice. We deployed an integrated approach for understanding the molecular mechanism of CPE using a stable EMS mutant line, CPE-109 of Samba Mahsuri (SM) exhibiting CPE. Two consistent genomic regions have been identified for CPE through QTL mapping [qCPE-4 (28.24-31.22 Mb) and qCPE-12 (2.30-3.18 Mb)] and QTL-sequencing [Chr-4 (31.21-33.69 Mb) and Chr-12 (0.12-3.15 Mb)]. Two non-synonymous SNPs, viz; KASP 12-12 (T→C; Chr12:1269983) in Os12g0126300; AP2/ERF transcription factor and KASP 12-16 (G→A; Chr12:1515198) in Os12g0131400; F-box domain-containing protein explained 81.05 and 59.61% phenotypic variance respectively and exhibited strong co-segregation with CPE in F2 mapping populations, advanced generation lines and CPE exhibiting SM mutants through KASP assays. The downregulation of these genes in CPE-109 compared to SM was observed in transcriptome sequencing of flag leaves which was validated through qRT-PCR. We propose that the abrogation of Os12g0126300 and Os12g0131400 in CPE-109 combinatorially influences the downregulation of ethylene biosynthetic genes viz. ACC synthase, ethylene-responsive factor-2, and up-regulation of gibberellic acid synthetic genes viz. ent-kaurene synthase and two cytokinin biosynthesis genes viz. cytokinin-O-glucosyltransferase 2, carboxy-lyase which result in complete panicle exsertion.

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Gliomas are highly malignant and invasive tumors lacking clear boundaries. Previous bioinformatics and experimental analyses have indicated that F-box and leucine-rich repeat protein 6 (FBXL6), a protein crucial for the cell cycle and tumorigenesis, is highly expressed in certain types of tumors. The high expression level of FBXL6 is reported to promote tumor growth and adversely affect patient survival. However, the molecular mechanism, prognostic value and drug sensitivity of FBXL6 in glioma remain unclear. To address this, the present study analyzed FBXL6 expression in gliomas, utilizing data from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. Analysis of FBXL6 mRNA expression levels, combined with patient factors such as age, sex and tumor grade using Kaplan-Meier plots and nomograms, demonstrated a strong correlation between FBXL6 expression and glioma progression. Co-expression networks provided further insights into the biological function of FBXL6. Additionally, using CIBERSORT and TISDB tools, the correlation between FBXL6 expression correlation tumor-infiltrating immune cells and immune genes was demonstrated to be statistically significant. These findings were validated by examining FBXL6 mRNA and protein levels in glioma tissues using various techniques, including western blot, reverse transcription-quantitative PCR and immunohistochemistry. These assays demonstrated the role of FBXL6 in glioma progression. Furthermore, drug sensitivity analysis demonstrated a strong correlation between FBXL6 expression and various drugs, which indicated that FBXL6 may potentially act as a future promising therapeutic target in glioma treatment. Therefore, the present study identified FBXL6 as a diagnostic and prognostic marker in patients with gliomas and highlighted its potential role in glioma progression.

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Rationale: Pulmonary fibrosis is a chronic progressive lung disease with limited therapeutic options. We previously revealed that there is iron deposition in alveolar epithelial type II cell (AECII) in pulmonary fibrosis, which can be prevented by the iron chelator deferoxamine. However, iron in the cytoplasm and the mitochondria has two relatively independent roles and regulatory systems. In this study, we aimed to investigate the role of mitochondrial iron deposition in AECII injury and pulmonary fibrosis, and to find potential therapeutic strategies. Methods: BLM-treated mice, MLE-12 cells, and primary AECII were employed to establish the mouse pulmonary fibrosis model and epithelial cells injury model, respectively. Mitochondrial transplantation, siRNA and plasmid transfection, western blotting (WB), quantitative real-time polymerase chain reaction (RT-qPCR), polymerase chain reaction (PCR), immunofluorescence, immunoprecipitation (IP), MitoSOX staining, JC-1 staining, oxygen consumption rate (OCR) measurement, and Cell Counting Kit-8 (CCK8) assay were utilized to elucidate the role of mitochondrial iron deposition in cell and lung fibrosis and determine its mechanism. Results: This study showed that prominent mitochondrial iron deposition occurs within AECII in bleomycin (BLM)-induced pulmonary fibrosis mouse model and in BLM-treated MLE-12 epithelial cells. Further, the study revealed that healthy mitochondria rescue BLM-damaged AECII mitochondrial iron deposition and cell damage loss. Mitoferrin-2 (MFRN2) is the main transporter that regulates mitochondrial iron metabolism by transferring cytosolic iron into mitochondria, which is upregulated in BLM-treated MLE-12 epithelial cells. Direct overexpression of MFRN2 causes mitochondrial iron deposition and cell damage. In this study, decreased ubiquitination of the ubiquitin ligase F-box/LRR-repeat protein 5 (FBXL5) degraded iron-reactive element-binding protein 2 (IREB2) and promoted MFRN2 expression as well as mitochondrial iron deposition in damaged AECII. Activation of the prostaglandin E2 receptor EP4 subtype (EP4) receptor signaling pathway counteracted mitochondrial iron deposition by downregulating IREB2-MFRN2 signaling through upregulation of FBXL5. This intervention not only reduced mitochondrial iron content but also preserved mitochondrial function and protected against AECII damage after BLM treatment. Conclusion: Our findings highlight the unexplored roles, mechanisms, and regulatory approaches of abnormal mitochondrial iron metabolism of AECII in pulmonary fibrosis. Therefore, this study deepens the understanding of the mechanisms underlying pulmonary fibrosis and offers a promising strategy for developing effective therapeutic interventions using the EP4 receptor activator.

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Self-incompatibility is a widespread genetic mechanism found in flowering plants. It plays a crucial role in preventing inbreeding and promoting outcrossing. The genes that control self-incompatibility in plants are typically determined by the S-locus female determinant factor and the S-locus male determinant factor. In the Solanaceae family, the male determinant factor is often the SLF gene. In this research, we cloned and analyzed 13 S2-LbSLF genes from the L. barbarum genome, which are located on chromosome 2 and close to the physical location of the S-locus female determinant factor S-RNase, covering a region of approximately 90.4 Mb. The amino acid sequence identity of the 13 S2-LbSLFs is 58.46%, and they all possess relatively conserved motifs and typical F-box domains, without introns. A co-linearity analysis revealed that there are no tandemly repeated genes in the S2-LbSLF genes, and that there are two pairs of co-linear genes between S2-LbSLF and the tomato, which also belongs to the Solanaceae family. A phylogenetic analysis indicates that the S2-LbSLF members can be divided into six groups, and it was found that the 13 S2-LbSLFs are clustered with the SLF genes of tobacco and Petunia inflata to varying degrees, potentially serving as pollen determinant factors regulating self-incompatibility in L. barbarum. The results for the gene expression patterns suggest that S2-LbSLF is only expressed in pollen tissue. The results of the yeast two-hybrid assay showed that the C-terminal region of S2-LbSLFs lacking the F-box domain can interact with S-RNase. This study provides theoretical data for further investigation into the functions of S2-LbSLF members, particularly for the identification of pollen determinant factors regulating self-incompatibility in L. barbarum.

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KEY MESSAGE: FKF1 dimerization is crucial for proper FT levels to fine-tune flowering time. Attenuating FKF1 homodimerization increased CO abundance by enhancing its COP1 binding, thereby accelerating flowering under long days. In Arabidopsis (Arabidopsis thaliana), the blue-light photoreceptor FKF1 (FLAVIN-BINDING, KELCH REPEAT, F-BOX 1) plays a key role in inducing the expression of FLOWERING LOCUS T (FT), encoding the main florigenic signal in plants, in the late afternoon under long-day conditions (LDs) by forming dimers with FT regulators. Although structural studies have unveiled a variant of FKF1 (FKF1 I160R) that disrupts homodimer formation in vitro, the mechanism by which disrupted FKF1 homodimer formation regulates flowering time remains elusive. In this study, we determined that the attenuation of FKF1 homodimer formation enhances FT expression in the evening by promoting the increased stability of CONSTANS (CO), a primary activator of FT, in the afternoon, thereby contributing to early flowering. In contrast to wild-type FKF1, introducing the FKF1 I160R variant into the fkf1 mutant led to increased FT expression under LDs. In addition, the FKF1 I160R variant exhibited diminished dimerization with FKF1, while its interaction with GIGANTEA (GI), a modulator of FKF1 function, was enhanced under LDs. Furthermore, the FKF1 I160R variant increased the level of CO in the afternoon under LDs by enhancing its binding to COP1, an E3 ubiquitin ligase responsible for CO degradation. These findings suggest that the regulation of FKF1 homodimerization and heterodimerization allows plants to finely adjust FT expression levels around dusk by modulating its interactions with GI and COP1.

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The F-box proteins in fungi perform diverse functions including regulation of cell cycle, circadian clock, development, signal transduction and nutrient sensing. Genome-wide analysis revealed 10 F-box genes in Puccinia triticina, the causal organism for the leaf rust disease in wheat and were characterized using in silico approaches for revealing phylogenetic relationships, gene structures, gene ontology, protein properties, sequence analysis and gene expression studies. Domain analysis predicted functional domains like WD40 and LRR at C-terminus along with the obvious presence of F-box motif in N-terminus. MSA showed amino acid replacements, which might be due to nucleotide substitution during replication. Phylogenetic analysis revealed the F-box proteins with similar domains to be clustered together while some sequences were spread out in different clades, which might be due to functional diversity. The clustering of Puccinia triticina GG705409 with Triticum aestivum TaAFB4/TaAFB5 in a single clade suggested the possibilities of horizontal gene transfer during the coevolution of P. triticina and wheat. Gene ontological annotation categorized them into three classes and were functionally involved in protein degradation through the protein ubiquitination pathway. Protein-protein interaction network revealed F-box proteins to interact with other components of the SCF complex involved in protein ubiquitination. Relative expression analysis of five F-box genes in a time course experiment denoted their involvement in leaf rust susceptible wheat plants. This study provides information on structure elucidation of F-box proteins of a basidiomycetes plant pathogenic fungi and their role during pathogenesis.

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KEY MESSAGE: The maize F-box protein ZmFBL41 targets abscisic acid synthase 9-cis-epoxycarotenoid dioxygenase 6 for degradation, and this regulatory module is exploited by Rhizoctonia solani to promote infection. F-box proteins are crucial regulators of plant growth, development, and responses to abiotic and biotic stresses. Previous research identified the F-box gene ZmFBL41 as a negative regulator of maize (Zea mays) defenses against Rhizoctonia solani. However, the precise mechanisms by which F-box proteins mediate resistance to R. solani remain poorly understood. In this study, we show that ZmFBL41 interacts with an abscisic acid (ABA) synthase, 9-cis-epoxycarotenoid dioxygenase 6 (ZmNCED6), promoting its degradation via the ubiquitination pathway. We discovered that the ectopic overexpression of ZmNCED6 in rice (Oryza sativa) inhibited R. solani infection by activating stomatal closure, callose deposition, and jasmonic acid (JA) biosynthesis, indicating that ZmNCED6 enhances plant immunity against R. solani. Natural variation at ZmFBL41 across different maize haplotypes did not affect the ZmFBL41-ZmNCED6 interaction. These findings suggest that ZmFBL41 targets ZmNCED6 for degradation, leading to a decrease in ABA levels in maize, in turn, inhibiting ABA-mediated disease resistance pathways, such as stomatal closure, callose deposition, and JA biosynthesis, ultimately facilitating R. solani infection.

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F-box only protein 8 (FBXO8) is a recently identified member of the F-box proteins, showcasing its novelty in this protein family. Extensive research has established FBXO8's role as a tumor suppressor in various cancers, including hepatocellular carcinoma, and colorectal cancer, Nevertheless, its functional, mechanistic, and prognostic roles in primary and metastatic breast cancer, particularly in different molecular subtypes of breast cancer, various stages, as well as its potential implications in immunotherapy, tumor microenvironment, and prognostic survival among breast cancer patients, remain unexplored. In this article, we employed a multi-dimensional investigation leveraging TCGA, TIMER, TISIDB, STRING, MEXPRESS, UALCAN, and cBioPortal databases to explore the underlying suppression mechanism of FBXO8 in breast cancer. FBXO8 negatively correlates with MYC, NOTCH, WNT and inflammatory signaling pathways in breast tumor microenvironment. Furthermore we conducted RT-PCR, western blot, cell proliferation, cell migration, and mRNA target gene RT-PCR analyses to elucidate the role of FBXO8 in breast cancer progression. Mechanistically, PTEN and FBXW7 expression were down-regulated and MYC, IL10, IL6, NOTCH1, WNT6 mRNA expressions were up-regulated in FBXO8 knockdown cell lines. c-MYC silenced cells showed an increase in FBXO8 protein level, which suggests a negative feedback loop between FBXO8 and c-MYC to control breast cancer metastasis. These findings illuminate the novel role of FBXO8 as a prognostic and therapeutic target across different molecular subtypes of breast cancer. Finally, through the utilization of virtual screening and Molecular Dynamics simulations, we successfully identified two FDA-approved medications, Ledipasvir and Paritaprevir, that demonstrated robust binding capabilities and interactions with FBXO8.

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Functions of the SKP1-CUL1-F box (SCF) ubiquitin E3 ligases are essential in plants. The F box proteins (FBPs) are substrate receptors that recruit substrates and assemble an active SCF complex, but the regulatory mechanism underlying the FBPs binding to CUL1 to activate the SCF cycle is not fully understood. We show that Arabidopsis csn1-10 is defective in SCFEBF1-mediated PIF3 degradation during de-etiolation, due to impaired association of EBF1 with CUL1 in csn1-10. EBF1 preferentially associates with un-neddylated CUL1 that is deficient in csn1-10 and the EBF1-CUL1 binding is rescued by the neddylation inhibitor MLN4924. Furthermore, we identify a subset of FBPs with impaired binding to CUL1 in csn1-10, indicating their assembly to form SCF complexes may depend on COP9 signalosome (CSN)-mediated deneddylation of CUL1. This study reports that a key role of CSN-mediated CULLIN deneddylation is to gate the binding of the FBP-substrate module to CUL1, thus initiating the SCF cycle of substrate ubiquitination.

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