WD40 superfamily genes are integral to various aspects of plant growth and development. Despite the economic importance and agricultural significance of the kiwifruit (Actinidia chinensis), a comprehensive characterization of the WD40 superfamily in this species remains elusive. In this study, we identified 280 WD40-encoding genes within the kiwifruit genome and systematically analyzed their phylogenetic relationships, gene structures, functional domains, and synteny. Our results reveal that AcWD40 genes exhibit diverse expression profiles with distinct spatio-temporal patterns. AcWD40.063, encoding TTG1 homolog (designated AcTTG1), was upregulated during light-induced anthocyanin accumulation. Heterologous expression, yeast two-hybrid (Y2H) interaction assays, and dual-luciferase reporter experiments revealed that AcTTG1 interacts with AcMYB75 and AcbHLH2, collectively promoting anthocyanin accumulation and enhancing the expression of anthocyanin biosynthesis genes, particularly AcANS. This study provides a robust framework for understanding the roles of AcWD40 gene family members and offers valuable insights for molecular breeding strategies aimed at improving kiwifruit quality.

Spermatogenesis involves complex dynamic mechanisms. Dynein-1 is a key carrier in cellular cargo transport, participating in nuclear deformation and acrosome formation during spermatogenesis. However, the regulatory mechanisms of Dynein-1 during cargo transport remain unknown. In this study, we explored the role of Lissencephaly 1 (LIS1) in spermatogenesis and its impact on Dynein-1 cargo transport in Portunus trituberculatus. LIS1 was known as a Dynein-1 regulator, which is a causative gene of anencephaly syndrome. Pt-Lis1 was cloned from the crab testis, and its highly expression was observed in the testis. Pt-LIS1 dynamically localized around the nucleus and acrosome during spermatogenesis, colocalizing with Dynein-1 subunits, microtubules, mitochondrial markers (PHB), and Acrosin. RNA interference reduced Pt-Lis1 expression, leading to decreased expression of Pt-dhc and Pt-dic. During spermatogenesis, the signals of Pt-LIS1, Pt-DHC, Pt-DIC, and α-Tubulin were weakened and showed disorganized distribution. The colocalization of Pt-LIS1 with Pt-DHC and Pt-DIC decreased, while abnormal colocalization significantly increased. In addition, caspase-3 and p53 expression significantly increased after Pt-Lis1 silencing, indicating association with apoptosis in spermatogenic cells. All these results suggest that LIS1 played a crucial role in crustacean spermatogenesis by regulating nuclear deformation and acrosome formation through modulating Dynein-1 transport cargoes along microtubules.

The WD40 repeat proteins are crucial components of eukaryotic genomes and contribute to a wide array of plant developmental processes and environmental interactions. However, the true extent of intraspecific WD40 diversity in plants is unclear.

We defined a nearly complete species-wide pan-WD40ome in maize based on the published genome sequences of 26 nested association mapping (NAM) population founders. The pan-WD40ome largely saturated with inclusion of approximately 20 inbred lines, with about 95% of the pan-WD40ome being present in at least two founders. The architectural diversity of the WD40 domains, additional domains, and consequent spatial protein structures suggested the functional diversity of the maize pan-WD40ome. This finding was supported by significant associations between 87 WD40 genes and 19 agronomic, 3 kernel-quality, and 3 biotic-stress traits, as well as the multiple molecular pathways through which the trait-associated WD40 genes were predicted to function. In addition, WD40 genes exhibited abundant genomic variations among the NAM founders. Sequence analysis indicated that gene duplications and gene translocations caused by Helitron transposons may play important roles in the amplification of WD40 genes during the evolution of the maize WD40 gene family.

In summary, this study provides a comprehensive framework for understanding the structural and functional diversity of the pan-WD40ome in maize and other agronomically important species with complex genomes, as well as excellent candidate genes/alleles for maize genetic improvement.

Sweet wormwood (Artemisia annua), an annual herb belonging to the Compositae family, is the main source of the potent anti-malarial drug artemisinin, which is mainly produced in glandular trichomes of A. annua leaves. The WD40 protein family is one of the largest protein families in eukaryotes and plays crucial roles in regulating plant growth and development, stress responses, and secondary metabolite biosynthesis. However, WD40 proteins have not been comprehensively identified in A. annua. In this study, we identified 236 WD40 proteins in the A. annua genome and examined their conserved domains, motifs, and cis-regulatory elements, gene structures, chromosomal distribution, duplication events of their encoding genes. Furthermore, we isolated and characterized TRANSPARENT TESTA GLABROUS 1 (AaTTG1), a homolog of Arabidopsis TTG1, and confirmed that AaTTG1 was localized to the nucleus and cytoplasm. Indeed, AaTTG1 can rescue the glabrous phenotype of the Arabidopsis ttg1 mutant and enhanced trichome production when heterologously expressed in wild-type Arabidopsis plants. Transgenic A. annua lines overexpressing AaTTG1 displayed a significantly higher density of glandular trichomes and higher artemisinin contents. Transgenic A. annua lines with inhibited AaTTG1 function had fewer glandular trichomes and lower artemisinin levels. Moreover, we demonstrated that AaTTG1 positively regulates glandular trichome development in A. annua through interactions with AaSPL9. This study thus provides fundamental insights into the role of WD40 proteins in A. annua and introduces a promising approach to enhance artemisinin production by manipulating glandular trichome development in this valuable medicinal plant.

Limited data, primarily from small case series, exist regarding the clinical profile, genetic variants, and outcomes of WDR72-associated distal renal tubular acidosis (WDR72-dRTA).

Our study enrolled children diagnosed with WDR72-dRTA below 18 years of age from 9 Indian centers and analyzed their clinical characteristics, genetic profiles, and outcomes. Potential genotype-phenotype correlations were explored.

We report 22 patients (59% female) with WDR72-dRTA who were diagnosed at a median age of 5.3 (3, 8) years with polyuria (n = 17; 77.3%), poor growth (16; 72.7%), and rickets (9; 40.9%). Amelogenesis imperfecta was present in 21 (95.5%) cases. At presentation, all patients had normal anion gap metabolic acidosis; hypokalemia and nephrocalcinosis were seen in 17 (77.3%) patients each. Seven (31.8%) patients had concomitant proximal tubular dysfunction. Genetic analysis identified biallelic nonsense variants in 18 (81.8%) patients, including novel variants in 6 cases. A previously reported variant, c.88C > T, and a novel variant, c.655C > T, were the most frequent variants, accounting for 10 (45.5%) cases. Over a median follow-up of 1.3 (1, 8) years, the height velocity improved by 0.74 (0.2, 1.2) standard deviation scores, while 3 children (13.6%) progressed to chronic kidney disease (CKD) stage 2, with eGFR ranging from 67 to 76 mL/min/1.73 m2, respectively, after 11.3-16 years of follow-up. No specific genotype-phenotype correlation could be established.

WDR72-dRTA should be considered in children with typical features of amelogenesis imperfecta and dRTA. Biallelic nonsense variants are common in Asians. While most patients respond well to treatment with improved growth and preserved eGFR, on long-term follow-up, a decline in eGFR may occur.

Flavonoids are a large group of secondary metabolites, which are responsible for pigmentation, signaling, protection from unfavorable environmental conditions, and other important functions, as well as providing numerous benefits for human health. Various stages of flavonoid biosynthesis are subject to complex regulation by three groups of transcription regulators-MYC-like bHLH, R2R3-MYB and WDR which form the MBW regulatory complex. We attempt to cover the main aspects of this intriguing regulatory system in plants, as well as to summarize information on their distinctive features in cereals. Published data revealed the following perspectives for further research: (1) In cereals, a large number of paralogs of MYC and MYB transcription factors are present, and their diversification has led to spatial and biochemical specialization, providing an opportunity to fine-tune the distribution and composition of flavonoid compounds; (2) Regulatory systems formed by MBW proteins in cereals possess distinctive features that are not yet fully understood and require further investigation; (3) Non-classical MB-EMSY-like complexes, WDR-independent MB complexes, and solely acting R2R3-MYB transcription factors are of particular interest for studying unique regulatory mechanisms in plants. More comprehensive understanding of flavonoid biosynthesis regulation will allow us to develop cereal varieties with the required flavonoid content and spatial distribution.

Gastric cancer remains a leading cause of cancer-related mortality worldwide. The prognosis often depends on early detection and understanding the molecular mechanisms involved in its progression. Periodic tryptophan protein 1 (PWP1) has emerged as a novel diagnostic marker, potentially linked to gastric cancer progression. This study aims to elucidate the impact of PWP1 on gastric cancer development, focusing on apoptosis, cell cycle regulation, and the role of p53. This study utilized gastric cancer cell lines to investigate the expression and functional role of Pwp1. Quantitative PCR and Western blot analyses were conducted to measure PWP1 expression levels. Apoptosis was assessed by using flow cytometry and TUNEL assays, and cell cycle analysis was performed to evaluate the impact of PWP1 modulation. Additionally, animal experiments were conducted using mouse models injected with gastric cancer cells, with PWP1 knockdown or overexpression, to observe tumor growth and progression. Statistical significance was evaluated using t-tests and ANOVA where appropriate. Elevated PWP1 expression was observed in gastric cancer tissues compared to normal tissues. PWP1's knockdown resulted in increased apoptosis and cell cycle arrest at the G1 phase, suggesting its role in promoting invasion and proliferation. Furthermore, animal experiments demonstrated reduced tumor growth in mice with PWP1 knockdown. PWP1 was found to transcriptionally regulate p53, affecting its expression and thereby influencing apoptosis and cell cycle pathways in gastric cancer. Our study identifies PWP1 as a novel oncogene frequently overexpressed in gastric cancer (GC). Through transcriptional regulation of p53, PWP1 enhances cell growth by influencing apoptosis and inducing G1 phase cell cycle arrest. These findings underscore PWP1 as a promising therapeutic target for treating GC, suggesting its potential for future clinical applications.

SUMMARYThe striatin-interacting phosphatase and kinase (STRIPAK) complex is involved in the regulation of many developmental processes in eukaryotic microorganisms and all animals, including humans. STRIPAK is a component of protein phosphatase 2A (PP2A), a highly conserved serine-threonine phosphatase composed of catalytic subunits (PP2Ac), a scaffolding subunit (PP2AA) and various substrate-directing B regulatory subunits. In particular, the B''' regulatory subunit called striatin has evoked major interest over the last 20 years. Studies in fungal systems have contributed substantially to our current knowledge about STRIPAK composition, assembly, and cellular localization, as well as its regulatory role in autophagy and the morphology of fungal development. STRIPAK represents a signaling hub with many kinases and thus integrates upstream and downstream information from many conserved eukaryotic signaling pathways. A profound understanding of STRIPAK's regulatory role in fungi opens the gateway to understanding the multifarious functions carried out by STRIPAK in higher eukaryotes, including its contribution to malignant cell growth.

WD repeat- and FYVE domain-containing protein 4 (WDFY4), coded by a gene on 10q11.23, is a member of the BEACH (Beige and Chediak-Higashi) domain-containing family. Genome-wide association studies identified WDFY4 variants as a risk factor for SLE in Asian and European populations. WDFY4 variants are also associated with RA and primary biliary cholangitis, in different ancestry populations. The WDFY4 protein plays an essential role in the cross-presentation of classic dendritic cells, reactive oxygen species-induced apoptosis of CD8+ T cells, and non-canonical autophagic activity in B cells. A novel variant rs7919656 was identified in Japanese clinically amyopathic dermatomyositis patients, with a highly expressed truncated isoform augmenting the melanoma differentiation-associated gene 5 (MDA5) signalling pathway. The same variant was later found to be significantly associated with RP-ILD in Chinese MDA5+DM patients. Here, we briefly review the association of WDFY4 with autoimmune diseases and its known function in the immune response.

WD repeat domain 12 (WDR12) plays a crucial role in the ribosome biogenesis pathway. However, its biological function in colorectal cancer (CRC) remains poorly understood. Therefore, this study aims to investigate the roles of WDR12 in the occurrence and progression of CRC, as well as its underlying mechanisms.

The expression of WDR12 was assessed through The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA) database. Functional experiments including Celigo assay, MTT assay, and Caspase-3/7 assay were conducted to validate the role of WDR12 in the malignant progression of CRC. Additionally, mRNA chip-sequencing and ingenuity pathway analysis (IPA) were performed to identify the molecular mechanism.

WDR12 expression was significantly upregulated in CRC tissues compared to normal colorectal tissues. Knockdown of WDR12 reduced proliferation and promoted apoptosis of CRC cell lines in vitro and in vivo experiments. Furthermore, WDR12 expression had a significantly inverse association with diseases and functions, including cancer, cell cycle, DNA replication, recombination, cellular growth, proliferation and repair, as revealed by IPA analysis of mRNA chip-sequencing data. Moreover, the activation of cell cycle checkpoint kinases proteins in the cell cycle checkpoint control signaling pathway was enriched in the WDR12 knockdown CRC cell lines. Additionally, downregulation of rac family small GTPase 1 (RAC1) occurred upon WDR12 knockdown, thereby facilitating the proliferation and anti-apoptosis of CRC cells.

Our study demonstrates that the WDR12/RAC1 axis promotes tumor progression in CRC. Therefore, WDR12 may serve as a novel oncogene and a potential target for individualized therapy in CRC. These findings provide an experimental foundation for the clinical development of drugs targeting the WDR12/RAC1 axis.

The WD40 domain, one of the most abundant in eukaryotic genomes, is widely involved in plant growth and development, secondary metabolic biosynthesis, and mediating responses to biotic and abiotic stresses. WD40 repeat (WD40) protein has been systematically studied in several model plants but has not been reported in the Capsicum annuum (pepper) genome.

Herein, 269, 237, and 257 CaWD40 genes were identified in the Zunla, CM334, and Zhangshugang genomes, respectively. CaWD40 sequences from the Zunla genome were selected for subsequent analysis, including chromosomal localization, phylogenetic relationships, sequence characteristics, motif compositions, and expression profiling. CaWD40 proteins were unevenly distributed on 12 chromosomes, encompassing 19 tandem duplicate gene pairs. The 269 CaWD40s were divided into six main branches (A to F) with 17 different types of domain distribution. The CaWD40 gene family exhibited diverse expression patterns, and several genes were specifically expressed in flowers and seeds. Yeast two-hybrid (Y2H) and dual-luciferase assay indicated that CaWD40-91 could interact with CaAN1 and CaDYT1, suggesting its involvement in anthocyanin biosynthesis and male sterility in pepper.

In summary, we systematically characterized the phylogeny, classification, structure, and expression of the CaWD40 gene family in pepper. Our findings provide a valuable foundation for further functional investigations on WD40 genes in pepper.

The past two decades has witnessed a remarkable increase in the number of microbial genomes retrieved from marine systems1,2. However, it has remained challenging to translate this marine genomic diversity into biotechnological and biomedical applications3,4. Here we recovered 43,191 bacterial and archaeal genomes from publicly available marine metagenomes, encompassing a wide range of diversity with 138 distinct phyla, redefining the upper limit of marine bacterial genome size and revealing complex trade-offs between the occurrence of CRISPR-Cas systems and antibiotic resistance genes. In silico bioprospecting of these marine genomes led to the discovery of a novel CRISPR-Cas9 system, ten antimicrobial peptides, and three enzymes that degrade polyethylene terephthalate. In vitro experiments confirmed their effectiveness and efficacy. This work provides evidence that global-scale sequencing initiatives advance our understanding of how microbial diversity has evolved in the oceans and is maintained, and demonstrates how such initiatives can be sustainably exploited to advance biotechnology and biomedicine.

Serine/threonine kinase receptor-associated protein (STRAP) serves as a scaffold protein and is engaged in a variety of cellular activities, although its importance in antiviral innate immunity is unknown. We discovered that STRAP works as an interferon (IFN)-inducible positive regulator, facilitating type I IFN signaling during pseudorabies virus infection. Mechanistically, STRAP interacts with TBK1 to activate type I IFN signaling. Both the CT and WD40 7 - 6 domains contribute to the function of STRAP. Furthermore, TBK1 competes with PRV-UL50 for binding to STRAP, and STRAP impedes the degradation of TBK1 mediated by PRV-UL50, thereby increasing the interaction between STRAP and TBK1. Overall, these findings reveal a previously unrecognized role for STRAP in innate antiviral immune responses during PRV infection. STRAP could be a potential therapeutic target for viral infectious diseases.

WD repeat domain 43 (WDR43) is a protein component that encodes WD-repeats and is involved in ribosome biogenesis. However, little is known about the role of WDR43 in cancer prognosis and immune modulation.

In this study, we analyzed the expression and prognostic significance of WDR43 in pan-cancer using the Cancer Genome Atlas, the Genotype-Tissue Expression, and the Human Protein Atlas. We also examined the differential expression of WDR43 in liver hepatocellular carcinoma (LIHC) and adjacent tissues of 48 patients using immunohistochemistry. Additionally, we investigated the correlation between WDR43 and clinical characteristics, gene alterations, tumor mutation burden, microsatellite instability, mismatch repair, tumor microenvironment, immune infiltrating cells, and immune-related genes using bioinformatics methods. Gene set enrichment analysis was conducted, and potential biological mechanisms were identified.

Immunohistochemistry staining showed that WDR43 was overexpressed in LIHC among 48 patients. Upregulation of WDR43 was associated with unfavorable prognosis, including overall survival in various types of cancer such as LIHC, uterine corpus endometrial cancer, head and neck squamous cell carcinoma, and pancreatic adenocarcinoma. Differential expression of WDR43 was significantly correlated with microsatellite instability, mismatch repair, and immune cell infiltration. Gene ontology annotation analysis revealed that these genes were significantly enriched in immune-related functions, including immune response, immune regulation, and signaling pathways.

We conducted a thorough investigation of the clinical features, phases of tumor development, immune infiltration, gene mutation, and functional enrichment analysis of WDR43 in various types of cancer. This research offers valuable insight into the significance and function of WDR43 in clinical therapy.

Proteolysis Targeting Chimeras (PROTACs) are an emerging therapeutic modality and chemical biology tools for Targeted Protein Degradation (TPD). PROTACs contain a ligand targeting the protein of interest, a ligand recruiting an E3 ligase and a linker connecting these two ligands. There are over 600 E3 ligases known so far, but only a handful have been exploited for TPD applications. A key reason for this is the scarcity of ligands binding various E3 ligases and the paucity of structural data available, which complicates ligand design across the family. In this study, we aim to progress PROTAC discovery by proposing a shortlist of E3 ligases that can be prioritized for covalent targeting by performing systematic structural ligandability analysis on a chemoproteomic dataset of potentially reactive cysteines across hundreds of E3 ligases. One of the goals of this study is to apply AlphaFold (AF) models for ligandability evaluations, as for a vast majority of these ligases an experimental structure is not available in the protein data bank (PDB). Using a combination of pocket features, AF model quality and additional aspects, we propose a shortlist of E3 ligases and corresponding cysteines that can be prioritized to potentially discover covalent ligands and expand the PROTAC toolbox.

Living organisms are frequently exposed to multiple biotic and abiotic stress forms during their lifetime. Organisms cope with stress conditions by regulating their gene expression programs. In response to different environmental stress conditions, yeast cells activate different tolerance mechanisms, many of which share common signaling pathways. Flocculation is one of the key mechanisms underlying yeast survival under unfavorable environmental conditions, and the Tup1-Cyc8 corepressor complex is a major regulator of this process. Additionally, yeast cells can utilize different mitogen-activated protein kinase (MAPK) pathways to modulate gene expression during stress conditions. Here, we show that the high osmolarity glycerol (HOG) MAPK pathway is involved in the regulation of yeast flocculation. We observed that the HOG MAPK pathway was constitutively activated in flocculating cells, and found that the interaction between phosphorylated Hog1 and the FLO genes promoter region increased significantly upon sodium chloride exposure. We found that treatment of cells with cantharidin decreased Hog1 phosphorylation, causing a sharp reduction in the expression of FLO genes and the flocculation phenotype. Similarly, deletion of HOG1 in yeast cells reduced flocculation. Altogether, our results suggest a role for HOG MAPK signaling in the regulation of FLO genes and yeast flocculation.

Identification of novel biomarkers for prediction of disease course and prognosis is needed to reduce morbidity of liver hepatocellular carcinoma (LIHC/HCC) patients. Although dysregulated Periodic tryptophan protein 1 homolog (PWP1/endonuclein) expression has been detected in several tumors, the potential regulatory effect of PWP1 on LIHC remains uncertain. Here we evaluated the expression of PWP1 using multiple online platforms, and demonstrated that PWP1 upregulation was consistently observed in LIHC relative to non-tumor liver tissues and correlated with unfavorable prognosis. Moreover, HCC prognosis was significantly influenced by the methylation status of various CpG sites in the PWP1 gene. Lastly, we provide direct evidence that PWP1 acts as a driver of HCC progression by showing that siRNA-mediated PWP1 silencing significantly suppressed HCC cell proliferation in vitro. These data strongly suggest that PWP1 silencing may be an effective therapeutic strategy to treat LIHC.

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.

Targeted protein degradation (TPD) has recently emerged as an exciting new drug modality. However, the strategy of developing small molecule-based protein degraders has evolved over the past two decades and has now established molecular tags that are already in clinical use, as well as chimeric molecules, PROteolysis TArgeting Chimeras (PROTACs), based mainly on ligand systems developed for the two E3 ligases CRBN and VHL. The large size of the human E3 ligase family suggests that PROTACs can be developed by targeting a large diversity of E3 ligases, some of which have restricted expression patterns with the potential to design disease- or tissue-specific degraders. Indeed, many new E3 ligands have been published recently, confirming the druggability of E3 ligases. This review summarises recent data on E3 ligases and highlights the challenges in developing these molecules into efficient PROTACs rivalling the established degrader systems.

Proteins of the armadillo repeat gene family play important roles in plant pathogen response. Here, 169 armadillo (ARM) genes were identified in upland cotton (Gossypium hirsutum). Phylogenetic analysis grouped these into 11 subfamilies, with conserved protein structures within each subfamily. The results signify that the expansion of the gene family occurred via whole genome duplication and dispersed duplication. Expression profiling and network analysis suggest that GhARM144 may regulate cotton resistance to Verticillium dahliae. GhARM144 was upregulated in roots by V. dahliae infection or salicylic acid treatment. This upregulation indicates a negative regulatory role of GhARM144' in the cotton immune responses, potentially by manipulating salicylic acid biosynthesis. Protein interaction studies found that GhARM144 associates with an osmotin-like protein, GhOSM34, at the plasma membrane. Silencing GhOSM34 reduced the resistance to V. dahliae, suggesting it may play a positive regulatory role. The results demonstrate that GhARM144 modulates cotton immunity through interaction with GhOSM34 and salicylic acid signalling. Further study of these proteins may yield insights into disease resistance mechanisms in cotton and other plants.

G protein coupled receptors (GPCRs) are seven-transmembrane domain proteins that modulate cellular processes in response to external stimuli. These receptors represent the largest family of membrane proteins, and in mammals, their signaling regulates important physiological functions, such as vision, taste, and olfaction. Many organisms, including yeast, slime molds, and viruses encode GPCRs. Cytomegaloviruses (CMVs) are large, betaherpesviruses, that encode viral GPCRs (vGPCRs). Human CMV (HCMV) encodes four vGPCRs, including UL33, UL78, US27, and US28. Each of these vGPCRs, as well as their rodent and primate orthologues, have been investigated for their contributions to viral infection and disease. Herein, we discuss how the CMV vGPCRs function during lytic and latent infection, as well as our understanding of how they impact viral pathogenesis.

Dynein, an ancient microtubule-based motor protein, performs diverse cellular functions in nearly all eukaryotic cells, with the exception of land plants. It has evolved into three subfamilies-cytoplasmic dynein-1, cytoplasmic dynein-2, and axonemal dyneins-each differentiated by their cellular functions. These megadalton complexes consist of multiple subunits, with the heavy chain being the largest subunit that generates motion and force along microtubules by converting the chemical energy of ATP hydrolysis into mechanical work. Beyond this catalytic core, the functionality of dynein is significantly enhanced by numerous non-catalytic subunits. These subunits are integral to the complex, contributing to its stability, regulating its enzymatic activities, targeting it to specific cellular locations, and mediating its interactions with other cofactors. The diversity of non-catalytic subunits expands dynein's cellular roles, enabling it to perform critical tasks despite the conservation of its heavy chains. In this review, we discuss recent findings and insights regarding these non-catalytic subunits.

Procaspase 9 is the initiator caspase for apoptosis, but how its levels and activities are maintained remains unclear. The gigantic Inhibitor-of-Apoptosis Protein BIRC6/BRUCE/Apollon inhibits both apoptosis and autophagy by promoting ubiquitylation of proapoptotic factors and the key autophagic protein LC3, respectively. Here we show that BIRC6 forms an anti-parallel U-shaped dimer with multiple previously unannotated domains, including a ubiquitin-like domain, and the proapoptotic factor Smac/DIABLO binds BIRC6 in the central cavity. Notably, Smac outcompetes the effector caspase 3 and the pro-apoptotic protease HtrA2, but not procaspase 9, for binding BIRC6 in cells. BIRC6 also binds LC3 through its LC3-interacting region, probably following dimer disruption of this BIRC6 region. Mutation at LC3 ubiquitylation site promotes autophagy and autophagic degradation of BIRC6. Moreover, induction of autophagy promotes autophagic degradation of BIRC6 and caspase 9, but not of other effector caspases. These results are important to understand how the balance between apoptosis and autophagy is regulated under pathophysiological conditions.

Transducin beta-like 1X-related protein 1 (TBL1XR1) was discovered two decades ago and was implicated as part of the nuclear transcription corepressor complex. Over the past 20 years, the emerging oncogenic function of TBL1XR1 in cancer development has been discovered. Recent studies have highlighted that the genetic aberrations of TBL1XR1 in cancers, especially in hematologic tumors, are closely associated with tumorigenesis. In solid tumors, TBL1XR1 is proposed to be a promising prognostic biomarker due to the correlation between abnormal expression and clinicopathological parameters. Post-transcriptional and post-translational modification are responsible for the expression and function of TBL1XR1 in cancer. TBL1XR1 exerts its functional role in various processes that involves cell cycle and apoptosis, cell proliferation, resistance to chemotherapy and radiotherapy, cell migration and invasion, stemness and angiogenesis. Multitude of cancer-related signaling cascades like Wnt-β-catenin, PI3K/AKT, ERK, VEGF, NF-κB, STAT3 and gonadal hormone signaling pathways are tightly modulated by TBL1XR1. This review provided a comprehensive overview of TBL1XR1 in tumorigenesis, shedding new light on TBL1XR1 as a promising diagnostic biomarker and druggable target in cancer.

Alzheimer's disease (AD) is a neurodegenerative disorder caused by a complex interplay of various factors. However, a satisfactory cure for AD remains elusive. Pharmacological interventions based on drug targets are considered the most cost-effective therapeutic strategy. Therefore, it is paramount to search potential drug targets and drugs for AD.

We aimed to provide novel targets and drugs for the treatment of AD employing transcriptomic data of AD and normal control brain tissues from a new perspective.

Our study combined the use of a multi-layer perceptron (MLP) with differential expression analysis, variance assessment and molecular docking to screen targets and drugs for AD.

We identified the seven differentially expressed genes (DEGs) with the most significant variation (ANKRD39, CPLX1, FABP3, GABBR2, GNG3, PPM1E, and WDR49) in transcriptomic data from AD brain. A newly built MLP was used to confirm the association between the seven DEGs and AD, establishing these DEGs as potential drug targets. Drug databases and molecular docking results indicated that arbaclofen, baclofen, clozapine, arbaclofen placarbil, BML-259, BRD-K72883421, and YC-1 had high affinity for GABBR2, and FABP3 bound with oleic, palmitic, and stearic acids. Arbaclofen and YC-1 activated GABAB receptor through PI3K/AKT and PKA/CREB pathways, respectively, thereby promoting neuronal anti-apoptotic effect and inhibiting p-tau and Aβ formation.

This study provided a new strategy for the identification of targets and drugs for the treatment of AD using deep learning. Seven therapeutic targets and ten drugs were selected by using this method, providing new insight for AD treatment.

The fungal Gβ-like protein has been reported to be involved in a variety of biological processes, such as mycelial growth, differentiation, conidiation, stress responses and infection. However, molecular mechanisms of the Gβ-like protein in regulating fungal development and pathogenicity are largely unknown. Here, we show that the Gβ-like protein gene Bcgbl1 in the gray mold fungus Botrytis cinerea plays a pivotal role in development and pathogenicity by regulating the mitogen-activated protein (MAP) kinases signaling pathways. The Bcgbl1 deletion mutants were defective in mycelial growth, sclerotial formation, conidiation, macroconidial morphogenesis, plant adhesion, and formation of infection cushions and appressorium-like structures, resulting in a complete loss of pathogenicity. Bcgbl1 interacted with BcSte50, the adapter protein of the cascade of MAP kinase (MAPK). Bcgbl1 mutants had reduced phosphorylation levels of two MAPKs, namely Bmp1 and Bmp3, thereby reducing infection. However, deletion of Bcgbl1 did not affect the intracellular cAMP level, and exogenous cAMP could not restore the defects. Moreover, Bcgbl1 mutants exhibited defects in cell wall integrity and oxidative stress tolerance. Transcriptional profiling revealed that Bcgbl1 plays a global role in regulation of gene expression upon hydrophobic surface induction. We further uncovered that three target genes encoding the hydrophobic surface binding proteins (HsbAs) contributed to the adhesion and virulence of B. cinerea. Overall, these findings suggest that Bcgbl1 had multiple functions and provided new insights for deciphering the Bcgbl1-mediated network for regulating development and pathogenicity of B. cinerea.

The concept of adenoma-to-cancer transformation in human colorectal cancer (CRC) is widely accepted. However, the relationship between transcriptome features and adenoma to carcinoma transformation in canines is not clear. We collected transcriptome data from 8 normal colon tissues, 4 adenoma tissues, and 15 cancer tissues. Differential analysis was unable to determine the dynamic changes of genes but revealed that PFKFB3 may play a key role in this process. Enrichment analysis explained metabolic dysregulation, immunosuppression, and typical cancer pathways in canine colorectal tumors. MFuzz generated specific dynamic expression patterns of five differentially expressed genes (DEGs). Weighted correlation network analysis showed that DEGs in cluster 3 were associated with malignant tissues, revealing the key role of inflammatory and immune pathways in canine CRC, and the S100A protein family was also found to be involved in the malignant transformation of canine colorectal tumors. By comparing strategies between humans and dogs, we found five novel markers that may be drivers of CRC. Among them, GTBP4 showed excellent diagnostic and prognostic ability. This study was the first systematic exploration of transformation in canine CRC, complemented the molecular characteristics of the development and progression of canine CRC, and provided new potential biomarkers and comparative oncologic evidence for biomarker studies in human colorectal cancer.

Endozoicomonas are often predominant bacteria and prominently important in coral health. Their role in dimethylsulfoniopropionate (DMSP) degradation has been a subject of discussion for over a decade. A previous study found that Endozoicomonas degraded DMSP through the dddD pathway. This process releases dimethyl sulfide, which is vital for corals coping with thermal stress. However, little is known about the related gene regulation and metabolic abilities of DMSP metabolism in Endozoicomonadaceae. In this study, we isolated a novel Endozoicomonas DMSP degrader and observed a distinct DMSP metabolic trend in two phylogenetically close dddD-harboring Endozoicomonas species, confirmed genetically by comparative transcriptomic profiling and visualization of the change of DMSP stable isotopes in bacterial cells using nanoscale secondary ion spectrometry. Furthermore, we found that DMSP cleavage enzymes are ubiquitous in coral Endozoicomonas with a preference for having DddD lyase. We speculate that harboring DMSP degrading genes enables Endozoicomonas to successfully colonize various coral species across the globe.

Foamy viruses (FVs) are unique nonpathogenic retroviruses, which remain latent in the host for a long time. Therefore, they may be safe, effective gene transfer vectors. In this study, were assessed FV-host cell interactions and the molecular mechanisms underlying FV latent infection.

We used the prototype FV (PFV) to infect HT1080 cells and a PFV indicator cell line (PFVL) to measure virus titers. After 48 h of infection, the culture supernatant (i.e., cell-free PFV particles) and transfected cells (i.e., cell-associated PFV particles) were harvested and incubated with PFVL. After another 48 h, the luciferase activity was used to measure virus titers.

Through transcriptomics sequencing, we found that PREB mRNA expression was significantly upregulated. Moreover, PREB overexpression reduced PFV replication, whereas endogenous PREB knockdown increased PFV replication. PREB interacted with the Tas DNA-binding and transcriptional activation domains and interfered with its binding to the PFV long terminal repeat and internal promoter, preventing the recruitment of transcription factors and thereby inhibiting the transactivation function of Tas. PREB C-terminal 329-418 aa played a major role in inhibiting PFV replication; PREB also inhibited bovine FV replication. Therefore, PREB has a broad-spectrum inhibitory effect on FV replication.

Our results demonstrated that PREB inhibits PFV replication by impeding its transcription.

WD40 transcription factors (TFs) constitute a large gene family in eukaryotes, playing diverse roles in cellular processes. However, their functions in the major ornamental plant, Rhododendron simsii, remain poorly understood. In this study, we identified 258 WD40 proteins in the R. simsii genome, which exhibited an uneven distribution across chromosomes. Based on domain compositions and phylogenetic analysis, we classified these 258 RsWD40 proteins into 42 subfamilies and 47 clusters. Comparative genomic analysis suggested that the expansion of the WD40 gene family predates the divergence of green algae and higher plants, indicating an ancient origin. Furthermore, by analyzing the duplication patterns of RsWD40 genes, we found that transposed duplication played a major role in their expansion. Notably, the majority of RsWD40 gene duplication pairs underwent purifying selection during evolution. Synteny analysis identified significant orthologous gene pairs between R. simsii and Arabidopsis thaliana, Oryza sativa, Vitis vinifera, and Malus domestica. We also investigated potential candidate genes involved in anthocyanin biosynthesis during different flower development stages in R. simsii using RNA-seq data. Specifically, we identified 10 candidate genes during the bud stage and 7 candidate genes during the full bloom stage. GO enrichment analysis of these candidate genes revealed the potential involvement of the ubiquitination process in anthocyanin biosynthesis. Overall, our findings provide a valuable foundation for further investigation and functional analysis of WD40 genes, as well as research on the molecular mechanisms underlying anthocyanin biosynthesis in Rhododendron species.

Plant synthetic biology has emerged as a powerful and promising approach to enhance the production of value-added metabolites in plants. Flavonoids, a class of plant secondary metabolites, offer numerous health benefits and have attracted attention for their potential use in plant-based products. However, achieving high yields of specific flavonoids remains challenging due to the complex and diverse metabolic pathways involved in their biosynthesis. In recent years, synthetic biology approaches leveraging transcription factors and enzyme diversity have demonstrated promise in enhancing flavonoid yields and expanding their production repertoire. This review delves into the latest research progress in flavonoid metabolic engineering, encompassing the identification and manipulation of transcription factors and enzymes involved in flavonoid biosynthesis, as well as the deployment of synthetic biology tools for designing metabolic pathways. This review underscores the importance of employing carefully-selected transcription factors to boost plant flavonoid production and harnessing enzyme promiscuity to broaden flavonoid diversity or streamline the biosynthetic steps required for effective metabolic engineering. By harnessing the power of synthetic biology and a deeper understanding of flavonoid biosynthesis, future researchers can potentially transform the landscape of plant-based product development across the food and beverage, pharmaceutical, and cosmetic industries, ultimately benefiting consumers worldwide.

Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by congenital immunodeficiency, bleeding diathesis, pyogenic infection, partial oculocutaneous albinism, and progressive neurodegeneration. Treatment is hematopoietic stem cell transplantation or bone marrow transplantation; however, this does not treat the neurologic aspect of the disease. Mutations in the lysosomal trafficking regulator (LYST) gene were identified to be causative of Chediak-Higashi, but despite many analyses, there is little functional information about the LYST protein. This review serves to provide an update on the clinical manifestations and cellular defects of Chediak-Higashi syndrome.

More recent papers expand the neurological spectrum of disease in CHS, to include hereditary spastic paraplegia and parkinsonism. Granule size and distribution in NK cells have been investigated in relation to the location of mutations in LYST. Patients with mutations in the ARM/HEAT domain had markedly enlarged granules, but fewer in number. By contrast, patients with mutations in the BEACH domain had more numerous granules that were normal in size to slightly enlarged, but demonstrated markedly impaired polarization. The role of LYST in autophagosome formation has been highlighted in recent studies; LYST was defined to have a prominent role in autophagosome lysosome reformation for the maintenance of lysosomal homeostasis in neurons, while in retinal pigment epithelium cells, LYST deficiency was shown to lead to phagosome accumulation.

Despite CHS being a rare disease, investigation into LYST provides an understanding of basic vesicular fusion and fission. Understanding of these mechanisms may provide further insight into the function of LYST.

WD repeat domain 3 (WDR3) is involved in tumor growth and proliferation, but its role in the pathological mechanism of prostate cancer (PCa) is still unclear.

WDR3 gene expression levels were obtained by analyzing databases and our clinical specimens. The expression levels of genes and proteins were determined by a real-time polymerase chain reaction, western blotting and immunohistochemistry, respectively. Cell-counting kit-8 assays were used to measure the proliferation of PCa cells. Cell transfection was used to investigate the role of WDR3 and USF2 in PCa. Fluorescence reporter and chromatin immunoprecipitation assays were used to detect USF2 binding to the promoter region of RASSF1A. Mouse experiments were used to confirm the mechanism in vivo.

By analyzing the database and our clinical specimens, we found that WDR3 expression was significantly increased in PCa tissues. Overexpression of WDR3 enhanced PCa cell proliferation, decreased cell apoptosis rate, increased spherical cell number and increased indicators of stem cell-like properties. However, these effects were reversed by WDR3 knockdown. WDR3 was negatively correlated with USF2, which was degraded by promoting ubiquitination of USF2, and USF2 interacted with promoter region-binding elements of RASSF1A to depress PCa stemness and growth. In vivo studies showed that WDR3 knockdown reduced tumor size and weight, reduced cell proliferation and enhanced cell apoptosis.

WDR3 ubiquitinated USF2 and inhibited its stability, whereas USF2 interacted with promoter region-binding elements of RASSF1A. USF2 transcriptionally activated RASSF1A, which inhibited the carcinogenic effect of WDR3 overexpression.

WD40 proteins are a superfamily of regulatory proteins widely found in eukaryotes that play an important role in regulating plant growth and development. However, the systematic identification and characterization of WD40 proteins in tomato (Solanum lycopersicum L.) have not been reported. In the present study, we identified 207 WD40 genes in the tomatoes genome and analyzed their chromosomal location, gene structure and evolutionary relationships. A total of 207 tomato WD40 genes were classified by structural domain and phylogenetic tree analyses into five clusters and 12 subfamilies and were found to be unevenly distributed across the 12 tomato chromosomes. We identified six tandem duplication gene pairs and 24 segmental duplication pairs in the WD40 gene family, with segmental duplication being the major mode of expansion in tomatoes. Ka/Ks analysis revealed that paralogs and orthologs of WD40 family genes underwent mainly purifying selection during the evolutionary process. RNA-seq data from different tissues and developmental periods of tomato fruit development showed tissue-specific expression of WD40 genes. In addition, we constructed four coexpression networks according to the transcriptome and metabolome data for WD40 proteins involved in fruit development that may be related to total soluble solid formation. The results provide a comprehensive overview of the tomato WD40 gene family and will provide valuable information for the validation of the function of tomato WD40 genes in fruit development.

In moth-pollinated petunias, production of floral volatiles initiates when the flower opens and occurs rhythmically during the day, for optimal flower-pollinator interaction. To characterize the developmental transcriptomic response to time of day, we generated RNA-Seq databases for corollas of floral buds and mature flowers in the morning and in the evening. Around 70% of transcripts accumulating in petals demonstrated significant changes in expression levels in response to the flowers' transition from a 4.5-cm bud to a flower 1 day postanthesis (1DPA). Overall, 44% of the petal transcripts were differentially expressed in the morning vs. evening. Morning/evening changes were affected by flower developmental stage, with a 2.5-fold larger transcriptomic response to daytime in 1DPA flowers compared to buds. Analyzed genes known to encode enzymes in volatile organic compound biosynthesis were upregulated in 1DPA flowers vs. buds-in parallel with the activation of scent production. Based on analysis of global changes in the petal transcriptome, PhWD2 was identified as a putative scent-related factor. PhWD2 is a protein that is uniquely present in plants and has a three-domain structure: RING-kinase-WD40. Suppression of PhWD2 (termed UPPER - Unique Plant PhEnylpropanoid Regulator) resulted in a significant increase in the levels of volatiles emitted from and accumulated in internal pools, suggesting that it is a negative regulator of petunia floral scent production.