The FEBS journal最新文献

{"title":"Integrated proteomics and connectivity map-based analysis reveal compounds with a potential antiviral effect against Japanese encephalitis virus infection in a mouse model.","authors":"Rohit Soni, Naina Soni, Abhijit Paul, Aarti Tripathi, Samrat Chatterjee, Arup Banerjee","doi":"10.1111/febs.17370","DOIUrl":"https://doi.org/10.1111/febs.17370","url":null,"abstract":"<p><p>Japanese encephalitis virus (JEV) is the leading causative agent of viral encephalitis in India and contributes to a significant disease burden in South Asian countries. However, no antiviral treatment is available against JEV-induced encephalitis, highlighting the urgent need for novel therapeutic approaches. Repurposing or repositioning drugs was found to be more economical and practical in the current drug development scenario. The present study aimed to develop a host-directed strategy through a computational drug repurposing approach. As part of the strategy, we first generated a dynamic signature of differentially expressed JEV infection-associated proteins in mice brains through a semiquantitative proteomics approach. With the help of the Connectivity Map (CMap) analysis, we narrowed down the lists of drugs with a high negative CMap score (-70 or lower). Based on the CMap score, we chose the top three compounds (Tipifarnib, Ly303511 and MDL11939) with CMap scores of -91.83, -88.18 and -91.15, respectively. The antiviral potential of these three compounds was further compared in both JEV-infected mouse neuroblastoma cells and C57BL/6 mice. Oral administration of Ly303511 and MDL11939, alone or in combination, showed improved outcomes (e.g. delayed death, increased survival, and less viral load than Tipifarnib alone or combined). The JEV-infected mice survived upon drug treatment, effectively reducing viral load and reversing the antiviral signature. Our results highlight Ly303511 and MDL11939 as promising host-targeted inhibitors of JEV infection and pathogenesis. Moreover, our results favor the combination of Ly303511 and MDL11939 therapy to improve clinical symptoms and reduce JEV-induced damage, thus warranting inclusion in clinical studies.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-induced translation of collagen-modifying enzymes PLOD2 and P4HA1 is dependent on RBM4 and eIF4E2 in human colon cancer HCT116 cells.","authors":"Hung-Hsuan Li, Hsin-Yuan Hung, Jau-Song Yu, Yu-Cheng Liao, Ming-Chih Lai","doi":"10.1111/febs.17371","DOIUrl":"https://doi.org/10.1111/febs.17371","url":null,"abstract":"<p><p>Hypoxia is a critical microenvironmental factor that induces tumorigenesis and cancer progression, including metastasis. The highly dynamic nature of the extracellular matrix (ECM) plays a crucial role in metastasis. Collagens are the predominant component of structural proteins embedded within the ECM. The biosynthesis of collagen typically undergoes a series of posttranslational modifications, such as hydroxylation of lysine and proline residues by procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) and prolyl 4-hydroxylases (P4Hs), respectively. Collagen hydroxylation is critical for ECM remodeling and maintenance. We recently investigated hypoxia-induced translation in human colon cancer HCT116 cells and identified several collagen-modifying enzymes, including procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) and prolyl 4-hydroxylase subunit alpha 1 (P4HA1). Although the translation of bulk mRNAs is repressed in hypoxia, specific mRNAs remain efficiently translated under such conditions. We have found that PLOD2 and P4HA1 are significantly upregulated in hypoxic HCT116 cells compared to normoxic cells. HIF-1 is known to induce the transcription of PLOD2 and P4HA1 during hypoxia. However, the molecular mechanisms of hypoxia-induced translation of PLOD2 and P4HA1 remain largely unclear. We provide evidence that RBM4 and eIF4E2 are required for hypoxia-induced translation of PLOD2 and P4HA1 mRNAs. The 3' UTRs of PLOD2 and P4HA1 mRNAs are involved in translational control during hypoxia in HCT116 cells.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence for corrin biosynthesis in the last universal common ancestor.","authors":"Luca D Modjewski, Val Karavaeva, Natalia Mrnjavac, Michael Knopp, William F Martin, Filipa L Sousa","doi":"10.1111/febs.17367","DOIUrl":"https://doi.org/10.1111/febs.17367","url":null,"abstract":"<p><p>Corrinoids are cobalt-containing tetrapyrroles. They include adenosylcobalamin (vitamin B₁₂) and cobamides that function as cofactors and coenzymes for methyl transfer, radical-dependent and redox reactions. Though cobamides are the most complex cofactors in nature, they are essential in the acetyl-CoA pathway, thought to be the most ancient CO₂-fixation pathway, where they perform a pterin-to-cobalt-to-nickel methyl transfer reaction catalyzed by the corrinoid iron-sulphur protein (CoFeS). CoFeS occurs in H₂-dependent archaeal methanogens, the oldest microbial lineage by measure of physiology and carbon isotope data, dating corrinoids to ca. 3.5 billion years. However, CoFeS and cobamides are also essential in the acetyl-CoA pathway of H₂-dependent bacterial acetogens. To determine whether corrin biosynthesis was established before archaea and bacteria diverged, whether the pathways arose independently or whether cobamide biosynthesis was transferred from the archaeal to the bacterial lineage (or vice versa) during evolution, we investigated phylogenies and structural data for 26 enzymes of corrin ring and lower ligand biosynthesis. The data trace cobamide synthesis to the common ancestor of bacteria and archaea, placing it in the last universal common ancestor of all lifeforms (LUCA), while pterin-dependent methyl synthesis pathways likely arose independently post-LUCA in the lineages leading to bacteria and archaea. Enzymes of corrin biosynthesis were recruited from preexisting ancient pathways. Evolutionary forerunners of CoFeS function were likely Fe-, Ni- and Co-containing solid-state surfaces, which, in the laboratory, catalyze the reactions of the acetyl-CoA pathway from CO₂ to pyruvate under serpentinizing hydrothermal conditions. The data suggest that enzymatic corrin biosynthesis replaced insoluble solid-state catalysts that tethered primordial CO₂ assimilation to the Earth's crust, suggesting a role for corrin synthesis in the origin of free-living cells.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bacterial purine metabolism modulates C. elegans development and stress tolerance via DAF-16.","authors":"Min Feng, Baizhen Gao, L Rene Garcia, Qing Sun","doi":"10.1111/febs.17363","DOIUrl":"https://doi.org/10.1111/febs.17363","url":null,"abstract":"<p><p>The purine metabolism is crucial for cellular function and is a conserved metabolic network from prokaryotes to humans. While extensively studied in microorganisms like yeast and bacteria, the impact of perturbing dietary intermediates from the purine biosynthesis on animal development and growth remains poorly understood. We utilized Caenorhabditis elegans as the metazoan model to investigate the mechanisms underlying this deficiency. Through a high-throughput screening of an Escherichia coli mutant library Keio collection, we identified 34 E. coli mutants that delay C. elegans development. Among these mutants, we found that E. coli purE gene is an essential genetic component that promotes host development in a dose-dependent manner. Further metabolites supplementation suggests that bacterial purE downstream metabolite 5-aminoimidazole-4-carboxamide ribotide (AICAR) can inhibit worm growth. Additionally, we found the FoxO transcription factor DAF-16 is indispensable in worm development delay induced by purE mutation, and observed increased nuclear accumulation of DAF-16 when fed E. coli purE- mutants, suggesting the role of DAF-16 in response to purE mutation. RNA-seq analysis and phenotypic assays revealed that worms fed the E. coli purE mutant exhibited elevated lifespan, thermotolerance, and pathogen resistance. These findings collectively suggest that certain intermediates in the bacterial purine biosynthesis can serve as a cue to modulate development and activate the defense response in the nematode C. elegans through DAF-16.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional factor ISL1 regulates palate development by tuning the SHH cascade.","authors":"Chujing Zhang, Yuting Zheng, Yaping Qu, Ruiqi Huang, Huarong Huang, Jianying Li, Mengsheng Qiu, Feixue Li","doi":"10.1111/febs.17369","DOIUrl":"https://doi.org/10.1111/febs.17369","url":null,"abstract":"<p><p>Cleft palate is one of the most common birth defects in humans, and palate morphogenesis depends on epithelial-mesenchymal interaction. In this study, we report that ablation of Isl1 in the epithelium leads to complete cleft palate. A significant reduction in mesenchymal cell proliferation was detected in the Isl1^Pitx2Cre mutant palates, but there was no significant difference in apoptosis between wild-type and mutant embryos. Fewer rugae structures were observed in Isl1^Pitx2Cre mutant embryos. Shh, Sox2, Foxe1, Foxd2, and Msx1 expression was downregulated in the developing palate in Isl1 mutant embryos. We found that ISL1 can directly regulate Shh expression in palatal epithelial cells, suggesting a critical role for ISL1 in epithelial-mesenchymal interactions during palate development. Remarkably, cleft palate defects due to Isl1 deletion were rescued by a conditional transgenic allele (Tg-pmes-Ihh), confirming the genetic integration of Hedgehog signaling. Our findings indicate that ISL1 controls palatal shelf morphogenesis by modulating epithelial-mesenchymal communication via SHH signaling.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conversion of pyridoxal to pyridoxamine with NH₃ and H₂ on nickel generates a protometabolic nitrogen shuttle under serpentinizing conditions.","authors":"Manon Laura Schlikker, Max Brabender, Loraine Schwander, Carolina Garcia Garcia, Maximillian Burmeister, Sabine Metzger, Joseph Moran, William F Martin","doi":"10.1111/febs.17357","DOIUrl":"https://doi.org/10.1111/febs.17357","url":null,"abstract":"<p><p>Serpentinizing hydrothermal vents are likely sites for the origin of metabolism because they produce H₂ as a source of electrons for CO₂ reduction while depositing zero-valent iron, cobalt, and nickel as catalysts for organic reactions. Recent work has shown that solid-state nickel can catalyze the H₂-dependent reduction of CO₂ to various organic acids and their reductive amination with H₂ and NH₃ to biological amino acids under the conditions of H₂-producing hydrothermal vents and that amino acid synthesis from NH₃, H₂, and 2-oxoacids is facile in the presence of Ni⁰. Such reactions suggest a metallic origin of metabolism during early biochemical evolution because single metals replace the function of over 130 enzymatic reactions at the core of metabolism in microbes that use the acetyl-CoA pathway of CO₂ fixation. Yet solid-state catalysts tether primordial amino synthesis to a mineral surface. Many studies have shown that pyridoxal catalyzes transamination reactions without enzymes. Here we show that pyridoxamine, the NH₂-transferring intermediate in pyridoxal-dependent transamination reactions, is generated from pyridoxal by reaction with NH₃ (as little as 5 mm) and H₂ (5 bar) on Ni⁰ as catalyst at pH 11 and 80 °C within hours. These conditions correspond to those in hydrothermal vents undergoing active serpentinization. The results indicate that at the origin of metabolism, pyridoxamine provided a soluble, organic amino donor for aqueous amino acid synthesis, mediating an evolutionary transition from NH₃-dependent amino acid synthesis on inorganic surfaces to pyridoxamine-dependent organic reactions in the aqueous phase.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.","authors":"Tristan N Samuels, Fanqi Wu, Maria Mahmood, Wajd A Abuzaid, Nancy Sun, Angelica Moresco, Victoria M Siu, Patrick O'Donoghue, Ilka U Heinemann","doi":"10.1111/febs.17361","DOIUrl":"https://doi.org/10.1111/febs.17361","url":null,"abstract":"<p><p>Aminoacyl-tRNA synthetases catalyze the ligation of a specific amino acid to its cognate tRNA. The resulting aminoacyl-tRNAs are indispensable intermediates in protein biosynthesis, facilitating the precise decoding of the genetic code. Pathogenic alleles in the aminoacyl-tRNA synthetases can lead to several dominant and recessive disorders. To date, disease-specific treatments for these conditions are largely unavailable. We review pathogenic human synthetase alleles, the molecular and cellular mechanisms of tRNA synthetase diseases, and emerging approaches to allele-specific treatments, including small molecules and nucleic acid-based therapeutics. Current treatment approaches to rescue defective or dysfunctional tRNA synthetase mutants include supplementation with cognate amino acids and delivery of cognate tRNAs to alleviate bottlenecks in translation. Complementary approaches use inhibitors to target the integrated stress response, which can be dysregulated in tRNA synthetase diseases.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cryo-EM structures of the full-length human contactin-2.","authors":"Zhenzhen Zhang, Wei Chen, Zhubing Shi, Fan Pan, Daping Wang","doi":"10.1111/febs.17364","DOIUrl":"https://doi.org/10.1111/febs.17364","url":null,"abstract":"<p><p>Contactin-2 (CNTN2), an immunoglobulin cell adhesion molecule (IgCAM) expressed on the neural cell surface, regulates the formation of myelin sheaths, facilitates communication between neurons and axoglial cells, and coordinates the migration of neural cells. However, the assembly of full-length CNTN2 is still not fully elucidated. Here, we found that the full-length human CNTN2 forms a concentration-dependent homodimer. We further determined the cryo-EM structures of the full-length CNTN2, revealing a novel bowknot-shaped scaffold constituted of the Ig1-6 repeats from two protomers, with the flexible ribbon-like FNIII repeats extending outward in opposite directions. The Ig1-6 domains, rather than the previously proposed Ig1-4 domains, have an indispensable role in mediating CNTN2-dependent cell adhesion and clustering. Moreover, structure-guided mutagenesis analyses supported the idea that CNTN2 homodimerization observed in our structure is essential for cell adhesion. Our findings offer novel insights into the mechanism through which CNTN2 forms a homodimer to maintain cell-cell contacts in the nervous system.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the interplay between inflammation and male fertility.","authors":"Oleksandra Fomichova, Pedro F Oliveira, Raquel L Bernardino","doi":"10.1111/febs.17366","DOIUrl":"https://doi.org/10.1111/febs.17366","url":null,"abstract":"<p><p>Male fertility results from a complex interplay of physiological, environmental, and genetic factors. It is conditioned by the properly developed anatomy of the reproductive system, hormonal regulation balance, and the interplay between different cell populations that sustain an appropriate and functional environment in the testes. Unfortunately, the mechanisms sustaining male fertility are not flawless and their perturbation can lead to infertility. Inflammation is one of the factors that contribute to male infertility. In the testes, it can be brought on by varicocele, obesity, gonadal infections, leukocytospermia, physical obstructions or traumas, and consumption of toxic substances. As a result of prolonged or untreated inflammation, the testicular resident cells that sustain spermatogenesis can suffer DNA damage, lipid and protein oxidation, and mitochondrial dysfunction consequently leading to loss of function in affected Sertoli cells (SCs) and Leydig cells (LCs), and the formation of morphologically abnormal dysfunctional sperm cells that lay in the basis of male infertility and subfertility. This is due mainly to the production and secretion of pro-inflammatory mediators, including cytokines, chemokines, and reactive oxygen species (ROS) by local immune cells (macrophages, lymphocytes T, mast cells) and tissue-specific cells [SCs, LCs, peritubular myoid cells (PMCs) and germ cells (GCs)]. Depending on the location, duration, and intensity of inflammation, these mediators can exert their toxic effect on different elements of the testes. In this review, we discuss the most prevalent inflammatory factors that negatively affect male fertility and describe the different ways inflammation can impair male reproductive function.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental tests challenge the evidence of a healthy human blood microbiome.","authors":"Leandro Di Gloria, Simone Baldi, Lavinia Curini, Sara Bertorello, Giulia Nannini, Francesco Cei, Elena Niccolai, Matteo Ramazzotti, Amedeo Amedei","doi":"10.1111/febs.17362","DOIUrl":"https://doi.org/10.1111/febs.17362","url":null,"abstract":"<p><p>The advent of next-generation sequencing (NGS) technologies has made it possible to investigate microbial communities in various environments, including different sites within the human body. Therefore, the previously established belief of the sterile nature of several body sites, including human blood, has now been challenged. However, metagenomics investigation of areas with an anticipated low microbial biomass may be susceptible to misinterpretation. Here, we critically evaluate the results of 16S targeted amplicon sequencing performed on total DNA collected from healthy donors' blood samples while incorporating specific negative controls aimed at addressing potential bias to supplement and strengthen the research in this area. We prepared negative controls by increasing the initial DNA quantity through sequences that can be recognized and subsequently discarded. We found that only three organisms were sporadically present among the samples, and this was mostly attributable to bacteria ubiquitously present in laboratory reagents. Despite not fully confirming or denying the existence of healthy blood microbiota, our results suggest that living bacteria, or at least their residual DNA sequences, are not a common feature of human blood in healthy people. Finally, our study poses relevant questions on the design of controls in this research area that must be considered in order to avoid misinterpreted results that appear to contaminate current high-throughput research.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}