The FEBS journal最新文献

{"title":"The oncoprotein DEK controls growth-regulated gene expression by enhancing the DNA-binding activity of basic leucine zipper transcription factors.","authors":"Takuma Hashimoto, Shoko Saito, Mike Ohata, Mitsuru Okuwaki","doi":"10.1111/febs.70124","DOIUrl":"https://doi.org/10.1111/febs.70124","url":null,"abstract":"<p><p>Overexpression of the oncogenic protein DEK is associated with a poor prognosis in various cancers. However, the molecular mechanisms by which DEK promotes cancer development and malignant transformation remain unclear. Previous studies have shown that DEK interacts with transcription factors, such as AP-2a and C/EBPα, and enhances their transcriptional activity. We hypothesized that DEK promotes cancer cell phenotypes by regulating transcription factors. We analyzed the interaction between DEK and the transcription factors to evaluate this hypothesis. We found that DEK binds to the basic regions within the basic leucine zipper (bZIP)- and basic helix-loop-helix leucine zipper (bHLH-ZIP)- transcription factors. Interestingly, DEK enhanced the DNA-binding capacity of two bZIP transcription factors, C/EBPα and ATF3, in vitro without being a component of the transcription factor-DNA complex. We performed DEK knockdown in lung adenocarcinoma A549 cells and examined the global transcriptome changes to determine the biological significance of the interaction between DEK and transcription factors. We found that diverse genes regulating cell growth and amino acid metabolism, which may potentially be regulated by c-Jun, a subunit of the bZIP transcription factor AP1, and c-Myc, a bHLH-ZIP transcription factor, were decreased by DEK knockdown. Consistent with these transcriptome changes, the cell growth, colony formation, and cell migration abilities of A549 cells were decreased by DEK knockdown. These results suggest that DEK promotes cancer cell malignancy by regulating the functions of the bZIP and bHLH-ZIP transcription factors.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053168","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":"Conserved function of a RasGEF-mediated pathway in the metabolic compensation of the circadian clock.","authors":"Orsolya Sárkány, Anita Szőke, Aladár Pettkó-Szandtner, Eszter Éva Kálmán, Michael Brunner, Norbert Gyöngyösi, Krisztina Káldi","doi":"10.1111/febs.70122","DOIUrl":"https://doi.org/10.1111/febs.70122","url":null,"abstract":"<p><p>Metabolic compensation of the circadian clock ensures endogenous timing across a broad range of nutrient conditions, enabling organisms to adapt efficiently to recurrent environmental changes, even during nutrient scarcity. In this study, we have identified a novel clock-controlled gene, rasgef (Rat Sarcoma Guanine Nucleotide Exchange Factor), that plays a crucial role in modulating the circadian clock under starvation conditions in the circadian model organism Neurospora crassa. The gene product, RasGEF-a nucleotide exchange factor for the small G protein RAS2P (Rat Sarcoma 2 Protein)-displays glucose-dependent phosphorylation and localization. We show that deletion of rasgef hinders metabolic compensation of the circadian clock to glucose-depleted conditions and disrupts the rhythmic expression of the output gene ccg2. Furthermore, we demonstrate in osteosarcoma cells that the period of the mammalian clock is also compensated across a wide range of extracellular glucose levels and adaptation of the clock to glucose-starved conditions depends on the RasGEF homolog SOS1 (Son of Sevenless 1) and its downstream signaling component ERK (Extracellular Signal-Regulated Kinase). Our results suggest a conserved role of RasGEF-mediated signaling in the maintenance of circadian rhythm under glucose-limited conditions.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016326","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":"The radical SAM enzyme NirJ cleaves off two propionate side chains with the release of acrylate during heme d₁ biosynthesis.","authors":"Heike Meyer, Maren H Hoock, Kai Zwara, Sören Jahn, Volker Schünemann, Gunhild Layer","doi":"10.1111/febs.70105","DOIUrl":"https://doi.org/10.1111/febs.70105","url":null,"abstract":"<p><p>Heme d₁ is an iron-containing, modified tetrapyrrole that serves as an essential prosthetic group in cytochrome cd₁ nitrite reductases. The biosynthesis of heme d₁ from the precursor siroheme requires three or four enzymatic steps, including the removal of two propionate side chains, the latter being catalyzed by the radical SAM enzyme NirJ. Although the removal of the propionate side chains by NirJ has been shown previously, several aspects of NirJ catalysis remained elusive, including the type of its auxiliary iron-sulfur cluster as well as the identity of the cleavage byproduct and the actual product of the NirJ reaction. Here, we demonstrate by Mössbauer spectroscopy that NirJ contains a [4Fe-4S] cluster ligated by cysteine residues as its auxiliary cluster. We show that acrylate is released during the NirJ reaction as the cleavage byproduct, as observed by HPLC-UV and HPLC-MS analysis of enzyme activity assay mixtures after derivatization. Finally, we provide strong evidence from HPLC-UV/Vis and HPLC-MS analysis that the NirJ reaction product contains methylene groups at positions C3 and C8 of the tetrapyrrole macrocycle. Based on these results, we propose a revised version of the NirJ reaction mechanism, including a potential role of the auxiliary iron-sulfur cluster as an electron donor for radical quenching.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995958","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":"On the synergy between myelin proteins P0, MBP, and P2 in peripheral nerve major dense line formation.","authors":"Oda C Krokengen, Arne Raasakka, Martin Berg Klenow, Antara Pal, Øystein Hetland, Anna Mularski, Salla Ruskamo, Jan Skov Pedersen, Adam Cohen Simonsen, Petri Kursula","doi":"10.1111/febs.70111","DOIUrl":"https://doi.org/10.1111/febs.70111","url":null,"abstract":"<p><p>The proper formation and function of the myelin sheath, a proteolipid membrane multilayer, relies on the coordinated action of several key myelin proteins. We studied how proteins from the peripheral myelin cytoplasmic apposition-myelin basic protein (MBP), the cytoplasmic tail of myelin protein zero (P0ct), and peripheral myelin protein 2 (P2)-interact with each other and with myelin-like membranes using various techniques, such as small-angle X-ray diffraction, differential scanning calorimetry (DSC), surface plasmon resonance (SPR), and electron and live epifluorescence microscopy. DSC revealed changes in lipid interactions depending on the protein combination, with altered membrane fluidity and stability. These results were supported by SPR, which indicated that the myelin proteins may compete for membrane surface binding. Analysis of the Bragg peaks induced by the myelin proteins in lipidic environments showed both lamellar and nonlamellar phases in protein-lipid complexes, indicating the formation of nanoscale structures that may be relevant for myelin assembly. Microscopy experiments showed the formation of new membrane structures with each of the proteins separately and together. Our data indicate both synergy and competition between the three main proteins residing in the peripheral nervous system myelin major dense line. The observed direct effects of myelin proteins on lipid membrane structure and properties may be relevant to their function in myelinating cells as well as their role in myelin disorders.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029085","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":"Type I interferon signalling and interferon-responsive microglia in health and disease.","authors":"Jose P Lopez-Atalaya, Aysha M Bhojwani-Cabrera","doi":"10.1111/febs.70126","DOIUrl":"https://doi.org/10.1111/febs.70126","url":null,"abstract":"<p><p>Recent evidence suggests that type I interferon (IFN-I) signalling extends beyond its canonical roles in antiviral defence and immunomodulation. Over the past decade, dysregulated IFN-I signalling has been linked to genetic disorders and neurodegenerative diseases, where it may contribute to neurological impairments. Microglia have emerged as key mediators of IFN-I responses in the central nervous system. A distinct transcriptional state responsive to interferons has recently been identified in microglia. The activation of the IFN-I pathway in these cells is now recognised as pivotal in both development and neurodegeneration. This review is divided into two main sections: the first examines the broader role of IFN-I signalling in the central nervous system, particularly its contribution to neurological dysfunction; the second focuses on the specific state of interferon-responsive microglia, exploring its mechanisms and relevance in neurodegenerative conditions. Finally, we discuss how these areas intersect and their implications for both healthy and diseased states.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034120","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":"Glutamine limits NLRP3 inflammasome activation and pyroptosis in macrophages by sustaining the IRG1/itaconate axis.","authors":"Xiaoli Chen, Yuanfeng Zhu, Lin Xia, Sen Su, Shijun Fan, Yongling Lu, Qian Chen, Yan Wei, Qianying Huang, Xin Liu, Xi Peng","doi":"10.1111/febs.70119","DOIUrl":"https://doi.org/10.1111/febs.70119","url":null,"abstract":"<p><p>Aberrant activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome increases the release of mature pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and enhances pyroptosis; thereby necessitating tight regulation of the NLRP3 inflammasome. Dysfunctional glutamine metabolism contributes to the pathogenesis of multiple inflammatory disorders, and the precise mechanism remains to be elucidated. Here, we provide evidence that glutamine deprivation enhances NLRP3 inflammasome activation in macrophages. Indeed, the absence of exogenous glutamine specifically enhanced NLRP3 inflammasome assembly, thereby accelerating pyroptosis and promoting the maturation of IL-1β and IL-18. Inhibition of glutaminolysis exhibited a similar effect to glutamine deprivation, whereas this effect was reversed by α-ketoglutarate (α-KG), a tricarboxylic acid (TCA)-cycle intermediate that can be replenished by glutamine supply. We further observed reduced generation of endogenous itaconate by glutamine deprivation and verified that both exogenous supplementation of itaconate derivative and increased endogenous itaconate production by overexpressing immune-responsive gene 1 [IRG1; also known as aconitate decarboxylase 1 (ACOD1)] could replace glutamine to inhibit the NLRP3 inflammasome. Mechanistically, glutamine deprivation decreased the source of substrate and inhibited transcription factor EB (TFEB)-dependent transcriptional upregulation of IRG1, thereby impairing the IRG1/itaconate axis that suppresses the NLRP3 inflammasome. Furthermore, glutamine deficiency was detected in a murine sepsis model, whereas extrinsic glutamine supplementation conferred protection against intestinal inflammation and tissue damage in septic mice. Taken together, our findings provide a novel insight into the link between glutamine metabolism and NLRP3 inflammasome activation, highlighting the target of glutamine metabolism, which holds as a potential therapeutic strategy for inflammatory diseases.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029066","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":"Identification of orphan GPR25 as a receptor for the chemokine CXCL17.","authors":"Wen-Feng Hu, Jie Yu, Juan-Juan Wang, Ru-Jiao Sun, Yong-Shan Zheng, Teng Zhang, Ya-Li Liu, Zeng-Guang Xu, Zhan-Yun Guo","doi":"10.1111/febs.70117","DOIUrl":"https://doi.org/10.1111/febs.70117","url":null,"abstract":"<p><p>C-X-C motif chemokine ligand 17 (CXCL17) is a small secretory protein primarily expressed in mucosal tissues, which likely functions as a chemoattractant; however, its receptor is controversial. Herein, we identified the rarely studied orphan G protein-coupled receptor 25 (GPR25) as a receptor of CXCL17 via prediction using the newly developed AlphaFold 3 algorithm and experimental validation. In the NanoLuc Binary Technology (NanoBiT)-based β-arrestin recruitment assay, recombinant human CXCL17 could activate human GPR25 in transfected human embryonic kidney (HEK) 293T cells with an EC₅₀ value around 100 nm, but it had no activation effect on the other 17 tested G protein-coupled receptors. Deletion of three conserved C-terminal residues from human CXCL17 almost abolished its activation effect. Alanine replacement of W95 or R178 of human GPR25, two conserved residues in the predicted orthosteric ligand binding pocket, almost abolished its response to CXCL17. Only the pairing of wild-type CXCL17 with wild-type GPR25 could cause shedding of transforming growth factor α and induce chemotactic movement of transfected HEK293T cells. These results were consistent with the AlphaFold 3-predicted binding model, in which the highly conserved C-terminal fragment of CXCL17 inserts into the orthosteric ligand binding pocket of GPR25. According to their expression pattern shown in the Human Protein Atlas, CXCL17 may be an endogenous agonist of GPR25 in humans and other mammals; however, this hypothesis needs to be tested experimentally in future studies. The present deorphanization paves the way for further functional characterization of the orphan receptor GPR25 and the orphan ligand CXCL17.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046853","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":"Augmenter of liver regeneration (ALR) can regulate iron homeostasis through the INOS/NO/SLC39A14 pathway to reduce ferroptosis in acute kidney injury.","authors":"Fangyan Tan, Dan Cao, Lili Huang, Yixin Ma, Chunxia Wang, Zheng Zhang, Xiaohui Liao","doi":"10.1111/febs.70103","DOIUrl":"https://doi.org/10.1111/febs.70103","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is a complex clinical syndrome that affects approximately 13.3 million people worldwide each year. Although ferroptosis has been implicated in the pathological progression of AKI, the underlying mechanisms remain elusive. Augmenter of liver regeneration (ALR) plays a role in apoptosis, autophagy and oxidative stress induction in renal tubular epithelial cells; however, the specific mechanisms through which ALR is involved in AKI are unclear. The present study investigated the effects of ALR on regulating iron uptake and ferroptosis in AKI under in vivo and in vitro conditions. Renal tubular epithelial cell-specific Alr knockout (AlrKO) mice and ischaemia/reperfusion (I/R)-induced AKI in vivo models were generated. ALR overexpression and hypoxia/reoxygenation (H/R)-induced AKI in vitro models were generated using human renal tubular epithelial cells. The effects of ALR on ferroptosis and kidney function in AKI were investigated through in vitro and in vivo studies involving biochemical analysis, RT-qPCR, western blotting assay, immunofluorescence assay, and transmission electron microscopy. Transcriptome sequencing, iron homeostasis, and inducible nitric oxide synthase (iNOS)/nitric oxide (NO) synthesis detection were performed to investigate the mechanisms through which ALR affects AKI. Loss-of-function experiments revealed that kidney tubule-specific Alr knockout in mice exacerbated iron uptake, ferroptosis, and acute kidney I/R injury. Mechanistically, we found that ALR could regulate iron homeostasis through the iNOS/NO/Solute carrier family 39 member 14 (SLC39A14) pathway to reduce ferroptosis in AKI. The results of this study reveal a previously undescribed function of ALR in iron homeostasis and ferroptosis in AKI, and suggest that targeting ALR could be a potential treatment option for AKI.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059139","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":"Roles and applications of autophagy in guarding against environmental stress and DNA damage in Saccharomyces cerevisiae.","authors":"Tong Zhang, Yuping Lin, Ziteng Zhang, Zhen Wang, Fanli Zeng, Qinhong Wang","doi":"10.1111/febs.70112","DOIUrl":"https://doi.org/10.1111/febs.70112","url":null,"abstract":"<p><p>Saccharomyces cerevisiae (S. cerevisiae), a famous chassis cell factory, often faces various environmental stress conditions like extreme temperature, osmolarity, and nutrient starvation during the fermentation process. Additionally, chromosomal replication and genome editing-assisted metabolic engineering may cause DNA damage to S. cerevisiae. S. cerevisiae has evolved multiple elaborate mechanisms to fend against these adverse conditions. One of these \"self-repair\" mechanisms is autophagy, a ubiquitous \"self-eating\" mechanism that transports intracellular components to the lysosome/vacuole for degradation. Here, we reviewed the current state of our knowledge about the role and application of autophagy regulation in S. cerevisiae in response to environmental stress and genome damage, which may provide new strategies for developing robust industrial yeast and accelerating genome engineering.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045590","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":"Identification of CO-binding modes in the Cu_B site of bovine cytochrome c oxidase by spatial mapping of binding energy.","authors":"Jiyoung Kang, Toru Matsuoka, Masaru Tateno","doi":"10.1111/febs.70115","DOIUrl":"https://doi.org/10.1111/febs.70115","url":null,"abstract":"<p><p>Cytochrome c oxidase (CcO) is the terminal enzyme of the electron-transfer system and reduces an oxygen molecule to two water molecules. The trigger of this reaction is the binding of an oxygen molecule to the binuclear center (BNC) comprising the Cu_B site and heme a₃. Due to the difficulty in obtaining the crystal structure of the complex with an oxygen molecule, other ligand molecules have been utilized to investigate the ligand-binding mechanism. In the previous studies, crystal structures of complexes with CO, NO, and CN^- ligands were determined, suggesting dynamic changes in helix X induced by ligand binding according to time-resolved infrared spectroscopic analysis. In this study, we employed ab initio quantum mechanical calculations to elucidate the ligand-recognition mechanisms of the Cu_B site and systematically analyzed the potential fields comprising the BNC and ligands. Additionally, we evaluated the effect of Tyr244 and Val243 located close to the BNC site on the potential fields, identifying Val243 as a critical factor in determining the configuration of the CO ligand bound to the Cu_B site by inducing hybridization between the 2p orbital of the O atom (CO) and the 3d orbital of the Fe atom (heme a₃). Furthermore, the Val243 model indicated the existence of two CO ligand configurations, which were consistent with experimental Fourier-transform infrared spectroscopy data. To the best of our knowledge, this represents the first elucidation of the functional role of Val243.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000977","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}