The FEBS journal最新文献_第5页

A non-redundant role of EAAT3 for ATP synthesis mediated by GDH in dopaminergic neuronal cells: a new avenue for glutamate metabolism and protection in Parkinson's disease.

The FEBS journal Pub Date : 2025-03-05 DOI: 10.1111/febs.70053

Alessandra Preziuso, Tiziano Serfilippi, Marwa Toujani, Valentina Terenzi, Salvatore Amoroso, Simona Magi, Vincenzo Lariccia, Silvia Piccirillo

{"title":"A non-redundant role of EAAT3 for ATP synthesis mediated by GDH in dopaminergic neuronal cells: a new avenue for glutamate metabolism and protection in Parkinson's disease.","authors":"Alessandra Preziuso, Tiziano Serfilippi, Marwa Toujani, Valentina Terenzi, Salvatore Amoroso, Simona Magi, Vincenzo Lariccia, Silvia Piccirillo","doi":"10.1111/febs.70053","DOIUrl":"https://doi.org/10.1111/febs.70053","url":null,"abstract":"Parkinson's disease (PD) is a devastating neurodegenerative disorder with a distinct loss of the nigrostriatal dopaminergic pathway. Despite the multiplicity in etiology, alterations that disrupt neuronal integrity can be traced back to defects in fundamental processes that typically run under mitochondrial inputs. Evidence indicates that mitochondrial activities are hierarchically integrated with the energetic performance of these organelles, so that an interesting perspective holds that interventions aimed at improving mitochondrial bioenergetics can potentially mitigate the severity of PD phenotype expression. In this mechanistic framework, approaches that facilitate the mitochondrial anaplerotic use of glutamate (Glut) might counteract the detrimental shift from Glut metabolism, which is typically altered in PD, to excessive Glut transmission that feeds excitotoxicity and the neurodegenerative spiral. In this study, we investigated whether the enhancement of glutamate dehydrogenase (GDH) activity, by using the GDH activator 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), has neuroprotective potential against PD injury. In both retinoic acid-differentiated SH-SY5Y cells and primary rat mesencephalic neurons challenged with α-synuclein plus rotenone to mimic PD, BCH-dependent GDH activation significantly ameliorated cell viability, improved mitochondrial ATP synthesis and lessened to control levels the cellular redox burden. Strikingly, we collected evidence for the existence of a functional axis connecting GDH activity to a specific intracellular pool of the Excitatory Amino Acid Transporters (EAATs), namely the EAAT3. Overall, our results reveal a novel and non-redundant role of EAAT3 for GDH-dependent protection against PD injury, which may inspire new pharmacological approaches against PD pathology.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569302","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}

引用次数: 0

Structure-activity analysis of imino-pyrimidinone-fused pyrrolidines aids the development of dual plasmepsin V and plasmepsin X inhibitors.

The FEBS journal Pub Date : 2025-03-04 DOI: 10.1111/febs.70038

Anthony N Hodder, Brad E Sleebs, Greg Adams, Sina Rezazadeh, Anna Ngo, Kate Jarman, Stephen Scally, Peter Czabotar, Hongwu Wang, John A McCauley, David B Olsen, Alan F Cowman

{"title":"Structure-activity analysis of imino-pyrimidinone-fused pyrrolidines aids the development of dual plasmepsin V and plasmepsin X inhibitors.","authors":"Anthony N Hodder, Brad E Sleebs, Greg Adams, Sina Rezazadeh, Anna Ngo, Kate Jarman, Stephen Scally, Peter Czabotar, Hongwu Wang, John A McCauley, David B Olsen, Alan F Cowman","doi":"10.1111/febs.70038","DOIUrl":"https://doi.org/10.1111/febs.70038","url":null,"abstract":"A library of known aspartic protease inhibitors was screened to identify compounds that inhibit plasmepsin V from Plasmodium vivax. This screen revealed compounds with an imino-pyrimidinone-fused pyrrolidine (IPF) scaffold that exhibited sub-micromolar inhibitory activity against plasmepsin V. Further screening of IPF analogs against the related aspartic protease plasmepsin X showed inhibitory activity, while a third aspartic protease, plasmepsin IX, was not significantly inhibited. Modifications to the P1 biaryl region of the IPF scaffold differentially modulated inhibition of both plasmepsin V and X. Notably, analogs with potent plasmepsin X inhibitory activity successfully blocked the growth of Plasmodium falciparum in vitro. X-ray structures of IPF analogs in complex with plasmepsin V provided insights into their binding mode and revealed avenues to further improve IPF potency and selectivity between plasmepsin V and X. This understanding of how these compounds interact with the active sites of plasmepsin V and X will serve as a foundation for the future design of dual inhibitors targeting these proteases.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545581","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}

引用次数: 0

Engineered T7 RNA polymerase reduces dsRNA formation by lowering terminal transferase and RNA-dependent RNA polymerase activities. 经改造的 T7 RNA 聚合酶通过降低末端转移酶和 RNA 依赖性 RNA 聚合酶的活性，减少了 dsRNA 的形成。

The FEBS journal Pub Date : 2025-03-03 DOI: 10.1111/febs.70051

Qiongwei Tang, Sisi Zhu, Nannan Hu, Sainan Yin, Yuhong Yang, Yigang Teng, Dongliang Song, Xiang Liu

{"title":"Engineered T7 RNA polymerase reduces dsRNA formation by lowering terminal transferase and RNA-dependent RNA polymerase activities.","authors":"Qiongwei Tang, Sisi Zhu, Nannan Hu, Sainan Yin, Yuhong Yang, Yigang Teng, Dongliang Song, Xiang Liu","doi":"10.1111/febs.70051","DOIUrl":"https://doi.org/10.1111/febs.70051","url":null,"abstract":"T7 RNA polymerase (RNAP), the preferred tool for in vitro transcription (IVT), can generate double-stranded RNA (dsRNA) by-products that elicit immune stress and pose safety concerns. By combining the molecular beacon-based fluorescence-activated droplet sorting (FADS) utilized for random library screening with site-directed mutagenesis aimed at facilitating conformational changes in T7 RNAP, we successfully identified four mutants that exhibit reduced dsRNA content: M1 (V214A), M7 (F162S/A247T), M11 (K180E) and M14 (A70Q). Furthermore, the combinatorial mutant M17 (A70Q/F162S/K180E) exhibited significantly reduced dsRNA production under various conditions. Cellular experiments confirm the application potential of the mutants, displaying mitigated immune stress responses and enhanced protein translation compared to the wild-type protein. We then observed a close correlation between the production of dsRNA and the terminal transferase and RNA-dependent RNAP (RDRP) activities of T7 RNAP. The terminal transferase activity adds several nucleotides to the terminus of RNAs, while the RDRP activity extends the complementary region formed by self-pairing. In summary, we developed a novel approach for engineering T7 RNAP and demonstrated its potential in screening for T7 RNAP variants with reduced dsRNA production or improved product integrity.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545562","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}

引用次数: 0

Bacterial transcriptional repressor NrdR - a flexible multifactorial nucleotide sensor.

The FEBS journal Pub Date : 2025-03-03 DOI: 10.1111/febs.70037

Inna Rozman Grinberg, Ornella Bimaï, Saher Shahid, Lena Philipp, Markel Martínez-Carranza, Ipsita Banerjee, Daniel Lundin, Pål Stenmark, Britt-Marie Sjöberg, Derek T Logan

{"title":"Bacterial transcriptional repressor NrdR - a flexible multifactorial nucleotide sensor.","authors":"Inna Rozman Grinberg, Ornella Bimaï, Saher Shahid, Lena Philipp, Markel Martínez-Carranza, Ipsita Banerjee, Daniel Lundin, Pål Stenmark, Britt-Marie Sjöberg, Derek T Logan","doi":"10.1111/febs.70037","DOIUrl":"https://doi.org/10.1111/febs.70037","url":null,"abstract":"NrdR is a bacterial transcriptional repressor consisting of a zinc (Zn)-ribbon domain followed by an ATP-cone domain. Understanding its mechanism of action could aid the design of novel antibacterials. NrdR binds specifically to two \"NrdR boxes\" upstream of ribonucleotide reductase operons, of which Escherichia coli has three: nrdHIEF, nrdDG and nrdAB, in the last of which we identified a new box. We show that E. coli NrdR (EcoNrdR) has similar binding strength to all three sites when loaded with ATP plus deoxyadenosine triphosphate (dATP) or equivalent diphosphate combinations. No other combination of adenine nucleotides promotes binding to DNA. We present crystal structures of EcoNrdR-ATP-dATP and EcoNrdR-ADP-dATP, which are the first high-resolution crystal structures of an NrdR. We have also determined cryo-electron microscopy structures of DNA-bound EcoNrdR-ATP-dATP and novel filaments of EcoNrdR-ATP. Tetrameric forms of EcoNrdR involve alternating interactions between pairs of Zn-ribbon domains and ATP-cones. The structures reveal considerable flexibility in relative orientation of ATP-cones vs Zn-ribbon domains. The structure of DNA-bound EcoNrdR-ATP-dATP shows that significant conformational rearrangements between ATP-cones and Zn-ribbons accompany DNA binding while the ATP-cones retain the same relative orientation. In contrast, ATP-loaded EcoNrdR filaments show rearrangements of the ATP-cone pairs and sequester the DNA-binding residues of NrdR such that they are unable to bind to DNA. Our results, in combination with a previous structural and biochemical study, point to highly flexible EcoNrdR structures that, when loaded with the correct nucleotides, adapt to an optimal promoter-binding conformation.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545559","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}

引用次数: 0

Membrane selectivity and pore formation of SprA1 and SprA2 hemolytic peptides from Staphylococcus aureus type I toxin-antitoxin systems.

The FEBS journal Pub Date : 2025-03-03 DOI: 10.1111/febs.70001

Laurence Fermon, Noëlla Germain-Amiot, Charlotte Oriol, Astrid Rouillon, Yoann Augagneur, Stéphane Dréano, Irène Nicolas, Alexandre Chenal, Arnaud Bondon, Soizic Chevance, Marie-Laure Pinel-Marie

{"title":"Membrane selectivity and pore formation of SprA1 and SprA2 hemolytic peptides from Staphylococcus aureus type I toxin-antitoxin systems.","authors":"Laurence Fermon, Noëlla Germain-Amiot, Charlotte Oriol, Astrid Rouillon, Yoann Augagneur, Stéphane Dréano, Irène Nicolas, Alexandre Chenal, Arnaud Bondon, Soizic Chevance, Marie-Laure Pinel-Marie","doi":"10.1111/febs.70001","DOIUrl":"https://doi.org/10.1111/febs.70001","url":null,"abstract":"SprA1 and SprA2 are small hydrophobic peptides that belong to the type I toxin-antitoxin systems expressed by Staphylococcus aureus. Both peptides induce S. aureus death when overexpressed. Although they share 71% of amino acids sequence similarity, SprA2 exhibits stronger hemolytic activity than SprA1. In this study, we investigated the mode of action of these toxins on both prokaryotic-like and eukaryotic-like membranes. We first confirmed that SprA2, like SprA1, is an alpha-helical peptide located at the S. aureus membrane. By overexpressing each toxin, we demonstrated that SprA1 forms stable pores in the S. aureus membrane, evidenced by concomitant membrane depolarization, permeabilization and ATP release leading to growth arrest, whereas SprA2 forms transient pores, causing concomitant membrane depolarization, ATP release, and growth arrest. We showed that the unique cysteine residue present in SprA1 and SprA2 is required for toxicity through disulfide bond formation. Next, we found that both synthetic peptides induce slight leakage in anionic DOPC-DOPG lipid vesicles mimicking prokaryotic membranes, concomitant with lipid vesicles aggregation and/or fusion. Moreover, we observed that SprA1 permeabilizes S. aureus protoplasts, via its ability to form stable pores, whereas SprA2 permeabilizes and lyses them. However, no permeabilization of intact bacteria was detected after the addition of SprA1 and SprA2 in the extracellular medium. Finally, we confirmed that SprA2 has strong activity on zwitterionic DOPC lipid vesicles mimicking eukaryotic membranes, without inducing aggregation. This work highlights the strong selectivity of SprA2 for eukaryotic membranes, suggesting that this toxin may play a role in S. aureus virulence.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545577","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}

引用次数: 0

Inflammation and epithelial-mesenchymal transition in a CFTR-depleted human bronchial epithelial cell line revealed by proteomics and human organ-on-a-chip. 蛋白质组学和人体器官芯片揭示了去除了 CFTR 的人支气管上皮细胞系中的炎症和上皮-间质转化。

The FEBS journal Pub Date : 2025-03-03 DOI: 10.1111/febs.70050

Domenico Mattoscio, Luis A Baeza, Haiqing Bai, Tommaso Colangelo, Simone Castagnozzi, Marta Marzotto, Maria Concetta Cufaro, Virginia Lotti, Yu-Chieh Yuan, Matteo Mucci, Longlong Si, Mariachiara Zuccarini, Maria Tredicine, Simona D'Orazio, Damiana Pieragostino, Piero Del Boccio, Claudio Sorio, Marco Trerotola, Mario Romano, Roberto Plebani

{"title":"Inflammation and epithelial-mesenchymal transition in a CFTR-depleted human bronchial epithelial cell line revealed by proteomics and human organ-on-a-chip.","authors":"Domenico Mattoscio, Luis A Baeza, Haiqing Bai, Tommaso Colangelo, Simone Castagnozzi, Marta Marzotto, Maria Concetta Cufaro, Virginia Lotti, Yu-Chieh Yuan, Matteo Mucci, Longlong Si, Mariachiara Zuccarini, Maria Tredicine, Simona D'Orazio, Damiana Pieragostino, Piero Del Boccio, Claudio Sorio, Marco Trerotola, Mario Romano, Roberto Plebani","doi":"10.1111/febs.70050","DOIUrl":"https://doi.org/10.1111/febs.70050","url":null,"abstract":"Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, leading to chronic, unresolved inflammation of the airways due to uncontrolled recruitment of polymorphonuclear leukocytes (PMNs). Evidence indicates that CFTR loss-of-function, in addition to promoting a pro-inflammatory phenotype, is associated with an increased risk of developing cancer, suggesting that CFTR can exert tumor-suppressor functions. Three-dimensional (3D) in vitro culture models, such as the CF lung airway-on-a-chip, can be suitable for studying PMN recruitment, as well as events of cancerogenesis, that is epithelial cell invasion and migration, in CF. To gather insight into the pathobiology of CFTR loss-of-function, we generated CFTR-knockout (KO) clones of the 16HBE14o- human bronchial cell line by CRISPR/Cas9 gene editing, and performed a comparative proteomic analysis of these clones with their wild-type (WT) counterparts. Systematic signaling pathway analysis of CFTR-KO clones revealed modulation of inflammation, PMN recruitment, epithelial cell migration, and epithelial-mesenchymal transition. Using a latest-generation organ-on-a-chip microfluidic platform, we confirmed that CFTR-KO enhanced PMN recruitment and epithelial cell invasion of the endothelial layer. Thus, a dysfunctional CFTR affects multiple pathways in the airway epithelium that ultimately contribute to sustained inflammation and cancerogenesis in CF.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545564","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}

引用次数: 0

Stabilization of the catalytically active structure of a molybdenum-dependent formate dehydrogenase depends on a highly conserved lysine residue.

The FEBS journal Pub Date : 2025-03-03 DOI: 10.1111/febs.70048

Feilong Li, Michael Lienemann

{"title":"Stabilization of the catalytically active structure of a molybdenum-dependent formate dehydrogenase depends on a highly conserved lysine residue.","authors":"Feilong Li, Michael Lienemann","doi":"10.1111/febs.70048","DOIUrl":"https://doi.org/10.1111/febs.70048","url":null,"abstract":"Molybdenum-dependent formate dehydrogenases (Mo-FDHs) reversibly catalyze the interconversion of CO2 and formate, and therefore may be utilized for the development of innovative energy storage and CO2 utilization concepts. Mo-FDHs contain a highly conserved lysine residue in the vicinity of a catalytically active molybdenum (Mo) cofactor and an electron-transferring [4Fe-4S] cluster. In order to elucidate the function of the conserved lysine, we substituted the residue Lys44 of Escherichia coli formate dehydrogenase H (EcFDH-H) with structurally and chemically diverse amino acids. Enzyme kinetic analysis of the purified EcFDH-H variants revealed the Lys-to-Arg substitution as the only amino acid exchange that retained formate oxidation catalytic activity, amounting to 7.1% of the wild-type level. Ultraviolet-visible (UV-Vis) spectroscopic analysis indicated that >90% of the [4Fe-4S] cluster was lost in the case of EcFDH-H variants -K44E and -K44M, whereas the cluster occupancy of the K44R variant decreased by merely 4.5%. Furthermore, the K44R substitution resulted in a slight decrease in its melting temperature and a significant formate affinity decrease, apparent as a 32-fold Km value increase. Consistent with these findings, molecular dynamics simulations predicted an increase in the backbone and cofactor mobility as a result of the K44R substitution. These results are consistent with the conserved lysine being essential for stabilizing the catalytically active structures in EcFDH-H and may support engineering efforts on Mo-FDHs to design more efficient biocatalysts for CO2 reduction.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545579","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}

引用次数: 0

Rhotekin-1 is a novel interacting protein and regulator of TRPC6 activity. Rhotekin-1是一种新型相互作用蛋白，也是TRPC6活性的调节因子。

The FEBS journal Pub Date : 2025-03-02 DOI: 10.1111/febs.70028

Boris Lavanderos, Octavio Orellana-Serradell, Diego Maureira, Pablo Cruz, Ian Silva, Jorge Toledo, Mariela González-Avendaño, Joaquín López, Rodrigo Santos, Felipe Arancibia, Diego Varela, Mónica Cáceres, Ariela Vergara-Jaque, Oscar Cerda

{"title":"Rhotekin-1 is a novel interacting protein and regulator of TRPC6 activity.","authors":"Boris Lavanderos, Octavio Orellana-Serradell, Diego Maureira, Pablo Cruz, Ian Silva, Jorge Toledo, Mariela González-Avendaño, Joaquín López, Rodrigo Santos, Felipe Arancibia, Diego Varela, Mónica Cáceres, Ariela Vergara-Jaque, Oscar Cerda","doi":"10.1111/febs.70028","DOIUrl":"https://doi.org/10.1111/febs.70028","url":null,"abstract":"Dysregulation of Transient Receptor Potential Canonical 6 (TRPC6) channel is associated with pathologies in which cell contraction is relevant. Therefore, understanding the molecular mechanisms underlying the regulation of actin cytoskeletal function by TRPC6 is important. Here, we observed that TRPC6 upregulates the activity of RhoA GTPase, affecting the organization and polymerization of the actin cytoskeleton and focal adhesion dynamics. Moreover, TRPC6 activity promoted cell contraction and migration. Using mass spectrometry, we identified Rhotekin-1 (RTKN-1), an effector of RhoA, as a new TRPC6-interacting protein. In addition, RTKN-1 expression prevented the effects of TRPC6 on cell contraction, migration, and spreading. Moreover, calcium imaging, TRPC6-jGCaMP8f recordings, and patch clamp assays showed that RTKN-1 acts as a negative regulator of TRPC6 activity by reducing the abundance of TRPC6 in the plasma membrane through a mechanism that depends on RhoA activation. In this context, we found that RTKN-1 expression increased the endocytosis of TRPC6 in the early endosome compartment. In summary, these results suggest RTKN-1 as a new interactor and regulator of TRPC6 activity through a novel mechanism involving the modulation of TRPC6 trafficking.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537852","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}

引用次数: 0

Physical and functional interactions between LDLR family members and CXCR4 in breast cancer. 乳腺癌中 LDLR 家族成员与 CXCR4 之间的物理和功能相互作用

The FEBS journal Pub Date : 2025-02-28 DOI: 10.1111/febs.70016

Jiankang Zhang, Jinxiao Chen, Da Wo, En Ma, Hongwei Yan, Jun Peng, Dan-Ni Ren, Weidong Zhu

{"title":"Physical and functional interactions between LDLR family members and CXCR4 in breast cancer.","authors":"Jiankang Zhang, Jinxiao Chen, Da Wo, En Ma, Hongwei Yan, Jun Peng, Dan-Ni Ren, Weidong Zhu","doi":"10.1111/febs.70016","DOIUrl":"https://doi.org/10.1111/febs.70016","url":null,"abstract":"C-X-C chemokine receptor type 4 (CXCR4) belongs to the seven-span G protein-coupled receptor family and plays an important role in promoting cancer metastasis. The single-span receptor, low-density lipoprotein receptor-related protein 6 (LRP6) is commonly considered to be a co-receptor of Wnt and plays an indispensable role during animal development. We recently demonstrated that LRP6 directly binds to CXCR4 via its ectodomain and prevents CXCR4-induced breast cancer metastasis. As a result of structural similarity, LRP6 is also categorized within the low-density lipoprotein receptor (LDLR) family that is involved in lipoprotein transport. We therefore explored whether other LDLR family members could interact with CXCR4. Immunoprecipitation and western blotting analysis showed that LDLR and very low-density lipoprotein receptor (VLDLR) physically interacted with CXCR4. Although stromal cell-derived factor 1/CXCR4 signaling was inhibited by LDLR and LRP1, it was promoted by VLDLR, LRP8 and apolipoprotein E, a general agonist of the LDLR family. Furthermore, breast cancer patients with high CXCR4 expression exhibited the worst prognosis only when combined with high levels of VLDLR/LRP8/apolipoprotein E or low expression of LDLR/LRP1, further suggesting distinct positive and negative roles of LDLR family members in regulating CXCR4. Additional members of the LDLR family, SORL1 and LRP2, also showed a negative correlation with CXCR4 in the prognosis of breast cancer patients. The findings of the present study show that the LDLR family can regulate CXCR4, endowing its members with a previously undescribed role, also suggesting their potential as new breast cancer therapeutic targets and prognostic markers.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532280","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}

引用次数: 0

The m6A demethylase FTO promotes C/EBPβ-LIP translation to perform oncogenic functions in breast cancer cells.

The FEBS journal Pub Date : 2025-02-28 DOI: 10.1111/febs.70033

Hidde R Zuidhof, Christine Müller, Gertrud Kortman, René Wardenaar, Ekaterina Stepanova, Fabricio Loayza-Puch, Cornelis F Calkhoven

{"title":"The m6A demethylase FTO promotes C/EBPβ-LIP translation to perform oncogenic functions in breast cancer cells.","authors":"Hidde R Zuidhof, Christine Müller, Gertrud Kortman, René Wardenaar, Ekaterina Stepanova, Fabricio Loayza-Puch, Cornelis F Calkhoven","doi":"10.1111/febs.70033","DOIUrl":"https://doi.org/10.1111/febs.70033","url":null,"abstract":"N6-methyladenosine (m6A) is a prevalent posttranscriptional mRNA modification involved in the regulation of transcript turnover, translation, and other aspects of RNA fate. The modification is mediated by multicomponent methyltransferase complexes (so-called writers) and is reversed through the action of the m6A-demethylases fat mass and obesity-associated (FTO) and alkB homolog 5 (ALKBH5) (so-called erasers). FTO promotes cell proliferation, colony formation and metastasis in models of triple-negative breast cancer (TNBC). However, little is known about genome-wide or specific downstream regulation by FTO. Here, we examined changes in the genome-wide transcriptome and translatome following FTO knockdown in TNBC cells. Unexpectedly, FTO knockdown had a limited effect on the translatome, while transcriptome analysis revealed that genes related to extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) are regulated through yet unidentified mechanisms. Differential translation of CEBPB mRNA into the C/EBPβ transcription factor isoform C/EBPβ-LIP is known to act in a pro-oncogenic manner in TNBC cells through regulation of EMT genes. Here we show that FTO is required for efficient C/EBPβ-LIP expression, suggesting that FTO has oncogenic functions through regulation of C/EBPβ-LIP.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532281","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}

引用次数: 0