FEBS LettersPub Date : 2024-11-12DOI: 10.1002/1873-3468.15053
Yomna Soliman, Jana Al-Khodor, Gülnaz Yildirim Köken, Nur Mustafaoglu
{"title":"A guide for blood-brain barrier models.","authors":"Yomna Soliman, Jana Al-Khodor, Gülnaz Yildirim Köken, Nur Mustafaoglu","doi":"10.1002/1873-3468.15053","DOIUrl":"https://doi.org/10.1002/1873-3468.15053","url":null,"abstract":"<p><p>Understanding the intricate mechanisms underlying brain-related diseases hinges on unraveling the pivotal role of the blood-brain barrier (BBB), an essential dynamic interface crucial for maintaining brain equilibrium. This review offers a comprehensive analysis of BBB physiology, delving into its cellular and molecular components while exploring a wide range of in vivo and in vitro BBB models. Notably, recent advancements in 3D cell culture techniques are explicitly discussed, as they have significantly improved the fidelity of BBB modeling by enabling the replication of physiologically relevant environments under flow conditions. Special attention is given to the cellular aspects of in vitro BBB models, alongside discussions on advances in stem cell technologies, providing valuable insights into generating robust cellular systems for BBB modeling. The diverse array of cell types used in BBB modeling, depending on their sources, is meticulously examined in this comprehensive review, scrutinizing their respective derivation protocols and implications. By synthesizing diverse approaches, this review sheds light on the improvements of BBB models to capture physiological conditions, aiding in understanding BBB interactions in health and disease conditions to foster clinical developments.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Glu592 of the axon guidance receptor ROBO3 mediates a pH-dependent interaction with NELL2 ligand.","authors":"Kimihiko Mizutani, Mayuko Toyoda, Teruyo Ojima-Kato, Andrés D Maturana, Tomoaki Niimi","doi":"10.1002/1873-3468.15054","DOIUrl":"https://doi.org/10.1002/1873-3468.15054","url":null,"abstract":"<p><p>There are only a few studies on the function of neuronal axon guidance molecules during low brain pH conditions. We previously reported that roundabout (ROBO) 2, a receptor for the axon guidance molecule SLIT, can bind to the neural epidermal growth factor-like-like (NELL) ligands in acidic conditions by conformational change of its ectodomain. Here, we show that the ROBO3 receptor also exhibits a pH-dependent increase in binding to the NELL2 ligand. We found that the Glu592 residue of ROBO3 at the binding interface between NELL2 and ROBO3 is a pH sensor and that the formation of a new hydrogen bonding network, due to protonation of the Glu592, leads to increased binding in acidic conditions. These results suggest that NELL2-ROBO3 signaling could be regulated by extracellular pH.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-11-12DOI: 10.1002/1873-3468.15057
Krystof Hlavac, Petra Pavelkova, Laura Ondrisova, Marek Mraz
{"title":"FoxO1 signaling in B cell malignancies and its therapeutic targeting.","authors":"Krystof Hlavac, Petra Pavelkova, Laura Ondrisova, Marek Mraz","doi":"10.1002/1873-3468.15057","DOIUrl":"https://doi.org/10.1002/1873-3468.15057","url":null,"abstract":"<p><p>FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highly evolutionary conserved subfamily of the 'forkhead' box proteins. They have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The complex nature of FoxO1 is illustrated by its various roles in B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. FoxO1 is tightly regulated at a transcriptional (STAT3, HEB, EBF, FoxOs) and post-transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAPK/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity have been described, underscoring the potential of its therapeutic inhibition. Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-11-07DOI: 10.1002/1873-3468.15046
Steven Lawrence, Jialiang Lin, Asma Khurshid, Wahyu Utami, Richa Singhania, Sadaf Ashraf, Graeme J Thorn, Irengbam Rocky Mangangcha, Keith Spriggs, Dong-Hyun Kim, David Barrett, Cornelia H de Moor
{"title":"Cordycepin generally inhibits growth factor signal transduction in a systems pharmacology study.","authors":"Steven Lawrence, Jialiang Lin, Asma Khurshid, Wahyu Utami, Richa Singhania, Sadaf Ashraf, Graeme J Thorn, Irengbam Rocky Mangangcha, Keith Spriggs, Dong-Hyun Kim, David Barrett, Cornelia H de Moor","doi":"10.1002/1873-3468.15046","DOIUrl":"https://doi.org/10.1002/1873-3468.15046","url":null,"abstract":"<p><p>Cordycepin (3' deoxyadenosine) has been widely researched as a potential cancer therapy, but many diverse mechanisms of action have been proposed. Here, we confirm that cordycepin triphosphate is likely to be the active metabolite of cordycepin and that it consistently represses growth factor-induced gene expression. Bioinformatic analysis, quantitative PCR and western blotting confirmed that cordycepin blocks the PI3K/AKT/mTOR and/or MEK/ERK pathways in six cell lines and that AMPK activation is not required. The effects of cordycepin on translation through mTOR pathway repression were detectable within 30 min, indicating a rapid process. These data therefore indicate that cordycepin has a universal mechanism of action, acting as cordycepin triphosphate on an as yet unknown target molecule involved in growth factor signalling.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-11-07DOI: 10.1002/1873-3468.15051
Sarika Tilwani, Karan Gandhi, Sorab N Dalal
{"title":"14-3-3ε conditional knockout mice exhibit defects in the development of the epidermis.","authors":"Sarika Tilwani, Karan Gandhi, Sorab N Dalal","doi":"10.1002/1873-3468.15051","DOIUrl":"https://doi.org/10.1002/1873-3468.15051","url":null,"abstract":"<p><p>The epidermis is a stratified epithelium that functions as the first line of defense against pathogenic invasion and acts as a barrier preventing water loss. In this study, we aimed to decipher the role of 14-3-3ε in the development of the epidermis. We report that loss of 14-3-3ε in the epidermis of juvenile and adult mice reduces cell division in the basal layer and increases the percentage of cells with multiple centrosomes, leading to a reduction in the thickness of the basal and stratified layers. We also demonstrate a decrease in the expression of differentiation markers, although no gross morphological defects in the skin or adverse effects on the survival of the mice were observed. These results suggest that loss of 14-3-3ε in the epidermis may lead to defects in proliferation and differentiation.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-11-07DOI: 10.1002/1873-3468.15048
Nicholas L Yan, Francisco Candido, Eric Tse, Arthur A Melo, Stanley B Prusiner, Daniel A Mordes, Daniel R Southworth, Nick A Paras, Gregory E Merz
{"title":"Cryo-EM structure of a novel α-synuclein filament subtype from multiple system atrophy.","authors":"Nicholas L Yan, Francisco Candido, Eric Tse, Arthur A Melo, Stanley B Prusiner, Daniel A Mordes, Daniel R Southworth, Nick A Paras, Gregory E Merz","doi":"10.1002/1873-3468.15048","DOIUrl":"https://doi.org/10.1002/1873-3468.15048","url":null,"abstract":"<p><p>Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by accumulation of α-synuclein cross-β amyloid filaments in the brain. Previous structural studies of these filaments by cryo-electron microscopy (cryo-EM) revealed three discrete folds distinct from α-synuclein filaments associated with other neurodegenerative diseases. Here, we use cryo-EM to identify a novel, low-populated MSA filament subtype (designated Type I<sub>2</sub>) in addition to a predominant class comprising MSA Type II<sub>2</sub> filaments. The 3.3-Å resolution structure of the Type I<sub>2</sub> filament reveals a fold consisting of two asymmetric protofilaments, one of which adopts a novel structure that is chimeric between two previously reported protofilaments. These results further define MSA-specific folds of α-synuclein filaments and have implications for designing MSA diagnostics and therapeutics.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cryo-EM structures of the zinc transporters ZnT3 and ZnT4 provide insights into their transport mechanisms.","authors":"Hanako Ishida, Riri Yo, Zhikuan Zhang, Toshiyuki Shimizu, Umeharu Ohto","doi":"10.1002/1873-3468.15047","DOIUrl":"https://doi.org/10.1002/1873-3468.15047","url":null,"abstract":"<p><p>Zinc transporters (ZnTs) act as H<sup>+</sup>/Zn<sup>2+</sup> antiporters, crucial for zinc homeostasis. Brain-specific ZnT3 expressed in synaptic vesicles transports Zn<sup>2+</sup> from the cytosol into vesicles and is essential for neurotransmission, with ZnT3 dysfunction associated with neurological disorders. Ubiquitously expressed ZnT4 localized to lysosomes facilitates the Zn<sup>2+</sup> efflux from the cytosol to lysosomes, mitigating the cell injury risk. Despite their importance, the structures and Zn<sup>2+</sup> transport mechanisms remain unclear. We characterized the three-dimensional structures of human ZnT3 (inward-facing) and ZnT4 (outward-facing) using cryo-electron microscopy. By combining these structures, we assessed the conformational changes that could occur within the transmembrane domain during Zn<sup>2+</sup> transport. Our results provide a structural basis for a more comprehensive understanding of the H<sup>+</sup>/Zn<sup>2+</sup> exchange mechanisms exhibited by ZnTs.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-10-27DOI: 10.1002/1873-3468.15040
Jigneshkumar A Mochi, Jaykumar Jani, Smit Shah, Anju Pappachan
{"title":"Leishmania donovani adenylosuccinate synthetase requires IMP for dimerization and organization of the active site.","authors":"Jigneshkumar A Mochi, Jaykumar Jani, Smit Shah, Anju Pappachan","doi":"10.1002/1873-3468.15040","DOIUrl":"https://doi.org/10.1002/1873-3468.15040","url":null,"abstract":"<p><p>Adenylosuccinate synthetase (AdSS), which catalyses the GTP-dependent conversion of inosine monophosphate (IMP) and aspartic acid to succinyl-AMP, plays a major role in purine biosynthesis. In some bacterial AdSS, it is implicated that IMP binding is important to organize the active site, but in certain plant AdSS, GTP performs this role. Here, we report that in Leishmania donovani AdSS, IMP binding favoured dimerization, induced greater conformational change and improved the protein stability more than GTP binding. IMP binding, which resulted in a network of hydrogen bonds, stabilized the conformation of active site loops and brought the switch loop to a closed conformation, which then facilitated GTP binding. Our results provide a basis for designing better inhibitors of leishmanial AdSS.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-10-27DOI: 10.1002/1873-3468.15036
Anqi Dong, Masao Yoshizumi, Hiroki Kokubo
{"title":"Odz4 upregulates SAN-specific genes to promote differentiation into cardiac pacemaker-like cells.","authors":"Anqi Dong, Masao Yoshizumi, Hiroki Kokubo","doi":"10.1002/1873-3468.15036","DOIUrl":"https://doi.org/10.1002/1873-3468.15036","url":null,"abstract":"<p><p>Cardiac arrhythmias stemming from abnormal sinoatrial node (SAN) function can lead to sudden death. Developing a biological pacemaker device for treating sick sinus syndrome (SSS) could offer a potential cure. Understanding SAN differentiation is crucial, yet its regulatory mechanism remains unclear. We reanalyzed published RNA-seq data and identified Odz4 as a SAN-specific candidate. In situ hybridization revealed Odz4 expression in the cardiac crescent and throughout the cardiac conduction system (CCS). To assess the role of Odz4 in CCS differentiation, we utilized a Tet-Off inducible system for its intracellular domain (ICD). Embryonic bodies (EBs) exogenously expressing Odz4-ICD exhibited an increased propensity to develop into pacemaker-like cells with enhanced automaticity and upregulated expression of SAN-specific genes. CellChat and GO analyses unveiled SAN-specific enrichment of ligand-receptor sets, especially Ptn-Ncl, and extracellular matrix components in the group exogenously expressing Odz4-ICD. Our findings underscore the significance of Odz4 in SAN development and offer fresh insights into biological pacemaker establishment.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-10-24DOI: 10.1002/1873-3468.15045
Barnava Banerjee, Chinmay K Kamale, Abhishek B Suryawanshi, Subrata Dasgupta, Santosh Noronha, Prasenjit Bhaumik
{"title":"Crystal structures of Aspergillus oryzae exo-β-(1,3)-glucanase reveal insights into oligosaccharide binding, recognition, and hydrolysis.","authors":"Barnava Banerjee, Chinmay K Kamale, Abhishek B Suryawanshi, Subrata Dasgupta, Santosh Noronha, Prasenjit Bhaumik","doi":"10.1002/1873-3468.15045","DOIUrl":"https://doi.org/10.1002/1873-3468.15045","url":null,"abstract":"<p><p>Exo-β-(1,3)-glucanases are promising enzymes for use in the biofuel industry as they hydrolyse sugars such as laminarin, a major constituent of the algal cell wall. This study reports structural and biochemical characterizations of Aspergillus oryzae exo-β-(1,3)-glucanase (AoBgl) belonging to the GH5 family. Purified AoBgl hydrolyses β-(1,3)-glycosidic linkages of the oligosaccharide laminaritriose and the polysaccharide laminarin effectively. We have determined three high-resolution structures of AoBgl: (a) the apo form at 1.75 Å, (b) the complexed form with bound cellobiose at 1.73 Å and (c) the glucose-bound form at 1.20 Å. The crystal structures, molecular dynamics simulation studies and site-directed mutagenesis reveal the mode of substrate binding and interactions at the active site. The results also indicate that AoBgl effectively hydrolyses trisaccharides and higher oligosaccharides. The findings from our structural and biochemical studies would aid in rational engineering efforts to generate superior AoBgl variants and similar GH5 enzymes for their industrial use.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}