FEBS LettersPub Date : 2025-08-29DOI: 10.1002/1873-3468.70149
Jie Wang, Ju Liu
{"title":"Circulating endothelial cells: the role in aging and brain pathology.","authors":"Jie Wang, Ju Liu","doi":"10.1002/1873-3468.70149","DOIUrl":"https://doi.org/10.1002/1873-3468.70149","url":null,"abstract":"<p><p>Circulating endothelial cells (CECs) are mature vascular cells found in peripheral blood, originating from the vascular wall. Normally, they are present in low numbers in the body. CECs are released into the blood during tissue turnover or vascular injury from various factors. In diseased patients, blood often has a higher and variable CEC concentration. Changes in CEC count can serve as a biomarker, indicating conditions involving endothelial cell changes, including hematological diseases. They reflect disease progression, predict treatment response, and prognosis in disease therapy. CECs serve a purpose and are thought to contribute to endothelial damage, revealing changes in the prognosis of disease in elderly patients and those with brain disorders. Additionally, CECs act as biomarkers for tumor vascular damage and therapy monitoring in cancers like glioblastoma. To understand their role as disease markers in brain and elderly patients, it is important to study CECs under pathological conditions. This review details the relationship between CECs, aging, and brain disorders and provides insights for prevention and treatment.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948099","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 : 2025-08-29DOI: 10.1002/1873-3468.70154
Alberto Angrisani, Maria Furia
{"title":"A working model for cytoplasmic assembly of H/ACA snoRNPs.","authors":"Alberto Angrisani, Maria Furia","doi":"10.1002/1873-3468.70154","DOIUrl":"https://doi.org/10.1002/1873-3468.70154","url":null,"abstract":"<p><p>Pseudouridylation occurs on all types of cellular RNAs. As a catalytic component of nuclear H/ACA ribonucleoproteins (RNPs), the pseudouridine synthase dyskerin exerts a general impact on multiple fundamental cellular processes. Although this protein has been investigated in detail, its cytoplasmic roles have been largely overlooked, despite the identification of a minor splice variant showing a prevalent cytoplasmic localization. In this perspective, we discuss the role of this minor isoform in the composition, assembly, and function of H/ACA RNPs. On this basis, we propose a model in which cytoplasmic regulation modulates the integration of distinct dyskerin isoforms within preassembly complexes, consequently also influencing their nuclear import. This mechanism could govern pseudouridylation, cellular growth, and mRNA translation. Impact statement Human Dyskerin is the pseudouridine-synthase component of H/ACA RNPs. Two isoforms have been characterized: the abundant Iso1, mainly nuclear, and Iso3, mainly cytoplasmic but occasionally imported into nuclei. We propose a model accounting for a regulated participation of both isoforms in the cytoplasmic pre-assembly of H/ACA RNPs.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948119","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 : 2025-08-27DOI: 10.1002/1873-3468.70148
Bianca J M Sansom, Victoria J Gibbs, Anja H Schiemann, Evelyn Sattlegger
{"title":"Mutational analysis of Yih1 and IMPACT reveals amino acids required for Gcn2 inhibition.","authors":"Bianca J M Sansom, Victoria J Gibbs, Anja H Schiemann, Evelyn Sattlegger","doi":"10.1002/1873-3468.70148","DOIUrl":"https://doi.org/10.1002/1873-3468.70148","url":null,"abstract":"<p><p>In response to amino acid starvation, the protein kinase Gcn2 phosphorylates the eukaryotic translation initiation factor eIF2α, allowing cells to adapt to adverse conditions. Gcn2 function requires direct binding to effector protein Gcn1 via the Gcn2 RWD-domain. The orthologues yeast Yih1 and mammalian IMPACT also contain an RWD-domain that can bind Gcn1, thereby impairing the Gcn2-Gcn1 interaction. In yeast, overexpressed Yih1/IMPACT impairs eIF2α phosphorylation, visible by reduced growth under starvation conditions. We found that Yih1 D102A and D108A substitutions each revert this defect, suggesting that Yih1-mediated Gcn2 inhibition is impaired. Similar effects were found for at least the D111A substitution in IMPACT. The respective amino acids are located in a common helix, suggesting this helix is a conserved determinant for Gcn1 binding.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948109","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 : 2025-08-25DOI: 10.1002/1873-3468.70123
Grant R Broomfield, Torsten Kleffmann, David J Saul, Sigurd M Wilbanks
{"title":"Thermostable neutral metalloprotease from Geobacillus sp. EA1 does not share thermolysin's preference for substrates with leucine at the P1' position.","authors":"Grant R Broomfield, Torsten Kleffmann, David J Saul, Sigurd M Wilbanks","doi":"10.1002/1873-3468.70123","DOIUrl":"https://doi.org/10.1002/1873-3468.70123","url":null,"abstract":"<p><p>Cleavage preference determines suitability of proteases for different applications. The cleavage preference of a thermophilic neutral metalloprotease (npr) from Geobacillus sp. EA1 was characterised using mass spectrometry, confirming its similarity to thermolysin in preferring P1' hydrophobic amino acids. While EA1 npr showed similar efficiencies while cleaving short peptides with any one of six hydrophobic amino acids at the P1' position, thermolysin showed marked preference for leucine. A single amino acid difference in the S1' pocket of these enzymes underlies this difference. A variant of EA1 npr (F133L) had intermediate preference, suggesting that approximately half the difference is attributable to this single amino acid change. Broader preference and higher efficiency make EA1 npr a superior candidate for quick digestion of varied substrates. Impact statement This investigation supported two new, useful conclusions. It characterised for the first time the substrate preference of EA1, a commercially significant protease. In the course of comparison to the very well-studied thermolysin, a hitherto unknown subtlety of thermolysin's substrate preference (marked preference for leucine) was found.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948044","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 : 2025-08-25DOI: 10.1002/1873-3468.70150
Yang Liu, Aziz Sancar
{"title":"Biochemical mechanism of the mammalian circadian clock.","authors":"Yang Liu, Aziz Sancar","doi":"10.1002/1873-3468.70150","DOIUrl":"https://doi.org/10.1002/1873-3468.70150","url":null,"abstract":"<p><p>Circadian rhythms, regulated by core clock proteins, coordinate physiological functions with daily environmental fluctuations across organisms, from bacteria to humans. The circadian clock interacts with various biological processes, and its disruption is associated with numerous human diseases, including sleep disorders, metabolic syndrome, and potentially cancer. In mammals, the circadian clock is driven by cell-autonomous transcription-translation feedback loops (TTFLs), in which CLOCK and BMAL1 act as transcriptional activators, while PER and CRY serve as transcriptional repressors. During the early repression phase, the CRY-PER-CK1 complex binds to CLOCK-BMAL1, displacing it from target promoters. In the late repression phase, in the absence of PER, CRY1 alone inhibits CLOCK-BMAL1 activity by blocking the recruitment of transcriptional coactivators. Biochemical and structural studies have highlighted the essential roles of protein-protein interactions, protein-DNA interactions, and posttranslational modifications in regulating the molecular clock. In this Review, we summarize the molecular mechanisms that govern the circadian clock and focus on the coordination of protein-protein interactions and posttranslational modifications, underscoring the importance of the circadian clock in disease progression and treatment strategies.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2025-08-21DOI: 10.1002/1873-3468.70145
Hanne Peeters, Shehab Ismail
{"title":"Spatial regulation of ARL3 and GSF-mediated lipidated cargo trafficking in the primary cilium.","authors":"Hanne Peeters, Shehab Ismail","doi":"10.1002/1873-3468.70145","DOIUrl":"https://doi.org/10.1002/1873-3468.70145","url":null,"abstract":"<p><p>Lipid-modified proteins are essential for ciliary signaling and structure, but their hydrophobic modifications hinder cytosolic transport and selective delivery. GDI-like solubilizing factors (GSFs), such as PDE6D and UNC119A/B, bind lipid moieties to shield cargo proteins and enable diffusion. However, the mechanisms that govern spatially restricted cargo release-particularly at the primary cilium-are not fully elucidated yet. In this Review, we highlight the central role of the small G protein ARL3 and its regulators in mediating selective release of lipidated cargoes. We discuss ARL13B, a ciliary-localized guanine nucleotide exchange factor (GEF) for ARL3, and BART, a co-GEF that enhances ARL3 activation by relieving autoinhibition. In contrast, RP2, a GTPase-activating protein (GAP) at the ciliary base, likely inactivates ARL3 outside the cilium, establishing a spatial ARL3·GTP gradient that restricts cargo release. Additional specificity arises from ARL2 exclusion from the cilium, differential GSF-cargo binding affinities, and putative docking platforms such as RPGR. Disruption of this pathway is implicated in ciliopathies, including Joubert syndrome. Current models and recent findings provide a framework for understanding spatial GTPase signaling in ciliary transport.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947938","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 : 2025-08-20DOI: 10.1002/1873-3468.70146
Torkel Berglund, Anna B Ohlsson
{"title":"The nicotinamide hypothesis revisited-plant defense signaling integrating PARP, nicotinamide, nicotinic acid, epigenetics, and glutathione.","authors":"Torkel Berglund, Anna B Ohlsson","doi":"10.1002/1873-3468.70146","DOIUrl":"https://doi.org/10.1002/1873-3468.70146","url":null,"abstract":"<p><p>A previously presented hypothesis, here updated, proposed nicotinamide produced by the activity of poly(ADP-ribose) polymerase (PARP) as a stress signaling compound in plants. PARP activation by DNA strand breaks caused by oxidative stress leads to the metabolization of NAD to ADP-ribose units and nicotinamide. Also, NAD-degrading histone deacetylases (sirtuins) produce nicotinamide. We suggest that nicotinamide, either alone or acting through its metabolite nicotinic acid, will generate epigenetic changes in the plant. We propose that this is an early step in a general stress response, making the DNA more accessible to the transcription machinery and specific stress signaling substances to activate the defense genes needed for the present stress situation. The role of glutathione in this context is discussed.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144948026","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 : 2025-08-19DOI: 10.1002/1873-3468.70144
Chong Zhang, Zhiting Feng, Min Yang, Peiqing Cong, Xiaohong Liu, Yaosheng Chen, Zuyong He
{"title":"Kit structural mutations associated with the porcine dominant white phenotype impair hematopoiesis in mice.","authors":"Chong Zhang, Zhiting Feng, Min Yang, Peiqing Cong, Xiaohong Liu, Yaosheng Chen, Zuyong He","doi":"10.1002/1873-3468.70144","DOIUrl":"10.1002/1873-3468.70144","url":null,"abstract":"<p><p>Kit encodes a receptor tyrosine kinase crucial for various biological processes. To investigate how Kit structural mutations associated with the porcine dominant white phenotype affect hematopoiesis, we utilized three distinct gene-edited mouse models: Kit coding sequence (CDS) duplication (Kit<sup>dup/+</sup>), Kit exon 17 deletion (Kit<sup>D17/+</sup>), and a compound heterozygous model carrying both mutations (Kit<sup>dup/D17</sup>), along with wild-type controls (Kit<sup>+/+</sup>). We observed that the Kit structural mutations significantly impaired erythropoiesis in bone marrow, resulting in hypoplastic macrocytic anemia and compensatory erythropoiesis in the spleen. Transcriptomic analyses revealed that these structural Kit mutations attenuate PI3K and MAPK signaling activation and downregulate genes essential for erythroid differentiation. Our findings provide novel mechanistic insights into how Kit mutations contribute to hematopoietic dysfunction.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144872174","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 : 2025-08-13DOI: 10.1002/1873-3468.70142
M Florencia Sampedro, Marta E Sian, Paulo E Cabral Filho, Adriana Fontes, Valeria Sigot
{"title":"EGTA-induced disruption of adherens junctions in zebrafish embryonic epidermis.","authors":"M Florencia Sampedro, Marta E Sian, Paulo E Cabral Filho, Adriana Fontes, Valeria Sigot","doi":"10.1002/1873-3468.70142","DOIUrl":"https://doi.org/10.1002/1873-3468.70142","url":null,"abstract":"<p><p>Zebrafish epidermis is an accessible tissue to evaluate the impact of drugs on epithelial integrity. Although ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA E3889, Sigma-Aldrich, CABA-Argentina), a calcium chelator, is widely used to disrupt epithelial monolayers in vitro, its application to zebrafish in vivo remains limited. We found that short-term exposure to EGTA induced tail damage ranging from minor and reversible to severe and lethal; at the tissue level, it caused disruption of cadherin-mediated cell-cell contacts and of the barrier function in the epidermis. Labeling with fluorescent quantum dots (QDs) enabled rapid characterization of damage severity, evidencing the disappearance of actin microridges in the enveloping layer. At least 15 min exposure to 25 mM EGTA induces reversible epithelial disruption at the pharyngula stage, providing a chemical model to study healing and regeneration in zebrafish embryos.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144845058","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 : 2025-08-13DOI: 10.1002/1873-3468.70134
Takashi Nobusawa, Makoto Kusaba
{"title":"The multidrug and toxin extrusion (MATE) transporter DTX51 antagonizes non-cell-autonomous HLS1-AMP1 signaling in a region-specific manner.","authors":"Takashi Nobusawa, Makoto Kusaba","doi":"10.1002/1873-3468.70134","DOIUrl":"https://doi.org/10.1002/1873-3468.70134","url":null,"abstract":"<p><p>Multidrug and toxin extrusion (MATE) transporters are widely conserved across all domains of life and play diverse roles in plant development. Here, we investigated the role of DETOXIFICATION 51 (DTX51), a MATE transporter in Arabidopsis. Overexpression of DTX51 led to pleiotropic phenotypes resembling those of hls1 hlh1 and amp1 lamp1 loss-of-function mutants, which have disruptions of key developmental regulators that act non-cell-autonomously. Genetic and gene expression analyses revealed that DTX51 and HLS1 act within the same genetic pathway, forming a negative feedback loop at the transcriptional level. Spatially restricted overexpression experiments showed that, in contrast to HLS1 and AMP1, DTX51 acts in a region-specific manner within the shoot apical meristem, suggesting that DTX51 fine-tunes development locally by modulating non-cell-autonomous signals. Impact statement This study reveals a role of the MATE transporter DTX51, whose transport substrate remains unknown, in Arabidopsis development, providing new insights into how this transporter fine-tunes non-cell-autonomous signals generated by the HLS1-AMP1 module.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947945","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}