{"title":"Macrophage metabolic reprogramming during dietary stress influences adult body size in Drosophila.","authors":"Anusree Mahanta, Sajad Ahmad Najar, Nivedita Hariharan, Ajit Bhowmick, Syed Iqra Rizvi, Manisha Goyal, Preethi Parupalli, Ramaswamy Subramanian, Angela Giangrande, Dasaradhi Palakodeti, Tina Mukherjee","doi":"10.1038/s44319-025-00574-7","DOIUrl":"https://doi.org/10.1038/s44319-025-00574-7","url":null,"abstract":"<p><p>Immune cells are increasingly recognized as nutrient sensors; however, their developmental role in regulating growth under homeostasis or dietary stress remains elusive. Here, we show that Drosophila larval macrophages, in response to excessive dietary sugar (HSD), reprogram their metabolic state by activating glycolysis, thereby enhancing TCA-cycle flux, and increasing lipogenesis-while concurrently maintaining a lipolytic state. Although this immune-metabolic configuration correlates with growth retardation under HSD, our genetic analyses reveal that enhanced lipogenesis supports growth, whereas glycolysis and lipolysis are growth-inhibitory. Notably, promoting immune-driven lipogenesis offsets early growth inhibition in imaginal discs caused by glycolytic and lipolytic immune-metabolic states. Our findings reveal a model of immune-metabolic imbalance, where growth-suppressive states (glycolysis, lipolysis) dominate over a growth-supportive lipogenic state, thereby impairing early organ size control and ultimately affecting adult size. Overall, this study provides important insights into dietary stress-induced immune-metabolic reprogramming and its link to organ size regulation and early developmental plasticity.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-09-08DOI: 10.1038/s44319-025-00575-6
Sunil Kumar Pradhan, Hui Zhang, Ksenia G Kolobynina, Alexander Rapp, Maria Arroyo, M Cristina Cardoso
{"title":"Dynamic association of H3K36me3 with pericentromeric heterochromatin regulates its replication time.","authors":"Sunil Kumar Pradhan, Hui Zhang, Ksenia G Kolobynina, Alexander Rapp, Maria Arroyo, M Cristina Cardoso","doi":"10.1038/s44319-025-00575-6","DOIUrl":"https://doi.org/10.1038/s44319-025-00575-6","url":null,"abstract":"<p><p>The flexibility of the spatio-temporal genome replication program during development and disease highlights the regulatory role of plastic epigenetic mechanisms over genetic determinants. Histone post-translational modifications are broadly implicated in replication timing control, yet the specific mechanisms through which individual histone marks influence replication dynamics, particularly in heterochromatin, remain unclear. Here, we demonstrate that H3K36me3 dynamically enriches at pericentromeric heterochromatin, composed of major satellite DNA repeats, prior to replication during mid S phase in mouse embryonic stem cells. By knocking down lysine 36-specific methyltransferases or by targeting the H3K36M oncohistone to pericentromeric heterochromatin, we reduce global or local H3K36me3 levels, respectively, revealing its essential role in preserving the replication timing of constitutive heterochromatin. Loss of H3K36me3 accompanies increased RNA polymerase II serine-5 phosphorylation and lowered major satellite RNA levels, indicating transcriptional dysregulation. Notably, we identify a strand-specific contribution of major satellite forward transcripts in regulating the replication timing of constitutive heterochromatin and maintaining chromatin stability, highlighting the importance of non-coding RNAs as critical regulators of replication timing.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-09-04DOI: 10.1038/s44319-025-00569-4
Yan Liang, Jingcheng Wei, Yue Kang, Allan M Carrillo-Baltodano, José M Martín-Durán
{"title":"Cell fate specification modes shape transcriptome evolution in the highly conserved spiral cleavage.","authors":"Yan Liang, Jingcheng Wei, Yue Kang, Allan M Carrillo-Baltodano, José M Martín-Durán","doi":"10.1038/s44319-025-00569-4","DOIUrl":"https://doi.org/10.1038/s44319-025-00569-4","url":null,"abstract":"<p><p>Early animal development can be remarkably variable, influenced by lineage-specific reproductive strategies and adaptations. Yet, early embryogenesis is also strikingly conserved in certain groups, such as Spiralia. In this clade, a shared cleavage program (i.e., spiral cleavage) and similar cell lineages are ancestral to at least seven phyla. Why early development is so conserved in specific groups and plastic in others is not fully understood. Here, we investigated two annelid species (Owenia fusiformis and Capitella teleta) with spiral cleavage but different modes of specifying their primary progenitor cells. By generating high-resolution transcriptomic time courses from the oocyte to gastrulation, we demonstrate that transcriptional dynamics differ markedly between these species during spiral cleavage and instead reflect their distinct timings of embryonic organiser specification. However, the end of cleavage and gastrulation exhibit high transcriptomic similarity, when orthologous transcription factors share gene expression domains, suggesting this period is a previously overlooked mid-developmental transition in annelid embryogenesis. Together, our data reveal hidden transcriptomic plasticity during spiral cleavage, indicating an evolutionary decoupling of morphological and transcriptomic conservation during early embryogenesis.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-09-01Epub Date: 2025-07-30DOI: 10.1038/s44319-025-00538-x
Jing-Jing Duan, Bin Jiang, Wei Yin, Yuan Lin, Guang-Mei Yan, Wei Lu
{"title":"Cell-autonomous GABAARs are essential for NMDAR-mediated synaptic transmission, LTP, and spatial memory.","authors":"Jing-Jing Duan, Bin Jiang, Wei Yin, Yuan Lin, Guang-Mei Yan, Wei Lu","doi":"10.1038/s44319-025-00538-x","DOIUrl":"10.1038/s44319-025-00538-x","url":null,"abstract":"<p><p>GABA<sub>A</sub> receptors (GABA<sub>A</sub>Rs) mediate most synaptic inhibition in the brain, but their cell-autonomous role in regulating glutamatergic transmission remains poorly understood. By targeting GABA<sub>A</sub>R β1-3 subunit alleles (GABRB1-3) at once, we genetically eliminated GABA<sub>A</sub>Rs in individual hippocampal CA1 pyramidal neurons. We find that single-cell silencing of GABAergic transmission does not alter AMPAR-mediated synaptic transmission, but leads to a reduction in NMDAR-mediated synaptic transmission, loss of long-term potentiation (LTP), and impaired spatial memory. Genetic rescue experiments reveal that NMDAR-mediated whole-cell currents and synaptic transmission depend on specific GABA<sub>A</sub>R subtypes and are tightly regulated by neuronal excitability. Pharmacologically restoring NMDAR function in β123-CRISPR mice rescues both LTP and spatial memory deficits induced by the loss of GABA<sub>A</sub>Rs in CA1 neurons. Our data uncover a previously unknown regulation of synaptic NMDAR functions by GABA<sub>A</sub>Rs at the single-cell level and provide insight into excitation and inhibition balance between GABA<sub>A</sub>Rs and NMDARs in the brain.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4456-4476"},"PeriodicalIF":6.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12457689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-09-01Epub Date: 2025-07-15DOI: 10.1038/s44319-025-00523-4
Reinis R Ruza, Chyi Wei Chung, Danny B H Gold, Michela Serena, Emile Roberts, Ulrike Gruneberg, Francis A Barr
{"title":"A pivot-tether model for nucleosome recognition by the chromosomal passenger complex.","authors":"Reinis R Ruza, Chyi Wei Chung, Danny B H Gold, Michela Serena, Emile Roberts, Ulrike Gruneberg, Francis A Barr","doi":"10.1038/s44319-025-00523-4","DOIUrl":"10.1038/s44319-025-00523-4","url":null,"abstract":"<p><p>Spatial restriction of Aurora B to T3-phosphorylated histone H3 (H3pT3) nucleosomes adjacent to centromeres during prometaphase and metaphase enables it to phosphorylate proteins necessary for spindle assembly checkpoint signalling and biorientation of chromosomes on the mitotic spindle. Aurora B binding to H3pT3-nucleosomes requires a multivalent targeting module, the chromosomal passenger complex (CPC), consisting of survivin, borealin, and INCENP. To shed light on how these components mediate CPC localisation during prometaphase and metaphase, we determined the structure of the CPC targeting module in complex with haspin-phosphorylated H3pT3-nucleosomes by cryo-electron microscopy. This structure shows how the N-terminus of borealin and the survivin BIR domain act as pivot and flexible tethering points, respectively, to increase CPC affinity for H3pT3 nucleosomes without limiting it to a specific orientation. We demonstrate that this flexible, yet constrained pivot-tether arrangement is important for the control of spindle assembly checkpoint signalling by Aurora B.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4219-4247"},"PeriodicalIF":6.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12420818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-09-01Epub Date: 2025-07-17DOI: 10.1038/s44319-025-00524-3
Wenbo Li, Juan Zhang, Qiang Liu
{"title":"Kin17 promotes rDNA transcription, ribosomal biogenesis, and cortical lamination.","authors":"Wenbo Li, Juan Zhang, Qiang Liu","doi":"10.1038/s44319-025-00524-3","DOIUrl":"10.1038/s44319-025-00524-3","url":null,"abstract":"<p><p>During brain development, neural progenitor cells (NPCs) undergo rapid division, necessitating efficient ribosomal biogenesis for proliferation. Yet, the regulatory mechanisms remain largely elusive. Here, we report that the DNA binding protein Kin17 exhibits development-dependent expression and plays a vital role in embryonic development. Complete loss of Kin17 in mice leads to embryonic lethality, while Kin17 depletion specifically in NPCs allows embryonic survival but results in reduced brain size and cortical lamination defects. Our findings demonstrate that these cortical malformation stems from impaired NPC proliferation and differentiation. Mechanistically, we show that Kin17 binds to the promoter region of rDNA, sequentially recruiting NCL and Polr1a, thereby promoting rDNA transcription. Consequently, Kin17 facilitates ribosome biogenesis and protein translation in NPCs. This study underscores a critical role of Kin17 in promoting rDNA transcription and ribosomal biogenesis in NPCs during brain development, which is essential for proper cortical lamination.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4283-4311"},"PeriodicalIF":6.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12420808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-09-01Epub Date: 2025-08-15DOI: 10.1038/s44319-025-00547-w
Frédérique Pompeo, Elodie Foulquier, Arnaud Chastanet, Leon Espinosa, Cyrille Billaudeau, Anthony Rodrigues, Charlène Cornilleau, Rut Carballido-López, Anne Galinier
{"title":"RagB stimulates the activity of the peptidoglycan polymerase RodA in Bacillus subtilis.","authors":"Frédérique Pompeo, Elodie Foulquier, Arnaud Chastanet, Leon Espinosa, Cyrille Billaudeau, Anthony Rodrigues, Charlène Cornilleau, Rut Carballido-López, Anne Galinier","doi":"10.1038/s44319-025-00547-w","DOIUrl":"10.1038/s44319-025-00547-w","url":null,"abstract":"<p><p>The bacterial cell wall is primarily composed of peptidoglycan (PG), a polymer essential for its protective envelope function, and any defect in its synthesis or repair can potentially result in bacterial lysis. Class A Penicillin-Binding Proteins (aPBPs) and Shape, Elongation, Division, and Sporulation (SEDS) proteins are PG polymerases acting in concert to ensure bacterial cell wall growth. Here, we identify the first regulator of the SEDS protein RodA in the Gram-positive model bacterium Bacillus subtilis. In the presence of the antibiotic moenomycin, which specifically inhibits glycosyltransferase activity of aPBPs, or in a strain deleted for all four aPBPs, bacterial survival depends on the presence of the YrrS protein (renamed RagB) and can be rescued by overexpression of RodA. No effect of RagB is observed on the rodA gene expression level or on the speed of circumferentially moving RodA associated with PG elongation by the Rod complex. However, we demonstrate that RagB interacts with RodA. We propose that RagB stimulates RodA activity and becomes essential in the absence of aPBPs and in particular of the major aPBP, PBP1.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4587-4606"},"PeriodicalIF":6.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12457691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"STING inhibits LINE-1 retrotransposition through sorting ORF1p to lysosomes for degradation.","authors":"Yu Huang, Fengwen Xu, Lingwa Wang, Shan Mei, Fei Zhao, Liming Wang, Yu Xie, Liang Wei, Yamei Hu, Zhao Gao, Tiffany Xue, Jugao Fang, Fei Guo","doi":"10.1038/s44319-025-00551-0","DOIUrl":"10.1038/s44319-025-00551-0","url":null,"abstract":"<p><p>The cyclic dinucleotide sensor stimulator of interferon (IFN) genes (STING) is known for its critical role in interferon and inflammatory responses. In addition, STING also has functions independent of interferon induction. In this study, we report that STING restricts the mobilization of the cellular retrotransposon long interspersed nuclear element 1 (LINE-1) independent of cGAS and interferon induction. LINE-1 is the only active autonomous retrotransposable element in the human genome and its transposition can cause genetic and autoimmune diseases. STING inhibition of LINE-1 requires its dimerization. Mechanistically, STING interacts with LINE-1 ORF1p, then the complex translocates to the ER-Golgi intermediate compartment (ERGIC) and the Golgi followed by sorting to Rab7-positive lysosomes for degradation. Our data unveil a function of STING in maintaining host genome integrity by restricting LINE-1 retrotransposition via an IFN-independent mechanism.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4607-4630"},"PeriodicalIF":6.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12457603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144872010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-09-01Epub Date: 2025-08-11DOI: 10.1038/s44319-025-00541-2
Na Jiang, Jing Wu, Yating He, Rui Zhang, Mengmeng Ji, Linjing Zhu, Shengwei Cui, Qiao You, Yurong Cai, Bingxin Liu, Ruining Lyu, Yuxin Chen, Jin Zhu, Zhiwei Wu
{"title":"sVEGFR1 up-regulation via EGR1 impairs vascular repair in SFTSV-induced hemorrhage.","authors":"Na Jiang, Jing Wu, Yating He, Rui Zhang, Mengmeng Ji, Linjing Zhu, Shengwei Cui, Qiao You, Yurong Cai, Bingxin Liu, Ruining Lyu, Yuxin Chen, Jin Zhu, Zhiwei Wu","doi":"10.1038/s44319-025-00541-2","DOIUrl":"10.1038/s44319-025-00541-2","url":null,"abstract":"<p><p>Hemorrhage is a major pathological manifestation of certain viral infections, such as severe fever with thrombocytopenia syndrome (SFTS), Ebola, Crimean-Congo hemorrhagic fever and Dengue. SFTS is an emerging viral hemorrhagic fever caused by the SFTS virus (SFTSV). Hemorrhage and angiogenesis dysfunction are key manifestations of SFTSV infection but the underlying mechanisms remain unclear. Here, we demonstrate that SFTSV infection increases soluble vascular endothelial growth factor-receptor 1 (sVEGFR1) secretion from monocytes/macrophages. Increased sVEGFR1 in the serum of SFTS patients is positively correlated with disease severity. Moreover, we show that SFTSV induces sVEGFR1 upregulation via early growth response gene 1 (EGR1), of which VEGFR1 is a downstream target. Serum from SFTS patients containing high levels of sVEGFR1 inhibit angiogenesis, which can be reversed by removal of sVEGFR1. Treatment of SFTSV-infected animals with sVEGFR1 neutralizing antibodies improves angiogenesis and prevents blood vessel leaks in vivo. In conclusion, we show that SFTSV infection induces sVEGFR1 secretion through EGR1 upregulation, thereby contributing to hemorrhage.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4477-4502"},"PeriodicalIF":6.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12457690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}