The EMBO JournalPub Date : 2025-04-29DOI: 10.1038/s44318-025-00443-y
Anna D Biela,Jakub S Nowak,Artur P Biela,Sunandan Mukherjee,Seyed Naeim Moafinejad,Satyabrata Maiti,Andrzej Chramiec-Głąbik,Rahul Mehta,Jakub Jeżowski,Dominika Dobosz,Priyanka Dahate,Veronique Arluison,Frank Wien,Paulina Indyka,Michal Rawski,Janusz M Bujnicki,Ting-Yu Lin,Sebastian Glatt
{"title":"Determining the effects of pseudouridine incorporation on human tRNAs.","authors":"Anna D Biela,Jakub S Nowak,Artur P Biela,Sunandan Mukherjee,Seyed Naeim Moafinejad,Satyabrata Maiti,Andrzej Chramiec-Głąbik,Rahul Mehta,Jakub Jeżowski,Dominika Dobosz,Priyanka Dahate,Veronique Arluison,Frank Wien,Paulina Indyka,Michal Rawski,Janusz M Bujnicki,Ting-Yu Lin,Sebastian Glatt","doi":"10.1038/s44318-025-00443-y","DOIUrl":"https://doi.org/10.1038/s44318-025-00443-y","url":null,"abstract":"Transfer RNAs (tRNAs) are ubiquitous non-coding RNA molecules required to translate mRNA-encoded sequence information into nascent polypeptide chains. Their relatively small size and heterogenous patterns of their RNA modifications have impeded the systematic structural characterization of individual tRNAs. Here, we use single-particle cryo-EM to determine the structures of four human tRNAs before and after incorporation of pseudouridines (Ψ). Following post-transcriptional modifications by distinct combinations of human pseudouridine synthases, we find that tRNAs become stabilized and undergo specific local structural changes. We establish interactions between the D- and T-arms as the key linchpin in the tertiary structure of tRNAs. Our structures of human tRNAs highlight the vast potential of cryo-EM combined with biophysical measurements and computational simulations for structure-function analyses of tRNAs and other small, folded RNA domains.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893186","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}
The EMBO JournalPub Date : 2025-04-28DOI: 10.1038/s44318-025-00445-w
Na Liu,Jia-Xin Li,Dan-Yang Yuan,Yin-Na Su,Pei Zhang,Qi Wang,Xiao-Min Su,Lin Li,Haitao Li,She Chen,Xin-Jian He
{"title":"Essential angiosperm-specific subunits of HDA19 histone deacetylase complexes in Arabidopsis.","authors":"Na Liu,Jia-Xin Li,Dan-Yang Yuan,Yin-Na Su,Pei Zhang,Qi Wang,Xiao-Min Su,Lin Li,Haitao Li,She Chen,Xin-Jian He","doi":"10.1038/s44318-025-00445-w","DOIUrl":"https://doi.org/10.1038/s44318-025-00445-w","url":null,"abstract":"Although the Arabidopsis thaliana RPD3-type histone deacetylase HDA19 and its close homolog HDA6 participate in SIN3-type histone deacetylase complexes, they display distinct biological roles, with the reason for these differences being poorly understood. This study identifies three angiosperm-specific HDA19-interacting homologous proteins, termed HDIP1, HDIP2, and HDIP3 (HDIP1/2/3). These proteins interact with HDA19 and other conserved histone deacetylase complex components, leading to the formation of HDA19-containing SIN3-type complexes, while they are not involved in the formation of HDA6-containing complexes. While mutants of conserved SIN3-type complex components show phenotypes divergent from the hda19 mutant, the hdip1/2/3 mutant closely phenocopies the hda19 mutant with respect to development, abscisic acid response, and drought stress tolerance. Genomic and transcriptomic analyses indicate that HDIP1/2/3 and HDA19 co-occupy chromatin and jointly repress gene transcription, especially for stress-related genes. An α-helix motif within HDIP1 has the capacity to bind to nucleosomes and architectural DNA, and is required for its function in Arabidopsis plants. These findings suggest that the angiosperm SIN3-type complexes have evolved to include additional subunits for the precise regulation of histone deacetylation and gene transcription.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889301","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":"Rbm24a dictates mRNA recruitment for germ granule assembly in zebrafish.","authors":"Yizhuang Zhang,Jiasheng Wang,Hailing Fang,Shuqi Hu,Boya Yang,Jiayi Zhou,Raphaëlle Grifone,Panfeng Li,Tong Lu,Zhengyang Wang,Chong Zhang,Yubin Huang,Dalei Wu,Qianqian Gong,De-Li Shi,Ang Li,Ming Shao","doi":"10.1038/s44318-025-00442-z","DOIUrl":"https://doi.org/10.1038/s44318-025-00442-z","url":null,"abstract":"The germ granules are ribonucleoprotein (RNP) biomolecular condensates that determine the fate of primordial germ cells (PGCs) and serve as a model for studying RNP granule assembly. Here, we show that the maternal RNA-binding protein Rbm24a is a key factor governing the specific sorting of mRNAs into germ granules. Mechanistically, Rbm24a interacts with the germ plasm component Buc to dictate the specific recruitment of germ plasm mRNAs into phase-separated condensates. Germ plasm particles lacking Rbm24a and mRNAs fail to undergo kinesin-dependent transport toward cleavage furrows where small granules fuse into large aggregates. Therefore, the loss of maternal Rbm24a causes a complete degradation of the germ plasm and the disappearance of PGCs. These findings demonstrate that the Rbm24a/Buc complex functions as a nucleating organizer of germ granules, highlighting an emerging mechanism for RNA-binding proteins in reading and recruiting RNA components into a phase-separated protein scaffold.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885102","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}
The EMBO JournalPub Date : 2025-04-25DOI: 10.1038/s44318-025-00417-0
Robert A Bone,Molly P Lowndes,Silvia Raineri,Alba R Riveiro,Sarah L Lundregan,Morten Dall,Karolina Sulek,Jose A H Romero,Luna Malzard,Sandra Koigi,Indra J Heckenbach,Victor Solis-Mezarino,Moritz Völker-Albert,Catherine G Vasilopoulou,Florian Meier,Ala Trusina,Matthias Mann,Michael L Nielsen,Jonas T Treebak,Joshua M Brickman
{"title":"Altering metabolism programs cell identity via NAD+-dependent deacetylation.","authors":"Robert A Bone,Molly P Lowndes,Silvia Raineri,Alba R Riveiro,Sarah L Lundregan,Morten Dall,Karolina Sulek,Jose A H Romero,Luna Malzard,Sandra Koigi,Indra J Heckenbach,Victor Solis-Mezarino,Moritz Völker-Albert,Catherine G Vasilopoulou,Florian Meier,Ala Trusina,Matthias Mann,Michael L Nielsen,Jonas T Treebak,Joshua M Brickman","doi":"10.1038/s44318-025-00417-0","DOIUrl":"https://doi.org/10.1038/s44318-025-00417-0","url":null,"abstract":"Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS) triggered by the replacement of D-glucose by D-galactose in ESC media. Enhanced OXPHOS in turn activates NAD + -dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, which results in a robustly enhanced ESC phenotype. This exploitation of a NAD + /NADH coenzyme coupled to OXPHOS as a means of programming lineage-specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885453","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":"Inherent fast inactivation particle of Nav channels as a new binding site for a neurotoxin.","authors":"Xi Zhou,Haiyi Chen,Shuijiao Peng,Yuxin Si,Gaoang Wang,Li Yang,Qing Zhou,Minjuan Lu,Qiaoling Xie,Xi He,Meijing Wu,Xin Xiao,Xiaoqing Luo,Xujun Feng,Wenxing Wang,Sen Luo,Yaqi Li,Jiaxin Qin,Minzhi Chen,Qianqian Zhang,Weijun Hu,Songping Liang,Tingjun Hou,Zhonghua Liu","doi":"10.1038/s44318-025-00438-9","DOIUrl":"https://doi.org/10.1038/s44318-025-00438-9","url":null,"abstract":"Neurotoxins derived from animal venoms are indispensable tools for probing the structure and function of voltage-gated sodium (Nav) channels. Utilizing a novel centipede peptide toxin called rpTx1, we show that the \"inherent inactivation particle\" of Nav channels represents a binding site for a neurotoxin. The toxin comprises two functional domains: one for cell penetration and one for modulating Nav channel activity. After crossing the cell membrane, rpTx1 preferentially binds to and stabilizes the IFMT motif (the conserved core region of the fast inactivation particle in mammalian Nav channels) in the unbound state, preventing this motif from associating with its receptor site and thereby inhibiting the fast inactivation of Nav channels. This competition between rpTx1 and the receptor site for interacting with the IFMT motif may account for the higher activity of rpTx1 on Nav1.8 than on other Nav subtypes, given the weaker relative affinity between the receptor site and the IFMT motif of Nav1.8. Overall, this study should promote the investigation of the intracellular modulation of Nav channels by neurotoxins.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"91 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866572","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}
The EMBO JournalPub Date : 2025-04-22DOI: 10.1038/s44318-025-00440-1
Phi-Long Tran,Okhwa Kim,Cheol Hwangbo,Hyo-Jin Kim,Young-Myeong Kim,Jeong-Hyung Lee
{"title":"SDCBP/Syntenin-1 stabilizes BACH1 by disassembling the SCFFBXO22-BACH1 complex in triple-negative breast cancer.","authors":"Phi-Long Tran,Okhwa Kim,Cheol Hwangbo,Hyo-Jin Kim,Young-Myeong Kim,Jeong-Hyung Lee","doi":"10.1038/s44318-025-00440-1","DOIUrl":"https://doi.org/10.1038/s44318-025-00440-1","url":null,"abstract":"BACH1 is a redox-sensitive transcription factor facilitating tumor progression in triple-negative breast cancer (TNBC). However, the molecular mechanisms regulating BACH1 function in TNBC remain unclear. In this study, we demonstrate that SDCBP, a tandem-PDZ-domain protein, stabilizes BACH1 by disassembling the Skp1-Cullin1-FBXO22 (SCFFBXO22)-BACH1 complex via a heme/heme-oxygenase-1-independent manner in TNBC cells. Our data revealed that SDCBP and BACH1 expression show a significant positive correlation in TNBC cells and TNBC patients tumor tissues. Mechanistically, SDCBP via its PDZ1 domain disassembles the SCFFBXO22-BACH1 complex via its PDZ1 domain, thereby preventing BACH1 K48-linked polyubiquitination and proteasomal degradation. Knocking down SDCBP induces BACH1 degradation and downregulates expressions of BACH1-induced metastatic genes, thereby suppressing tumor progression in mice bearing TNBC tumors. Moreover, depleting SDCBP leads to upregulation of BACH1-repressed electron transport chain (ETC) genes, such as NDUFA4 and COX6B2, and increases mitochondrial activity, enhancing anti-tumor efficacy of metformin against TNBC both in vitro and in vivo. These data demonstrate a novel alternative mechanism for BACH1 stabilization mediated by SDCBP, implicating the SDCBP-BACH1 axis as a potential target for enhancing ETC inhibitor efficacy in TNBC combinational therapy.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"108 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866574","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}
The EMBO JournalPub Date : 2025-04-17DOI: 10.1038/s44318-025-00426-z
Nicola J Smyllie,Alex A Koch,Antony D Adamson,Andrew P Patton,Adam Johnson,James S Bagnall,Olivia Johnson,Qing-Jun Meng,Andrew S I Loudon,Michael H Hastings
{"title":"Quantitative measures of clock protein dynamics in the mouse suprachiasmatic nucleus extends the circadian time-keeping model.","authors":"Nicola J Smyllie,Alex A Koch,Antony D Adamson,Andrew P Patton,Adam Johnson,James S Bagnall,Olivia Johnson,Qing-Jun Meng,Andrew S I Loudon,Michael H Hastings","doi":"10.1038/s44318-025-00426-z","DOIUrl":"https://doi.org/10.1038/s44318-025-00426-z","url":null,"abstract":"The suprachiasmatic nucleus (SCN) synchronises circadian rhythmicity (~24 h) across the body. The SCN cell-autonomous clock is modelled qualitatively as a transcriptional-translational feedback loop (TTFL), with heteromeric complexes of transcriptional activator and repressor proteins driving cyclical gene expression. How these proteins really behave within the SCN, individually and in relation to each other, is poorly understood. Imaging SCN slices from a novel array of knock-in reporter mice, we quantify the dynamic behaviours of combined repressors PERIOD2 (PER2) and CRYPTOCHROME1 (CRY1), and activator BMAL1. We reveal a spectrum of protein-specific intracellular and spatiotemporal behaviours that run counter to the qualitative TTFL model. We also show that PER and CRY1 exert independent actions on TTFL oscillations, and that their individual stabilities play a critical role in SCN circadian dynamics. These results reveal a rich and unanticipated complexity in the dynamic behaviours and functions of endogenous circadian proteins, prompting re-appraisal of current transcriptional-translational feedback loop models of the suprachiasmatic nucleus.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849426","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}
The EMBO JournalPub Date : 2025-04-16DOI: 10.1038/s44318-025-00433-0
Nikita V Ivanisenko,Corinna König,Laura K Hillert-Richter,Maria A Feoktistova,Sabine Pietkiewicz,Max Richter,Diana Panayotova-Dimitrova,Thilo Kaehne,Inna N Lavrik
{"title":"Oligomerised RIPK1 is the main core component of the CD95 necrosome.","authors":"Nikita V Ivanisenko,Corinna König,Laura K Hillert-Richter,Maria A Feoktistova,Sabine Pietkiewicz,Max Richter,Diana Panayotova-Dimitrova,Thilo Kaehne,Inna N Lavrik","doi":"10.1038/s44318-025-00433-0","DOIUrl":"https://doi.org/10.1038/s44318-025-00433-0","url":null,"abstract":"The necrosome is the key macromolecular signaling platform initiating necroptosis, i.e., a RIPK1/RIPK3-dependent program of cell death with an important role in the control of inflammation in multicellular organisms. However, the composition and structure of the necrosome remain incompletely understood. Here we use biochemical assays, quantitative mass spectrometry, and AlphaFold modeling to decipher the composition and derive a structural model of the CD95L/BV6-induced necrosome. We identify RIPK1 as the central component of the necrosome, forming the core of this complex. In addition, AlphaFold modeling provides insights into the structural mechanisms underlying RIPK1 oligomerization, highlighting the critical role of type-II interactions between the Death Domains (DDs) of FADD and RIPK1 in the assembly of RIPK1-mediated complexes. The role of type-II DD interactions in necroptosis induction is further validated through structure-guided site-directed mutagenesis. Our findings could be useful for the pharmacological targeting of the necroptosis network to treat diseases associated with dysregulated cell death and inflammation.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846320","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":"Glutamylation of centrosomes ensures their function by recruiting microtubule nucleation factors.","authors":"Shi-Rong Hong,Yi-Chien Chuang,Wen-Ting Yang,Chiou-Shian Song,Hung-Wei Yeh,Bing-Huan Wu,I-Hsuan Lin,Po-Chun Chou,Shiau-Chi Chen,Lohitaksh Sharma,Jui-Chen Lu,Rou-Ying Li,Ya-Chu Chang,Kuan-Ju Liao,Hui-Chun Cheng,Won-Jing Wang,Lily Hui-Ching Wang,Yu-Chun Lin","doi":"10.1038/s44318-025-00435-y","DOIUrl":"https://doi.org/10.1038/s44318-025-00435-y","url":null,"abstract":"Centrosomes are tubulin-based organelles that undergo glutamylation, a post-translational modification that conjugates glutamic acid residues to tubulins. Although centrosomal glutamylation has been known for several decades, how this modification regulates centrosome structure and function remains unclear. To address this long-standing issue, we developed a method to spatiotemporally reduce centrosomal glutamylation by recruiting an engineered deglutamylase to centrosomes. We found that centrosome structure remains largely unaffected by centrosomal hypoglutamylation. Intriguingly, glutamylation physically recruits, via electrostatic forces, the NEDD1/CEP192/γ-tubulin complex to centrosomes, ensuring microtubule nucleation and proper trafficking of centriolar satellites. The consequent defect in centriolar satellite trafficking leads to reduced levels of the ciliogenesis factor Talpid3, suppressing ciliogenesis. Centrosome glutamylation also promotes proper mitotic spindle formation and mitosis. In summary, our study provides a new approach to spatiotemporally manipulate glutamylation at centrosomes, and offers novel insights into how centrosomes are organized and regulated by glutamylation.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836489","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}
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