The EMBO Journal最新文献

Early coordination of cell migration and cardiac fate determination during mammalian gastrulation. 哺乳动物原肠胚形成过程中细胞迁移和心脏命运决定的早期协调。

The EMBO Journal Pub Date : 2025-05-13 DOI: 10.1038/s44318-025-00441-0

Shayma Abukar,Peter A Embacher,Alessandro Ciccarelli,Sunita Varsani-Brown,Isabel G W North,Jamie A Dean,James Briscoe,Kenzo Ivanovitch

{"title":"Early coordination of cell migration and cardiac fate determination during mammalian gastrulation.","authors":"Shayma Abukar,Peter A Embacher,Alessandro Ciccarelli,Sunita Varsani-Brown,Isabel G W North,Jamie A Dean,James Briscoe,Kenzo Ivanovitch","doi":"10.1038/s44318-025-00441-0","DOIUrl":"https://doi.org/10.1038/s44318-025-00441-0","url":null,"abstract":"During gastrulation, mesodermal cells derived from distinct regions are destined to acquire specific cardiac fates after undergoing complex migratory movements. Here, we used light-sheet imaging of live mouse embryos between gastrulation and heart tube formation to track mesodermal cells and to reconstruct lineage trees and 3D migration paths for up to five cell divisions. We found independent progenitors emerging at specific times, contributing exclusively to left ventricle/atrioventricular canal (LV/AVC) or atrial myocytes. LV/AVC progenitors differentiated early to form the cardiac crescent, while atrial progenitors later generated the heart tube's Nr2f2+ inflow tract during morphogenesis. We also identified short-lived multipotent progenitors with broad potential, illustrating early developmental plasticity. Descendants of multipotent progenitors displayed greater dispersion and more diverse migratory trajectories within the anterior mesoderm than the progeny of uni-fated progenitors. Progenitors contributing to extraembryonic mesoderm (ExEm) exhibited the fastest and most dispersed migrations. In contrast, those giving rise to endocardial, LV/AVC, and pericardial cells showed a more gradual divergence, with late-stage behavioural shifts: endocardial cells increased in speed, while pericardial cells slowed down in comparison to LV/AVC cells. Together, these data reveal patterns of individual cell directionality and cardiac fate allocation within the seemingly unorganised migratory pattern of mesoderm cells.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945393","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

Aldolase-regulated G3BP1/2+ condensates control insulin mRNA storage in beta cells. 醛缩酶调节的G3BP1/2+凝聚物控制β细胞中胰岛素mRNA的储存。

The EMBO Journal Pub Date : 2025-05-12 DOI: 10.1038/s44318-025-00448-7

Esteban Quezada,Klaus-Peter Knoch,Jovana Vasiljevic,Annika Seiler,Akshaye Pal,Abishek Gunasekaran,Carla Münster,Daniela Friedland,Eyke Schöniger,Anke Sönmez,Pascal Roch,Carolin Wegbrod,Katharina Ganß,Nicole Kipke,Simon Alberti,Rita Nano,Lorenzo Piemonti,Daniela Aust,Jürgen Weitz,Marius Distler,Michele Solimena

{"title":"Aldolase-regulated G3BP1/2+ condensates control insulin mRNA storage in beta cells.","authors":"Esteban Quezada,Klaus-Peter Knoch,Jovana Vasiljevic,Annika Seiler,Akshaye Pal,Abishek Gunasekaran,Carla Münster,Daniela Friedland,Eyke Schöniger,Anke Sönmez,Pascal Roch,Carolin Wegbrod,Katharina Ganß,Nicole Kipke,Simon Alberti,Rita Nano,Lorenzo Piemonti,Daniela Aust,Jürgen Weitz,Marius Distler,Michele Solimena","doi":"10.1038/s44318-025-00448-7","DOIUrl":"https://doi.org/10.1038/s44318-025-00448-7","url":null,"abstract":"Upregulation of insulin mRNA translation upon hyperglycemia in pancreatic islet β-cells involves several RNA-binding proteins. Here, we found that G3BP1, a stress granule marker downregulated in islets of subjects with type 2 diabetes, binds to insulin mRNA in glucose concentration-dependent manner. We show in mouse insulinoma MIN6-K8 cells exposed to fasting glucose levels that G3BP1 and its paralog G3BP2 colocalize to cytosolic condensates with eIF3b, phospho-AMPKαThr172 and Ins1/2 mRNA. Glucose stimulation dissolves G3BP1+/2+ condensates with cytosolic redistribution of their components. The aldolase inhibitor aldometanib prevents the glucose- and pyruvate-induced dissolution of G3BP1+/2+ condensates, increases phospho-AMPKαThr172 levels and reduces those of phospho-mTORSer2448. G3BP1 or G3BP2 depletion precludes condensate assembly. KO of G3BP1 decreases Ins1/2 mRNA abundance and translation as well as proinsulin levels, and impaires glucose-stimulated insulin secretion. Further, other insulin secretagogues such as exendin-4 and palmitate, but not high KCl, prompts the dissolution of G3BP1+/2+ condensates. G3BP1+/2+/Ins mRNA+ condensates are also found in primary mouse and human β-cells. Hence, G3BP1+/2+ condensates represent a conserved glycolysis/aldolase-regulated compartment for the physiological storage and protection of insulin mRNA in resting β-cells.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945067","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

YTHDC1 promotes postnatal brown adipose tissue development and thermogenesis by stabilizing PPARγ. YTHDC1通过稳定PPARγ促进出生后棕色脂肪组织的发育和产热。

The EMBO Journal Pub Date : 2025-05-12 DOI: 10.1038/s44318-025-00460-x

Lihua Wang,Yuqin Wang,Kaixin Ding,Zhenzhi Li,Zhipeng Zhang,Xinzhi Li,Yue Song,Liwei Xie,Zheng Chen

引用次数: 0

Approaches to stable isotope tracing and in vivo metabolomics in the cancer clinic. 稳定同位素示踪和体内代谢组学在癌症临床中的应用。

The EMBO Journal Pub Date : 2025-05-12 DOI: 10.1038/s44318-025-00450-z

Brandon Faubert,Alpaslan Tasdogan

引用次数: 0

Mechanistic insight into anaphase bridge signaling to the abscission checkpoint. 对分离检查点的后期桥接信号机制的洞察。

The EMBO Journal Pub Date : 2025-05-12 DOI: 10.1038/s44318-025-00453-w

Manika I Singh,Girish Rajendraprasad,Vasileios Katopodis,Rui Cui,Marin Barisic,Rahul Bhowmick,Ian D Hickson

引用次数: 0

The microprotein C16orf74/MICT1 promotes thermogenesis in brown adipose tissue. 微蛋白C16orf74/MICT1促进棕色脂肪组织产热。

The EMBO Journal Pub Date : 2025-05-12 DOI: 10.1038/s44318-025-00444-x

Jennie Dinh,Danielle Yi,Frances Lin,Pengya Xue,Nicholas D Holloway,Ying Xie,Nnejiuwa U Ibe,Hai P Nguyen,Jose A Viscarra,Yuhui Wang,Hei Sook Sul

{"title":"The microprotein C16orf74/MICT1 promotes thermogenesis in brown adipose tissue.","authors":"Jennie Dinh,Danielle Yi,Frances Lin,Pengya Xue,Nicholas D Holloway,Ying Xie,Nnejiuwa U Ibe,Hai P Nguyen,Jose A Viscarra,Yuhui Wang,Hei Sook Sul","doi":"10.1038/s44318-025-00444-x","DOIUrl":"https://doi.org/10.1038/s44318-025-00444-x","url":null,"abstract":"Brown and beige adipose tissues are metabolically beneficial for increasing energy expenditure via thermogenesis, mainly through UCP1 (uncoupling protein 1). Here, we identify C16orf74, subsequently named MICT1 (microprotein for thermogenesis 1), as a microprotein that is specifically and highly expressed in brown adipose tissue (BAT) and is induced upon cold exposure. MICT1 interacts with protein phosphatase 2B (PP2B, calcineurin) through the docking motif PNIIIT, thereby interfering with dephosphorylation of the regulatory subunit of protein kinase A (PKA), RIIβ, and potentiating PKA activity in brown adipocytes. Overexpression of MICT1 in differentiated brown adipocytes promotes thermogenesis, showing increased oxygen consumption rate (OCR) with higher thermogenic gene expression during β3-adrenergic stimulation, while knockdown of MICT1 impairs thermogenic responses. Moreover, BAT-specific MICT1 ablation in mice suppresses thermogenic capacity to increase adiposity and insulin resistance. Conversely, MICT1 overexpression in BAT or treating mice with a chemical inhibitor that targets the PP2B docking motif of MICT1 enhances thermogenesis. This results in cold tolerance and increased energy expenditure, protection against diet-induced and genetic obesity and insulin resistance, thus suggesting a therapeutic potential of MICT1 targeting.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945234","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

Inhibitors of eIF1A-ribosome interaction unveil uORF-dependent regulation of translation initiation and antitumor and antiviral effects. eif1a -核糖体相互作用抑制剂揭示了uorf依赖的翻译起始调控和抗肿瘤和抗病毒作用。

The EMBO Journal Pub Date : 2025-05-12 DOI: 10.1038/s44318-025-00449-6

Daniel Hayat,Ariel Ogran,Shaked Ashkenazi,Alexander Plotnikov,Roni Oren,Mirie Zerbib,Amir Ben-Shmuel,Rivka Dikstein

{"title":"Inhibitors of eIF1A-ribosome interaction unveil uORF-dependent regulation of translation initiation and antitumor and antiviral effects.","authors":"Daniel Hayat,Ariel Ogran,Shaked Ashkenazi,Alexander Plotnikov,Roni Oren,Mirie Zerbib,Amir Ben-Shmuel,Rivka Dikstein","doi":"10.1038/s44318-025-00449-6","DOIUrl":"https://doi.org/10.1038/s44318-025-00449-6","url":null,"abstract":"During translation initiation, eIF1A binds the ribosome through its N- and C-terminal tails, but the functional importance of this temporal interaction in mammalian cells is lacking. Using a high-throughput drug screen targeting eIF1A-RPS10 interaction, we identified inhibitors (1Ais) for eIF1A, RPS10, or both. Applying 1Ais in biochemical assays along specific and global translation experiments, we confirmed known functions of eIF1A and uncovered new roles for both eIF1A and RPS10. Specifically, the eIF1A N-terminal tail (NTT) binding inhibitors revealed the requirement of eIF1A for translation re-initiation. Moreover, a cytosine at position +5 relative to the start codon AUG, located near eIF1A-NTT in the 48S structure, enhances sensitivity to 1Ais, suggesting that the initiating ribosome recognizes a broader AUG context than the conventional Kozak. Additionally, eIF1A-specific 1Ais predominately affect cancer-related pathways. In xenograft models of ovarian cancer, these 1Ais reduced tumor growth without apparent toxicity. Furthermore, inhibition of RPS10, but not eIF1A, modulates a context-dependent regulatory translation initiation at CUG codon of SARS-CoV-2 and impedes infection. Our study underscores 1Ais as effective means to study the role of eIF1A and RPS10 in translation and suggests their targeted inhibition as potential therapies for cancer and viral infections.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945233","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

Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis. 膜联蛋白A5控制vdac1依赖的线粒体Ca2+稳态并决定细胞对凋亡的易感性。

The EMBO Journal Pub Date : 2025-05-09 DOI: 10.1038/s44318-025-00454-9

Furkan E Oflaz,Alexander I Bondarenko,Michael Trenker,Markus Waldeck-Weiermair,Benjamin Gottschalk,Eva Bernhart,Zhanat Koshenov,Snježana Radulović,Rene Rost,Martin Hirtl,Johannes Pilic,Aditya Karunanithi Nivedita,Adlet Sagintayev,Gerd Leitinger,Bent Brachvogel,Susanne Summerauer,Varda Shoshan-Barmatz,Roland Malli,Wolfgang F Graier

{"title":"Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.","authors":"Furkan E Oflaz,Alexander I Bondarenko,Michael Trenker,Markus Waldeck-Weiermair,Benjamin Gottschalk,Eva Bernhart,Zhanat Koshenov,Snježana Radulović,Rene Rost,Martin Hirtl,Johannes Pilic,Aditya Karunanithi Nivedita,Adlet Sagintayev,Gerd Leitinger,Bent Brachvogel,Susanne Summerauer,Varda Shoshan-Barmatz,Roland Malli,Wolfgang F Graier","doi":"10.1038/s44318-025-00454-9","DOIUrl":"https://doi.org/10.1038/s44318-025-00454-9","url":null,"abstract":"Annexin A5 (AnxA5) is a Ca2+-dependent phospholipid-binding protein associated with the regulation of intracellular Ca2+ homeostasis. However, the precise role of AnxA5 in controlling mitochondrial Ca2+ signaling remains elusive. Here, we introduce a novel function of AnxA5 in regulating mitochondrial Ca2+ signaling. Our investigation revealed that AnxA5 localizes at and in the mitochondria and orchestrates intermembrane space Ca2+ signaling upon high Ca2+ elevations induced by ER Ca2+ release. Proximity ligation assays and co-immunoprecipitation revealed a close association but no direct contact of AnxA5 with the voltage-dependent anion channel (VDAC1) in the outer mitochondrial membrane (OMM). In single-cell mitochondrial Ca2+ measurements and electrophysiological recordings, AnxA5 was found to enhance Ca2+ flux through the OMM by promoting the Ca2+-permeable state of VDAC1. By modulating intermembrane space Ca2+ signaling, AnxA5 shapes mitochondrial ultrastructure and influences the dynamicity of the mitochondrial Ca2+ uniporter. Furthermore, by controlling VDAC1's oligomeric state, AnxA5 is protective against cisplatin and selenite-induced apoptotic cell death. Our study uncovers AnxA5 as an integral regulator of VDAC1 in physiological and pathological conditions.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932628","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

Control of replication and gene expression by ADP-ribosylation of DNA in Mycobacterium tuberculosis. adp核糖基化对结核分枝杆菌复制和基因表达的控制。

The EMBO Journal Pub Date : 2025-05-08 DOI: 10.1038/s44318-025-00451-y

Rachel E Butler,Marion Schuller,Ritu Jaiswal,Jayanta Mukhopadhyay,Jim Barber,Suzie Hingley-Wilson,Emily Wasson,Alex Couto Alves,Ivan Ahel,Graham R Stewart

{"title":"Control of replication and gene expression by ADP-ribosylation of DNA in Mycobacterium tuberculosis.","authors":"Rachel E Butler,Marion Schuller,Ritu Jaiswal,Jayanta Mukhopadhyay,Jim Barber,Suzie Hingley-Wilson,Emily Wasson,Alex Couto Alves,Ivan Ahel,Graham R Stewart","doi":"10.1038/s44318-025-00451-y","DOIUrl":"https://doi.org/10.1038/s44318-025-00451-y","url":null,"abstract":"Mycobacterium tuberculosis maintains long-term infections characterised by the need to regulate growth and adapt to contrasting in vivo environments. Here we show that M. tuberculosis complex bacteria utilise reversible ADP-ribosylation of single-stranded DNA as a mechanism to coordinate stationary phase growth with transcriptional adaptation. The DNA modification is controlled by DarT, an ADP-ribosyltransferase, which adds ADP-ribose to thymidine, and DarG, which enzymatically removes this base modification. Using darG-knockdown M. bovis BCG, we map the first DNA ADP-ribosylome from any organism. We show that inhibition of replication by DarT is reversible and accompanied by extensive ADP-ribosylation at the origin of replication (OriC). In addition, we observe ADP-ribosylation across the genome and demonstrate that ADP-ribose-thymidine alters the transcriptional activity of M. tuberculosis RNA polymerase. Furthermore, we demonstrate that during stationary phase, DarT-dependent ADP-ribosylation of M. tuberculosis DNA is required to optimally induce expression of the Zur regulon, including the ESX-3 secretion system and multiple alternative ribosome proteins. Thus, ADP-ribosylation of DNA can provide a mechanistic link through every aspect of DNA biology from replication to transcription to translation.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"229 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932401","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

CHD8 interacts with BCL11A to induce oncogenic transcription in triple negative breast cancer. CHD8与BCL11A相互作用诱导三阴性乳腺癌的致癌转录。

The EMBO Journal Pub Date : 2025-05-06 DOI: 10.1038/s44318-025-00447-8

Mark Waterhouse,Kyren Lazarus,Maria Francesca Santolla,Sara Pensa,Eleanor Williams,Abigail J Q Siu,Hisham Mohammed,Irina Mohorianu,Marcello Maggiolini,Jason Carroll,Laura S Itzhaki,Taufiq Rahman,Walid T Khaled

{"title":"CHD8 interacts with BCL11A to induce oncogenic transcription in triple negative breast cancer.","authors":"Mark Waterhouse,Kyren Lazarus,Maria Francesca Santolla,Sara Pensa,Eleanor Williams,Abigail J Q Siu,Hisham Mohammed,Irina Mohorianu,Marcello Maggiolini,Jason Carroll,Laura S Itzhaki,Taufiq Rahman,Walid T Khaled","doi":"10.1038/s44318-025-00447-8","DOIUrl":"https://doi.org/10.1038/s44318-025-00447-8","url":null,"abstract":"The identification of tumour-specific protein-protein interactions remains a challenge for the development of targeted cancer therapies. In this study we describe our approach for the identification of triple negative breast cancer (TNBC)-specific protein-protein interactions focusing on the oncogene BCL11A. We used a proteomic approach to identify the BCL11A protein networks in TNBC and compared it to its network in B-cells, a cell type in which BCL11A plays crucial roles. This approach identified the chromatin remodeller CHD8 as a TNBC-specific interaction partner of BCL11A. We show that CHD8 also plays a key role in TNBC pathogenesis, with detailed multi-omics analysis revealing that BCL11A and CHD8 co-regulate several targets and synergise to drive tumour development and progression. Using a battery of biophysical assays, we confirm that the BCL11A-CHD8 interaction is direct and identify chemical fragments that disrupt this interaction and affect downstream targets, decreasing proliferation in 3D colony assays. Our study provides a proof-of-principle approach for investigating tumour-specific protein-protein interactions and identifies lead chemical compounds that could be developed into novel therapeutics for TNBC.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915012","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