EMBO Journal最新文献_第2页

Modular in vivo assembly of Arabidopsis FCA oligomers into condensates competent for RNA 3' processing.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-24 DOI: 10.1038/s44318-025-00394-4

Geng-Jen Jang, Alex L Payne-Dwyer, Robert Maple, Zhe Wu, Fuquan Liu, Sergio G Lopez, Yanning Wang, Xiaofeng Fang, Mark C Leake, Caroline Dean

{"title":"Modular in vivo assembly of Arabidopsis FCA oligomers into condensates competent for RNA 3' processing.","authors":"Geng-Jen Jang, Alex L Payne-Dwyer, Robert Maple, Zhe Wu, Fuquan Liu, Sergio G Lopez, Yanning Wang, Xiaofeng Fang, Mark C Leake, Caroline Dean","doi":"10.1038/s44318-025-00394-4","DOIUrl":"10.1038/s44318-025-00394-4","url":null,"abstract":"Our understanding of the functional requirements underpinning biomolecular condensation in vivo is still relatively poor. The Arabidopsis RNA binding protein FLOWERING CONTROL LOCUS A (FCA) is found in liquid-like nuclear condensates that function in transcription termination, promoting proximal polyadenylation at many target genes in the Arabidopsis genome. To further understand the properties of these condensates in vivo, we used single-particle tracking experiments on FCA reporters stably expressed at endogenous levels in plant nuclei. SEC-MALS analyses suggested that FCA forms a core oligomer consistent with a size of four molecules; in vivo particle tracking indicated that this core molecule multimerizes into higher-order particles. The ensuing assemblies coalesce into macromolecular condensates via the coiled-coil protein FLL2, which is genetically required for FCA function. Accordingly, FLL2 predominately co-localizes with FCA in larger-sized condensates. A missense mutation in the FCA RRM domain, also genetically required for FCA function, reduced average size of both FCA particles and condensates, but did not perturb the core oligomer. Our work points to a modular structure for FCA condensates, involving multimerization of core oligomers assembled into functional macromolecular condensates via associated RNA and FLL2 interactions.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2056-2074"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143494525","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}

引用次数: 0

The green side of splicing: algal spliceosome shows remarkable structural conservation.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-03-06 DOI: 10.1038/s44318-025-00403-6

Wojciech P Galej

引用次数: 0

Local weakening of cell-extracellular matrix adhesion triggers basal epithelial tissue folding.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-17 DOI: 10.1038/s44318-025-00384-6

Andrea Valencia-Expósito, Nargess Khalilgharibi, Ana Martínez-Abarca Millán, Yanlan Mao, María D Martín-Bermudo

{"title":"Local weakening of cell-extracellular matrix adhesion triggers basal epithelial tissue folding.","authors":"Andrea Valencia-Expósito, Nargess Khalilgharibi, Ana Martínez-Abarca Millán, Yanlan Mao, María D Martín-Bermudo","doi":"10.1038/s44318-025-00384-6","DOIUrl":"10.1038/s44318-025-00384-6","url":null,"abstract":"During development, epithelial sheets sculpt organs by folding, either apically or basally, into complex 3D structures. Given the presence of actomyosin networks and cell adhesion sites on both sides of cells, a common machinery mediating apical and basal epithelial tissue folding has been proposed. However, unlike for apical folding, little is known about the mechanisms that regulate epithelial folding towards the basal side. Here, using the Drosophila wing imaginal disc and combining genetic perturbations and computational modeling, we demonstrate opposing roles for cell-cell and cell-extracellular matrix (ECM) adhesion systems during epithelial folding. While cadherin-mediated adhesion, linked to actomyosin network, regulates apical folding, a localized reduction on integrin-dependent adhesion, followed by changes in cell shape and reorganization of the basal actomyosin cytoskeleton and E-Cadherin (E-Cad) levels, is necessary and sufficient to trigger basal folding. These results suggest that modulation of the cell mechanical landscape through the crosstalk between integrins and cadherins is essential for correct epithelial folding.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2002-2024"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442654","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}

引用次数: 0

A one-two punch against cancer: combining CDK4 inhibitors with lysosomotropic agents.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-24 DOI: 10.1038/s44318-025-00396-2

Gerardo Ferbeyre

引用次数: 0

Maintenance of p-eIF2α levels by the eIF2B complex is vital for colorectal cancer.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-27 DOI: 10.1038/s44318-025-00381-9

Ivana Paskov Škapik, Chiara Giacomelli, Sarah Hahn, Hanna Deinlein, Peter Gallant, Mathias Diebold, Josep Biayna, Anne Hendricks, Leon Olimski, Christoph Otto, Carolin Kastner, Elmar Wolf, Christina Schülein-Völk, Katja Maurus, Andreas Rosenwald, Nikolai Schleussner, Rene-Filip Jackstadt, Nicolas Schlegel, Christoph-Thomas Germer, Martin Bushell, Martin Eilers, Stefanie Schmidt, Armin Wiegering

{"title":"Maintenance of p-eIF2α levels by the eIF2B complex is vital for colorectal cancer.","authors":"Ivana Paskov Škapik, Chiara Giacomelli, Sarah Hahn, Hanna Deinlein, Peter Gallant, Mathias Diebold, Josep Biayna, Anne Hendricks, Leon Olimski, Christoph Otto, Carolin Kastner, Elmar Wolf, Christina Schülein-Völk, Katja Maurus, Andreas Rosenwald, Nikolai Schleussner, Rene-Filip Jackstadt, Nicolas Schlegel, Christoph-Thomas Germer, Martin Bushell, Martin Eilers, Stefanie Schmidt, Armin Wiegering","doi":"10.1038/s44318-025-00381-9","DOIUrl":"10.1038/s44318-025-00381-9","url":null,"abstract":"Protein synthesis is an essential process, deregulated in multiple tumor types showing differential dependence on translation factors compared to untransformed tissue. We show that colorectal cancer (CRC) with loss-of-function mutation in the APC tumor suppressor depends on an oncogenic translation program regulated by the ability to sense phosphorylated eIF2α (p-eIF2α). Despite increased protein synthesis rates following APC loss, eIF2α phosphorylation, typically associated with translation inhibition, is enhanced in CRC. Elevated p-eIF2α, and its proper sensing by the decameric eIF2B complex, are essential to balance translation. Knockdown or mutation of eIF2Bα and eIF2Bδ, two eIF2B subunits responsible for sensing p-eIF2α, impairs CRC viability, demonstrating that the eIF2B/p-eIF2α nexus is vital for CRC. Specifically, the decameric eIF2B linked by two eIF2Bα subunits is critical for translating growth-promoting mRNAs which are induced upon APC loss. Depletion of eIF2Bα in APC-deficient murine and patient-derived organoids establishes a therapeutic window, validating eIF2Bα as a target for clinical intervention. In conclusion, we demonstrate how the expression of the oncogenic signature in CRC is crucially controlled at the translational level.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2075-2105"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525048","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}

引用次数: 0

PLK1 inhibition delays mitotic entry revealing changes to the phosphoproteome of mammalian cells early in division.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-03-03 DOI: 10.1038/s44318-025-00400-9

Monica Gobran, Antonio Z Politi, Luisa Welp, Jasmin Jakobi, Henning Urlaub, Peter Lenart

{"title":"PLK1 inhibition delays mitotic entry revealing changes to the phosphoproteome of mammalian cells early in division.","authors":"Monica Gobran, Antonio Z Politi, Luisa Welp, Jasmin Jakobi, Henning Urlaub, Peter Lenart","doi":"10.1038/s44318-025-00400-9","DOIUrl":"10.1038/s44318-025-00400-9","url":null,"abstract":"Polo-like kinase 1 (PLK1) is a conserved regulator of cell division. During mitotic prophase, PLK1 contributes to the activation of the cyclin-dependent kinase 1 (CDK1). However, the exact functions of PLK1 in prophase remain incompletely understood. Here, we show that PLK1 inhibition in synchronous G2 cell populations of multiple mammalian cell lines delays or prevents mitotic entry with high variability between individual cells. Using a mathematical model, we recapitulate this phenomenon and provide an explanation for the observed phenotypic variability. We show that PLK1-inhibited cells are delayed in a prophase-like state with low CDK1 activity that increases slowly and gradually over hours. These cells display progressively condensing chromosomes, increased microtubule dynamics, and reorganization of the actin cortex, while the nuclear envelope remains intact. We characterize this state further by phosphoproteomics, revealing phosphorylation of regulators of chromatin organization and the cytoskeleton consistent with the cellular phenotypes. Together, our results indicate that PLK1 inhibition stabilizes cells in a prophase-like state with low CDK1 activity displaying a specific set of early mitotic phosphorylation events.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1891-1920"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544308","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}

引用次数: 0

SIRT5-mediated desuccinylation of PPA2 enhances HIF-1alpha-dependent adaptation to hypoxic stress and colorectal cancer metastasis.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-31 DOI: 10.1038/s44318-025-00416-1

Xiang Zhang, Yuqin Di, Youpeng Wang, Jiale Qin, Lvlan Ye, Xiangqiong Wen, Zunfu Ke, Ziyang Wang, Weiling He

{"title":"SIRT5-mediated desuccinylation of PPA2 enhances HIF-1alpha-dependent adaptation to hypoxic stress and colorectal cancer metastasis.","authors":"Xiang Zhang, Yuqin Di, Youpeng Wang, Jiale Qin, Lvlan Ye, Xiangqiong Wen, Zunfu Ke, Ziyang Wang, Weiling He","doi":"10.1038/s44318-025-00416-1","DOIUrl":"10.1038/s44318-025-00416-1","url":null,"abstract":"Metastasis is the primary cause of death in patients with colorectal cancer (CRC). Hypoxia is a hallmark of solid tumors that promotes cellular metabolic adaptation and dissemination. However, the mechanisms linking hypoxia-regulated metabolic adaptation to CRC metastasis remain unclear. Here, we found that inorganic pyrophosphatase 2 (PPA2) suppresses metastatic progression of CRC via its phosphatase function. PPA2 expression levels are reduced in CRC specimen and correlate with enhanced response to hypoxia by promoting hypoxia-inducible factor-1 (HIF-1) signaling to promote CRC cell glycolysis and dissemination. Mechanistically, PPA2 decreases HIF-1alpha stability through non-canonical ubiquitin-mediated proteasomal degradation via recruitment of E3 ligase NEDD4. Furthermore, PPA2 directly dephosphorylates NEDD4 at threonine 758 residue, resulting in its activation. Under hypoxic stress, NAD-dependent protein deacetylase sirtuin-5 promotes the dissociation of PPA2 and NEDD4 by inducing PPA2 desuccinylation at lysine 176, contributing to the improved stability of HIF-1alpha under hypoxic conditions. Our findings reveal a tumor-suppressive role of PPA2 in HIF-1alpha-dependent colorectal cancer, providing a potential therapeutic target and prognostic strategy.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755566","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}

引用次数: 0

The biochemical mechanism of Rho GTPase membrane binding, activation and retention in activity patterning.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-31 DOI: 10.1038/s44318-025-00418-z

Michael C Armstrong, Yannic R Weiß, Lila E Hoachlander-Hobby, Ankit A Roy, Ilaria Visco, Alison Moe, Adriana E Golding, Scott D Hansen, William M Bement, Peter Bieling

{"title":"The biochemical mechanism of Rho GTPase membrane binding, activation and retention in activity patterning.","authors":"Michael C Armstrong, Yannic R Weiß, Lila E Hoachlander-Hobby, Ankit A Roy, Ilaria Visco, Alison Moe, Adriana E Golding, Scott D Hansen, William M Bement, Peter Bieling","doi":"10.1038/s44318-025-00418-z","DOIUrl":"10.1038/s44318-025-00418-z","url":null,"abstract":"Rho GTPases form plasma membrane-associated patterns that control the cytoskeleton during cell division, morphogenesis, migration, and wound repair. Their patterning involves transitions between inactive cytosolic and active membrane-bound states, regulated by guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs). However, the relationships between these transitions and role of different regulators remain unclear. We developed a novel reconstitution approach to study Rho GTPase patterning with all major GTPase regulators in a biochemically defined system. We show that Rho GTPase dissociation from RhoGDI is rate-limiting for its membrane association. Rho GTPase activation occurs after membrane insertion, which is unaffected by GEF activity. Once activated, Rho GTPases are retained at the membrane through effector interactions, essential for their enrichment at activation sites. Thus, high cytosolic levels of RhoGDI-bound GTPases ensure a constant supply of inactive GTPases for the membrane, where GEF-mediated activation and effector binding stabilize them. These results delineate the route by which Rho GTPase patterns are established and define stage-dependent roles of its regulators.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755572","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}

引用次数: 0

HAND1 level controls the specification of multipotent cardiac and extraembryonic progenitors from human pluripotent stem cells.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-31 DOI: 10.1038/s44318-025-00409-0

Adam T Lynch, Naomi Phillips, Megan Douglas, Marta Dorgnach, I-Hsuan Lin, Antony D Adamson, Zoulfia Darieva, Jessica Whittle, Neil A Hanley, Nicoletta Bobola, Matthew J Birket

{"title":"HAND1 level controls the specification of multipotent cardiac and extraembryonic progenitors from human pluripotent stem cells.","authors":"Adam T Lynch, Naomi Phillips, Megan Douglas, Marta Dorgnach, I-Hsuan Lin, Antony D Adamson, Zoulfia Darieva, Jessica Whittle, Neil A Hanley, Nicoletta Bobola, Matthew J Birket","doi":"10.1038/s44318-025-00409-0","DOIUrl":"10.1038/s44318-025-00409-0","url":null,"abstract":"Diverse sets of progenitors contribute to the development of the embryonic heart, but the mechanisms of their specification have remained elusive. Here, using a human pluripotent stem cell (hPSC) model, we deciphered cardiac and non-cardiac lineage trajectories in differentiation and identified transcription factors underpinning cell specification, identity and function. We discovered a concentration-dependent, fate determining function for the basic helix-loop-helix transcription factor HAND1 in mesodermal progenitors and uncovered its gene regulatory network. At low expression level, HAND1 directs differentiation towards multipotent juxta-cardiac field progenitors able to make cardiomyocytes and epicardial cells, whereas at high level it promotes the development of extraembryonic mesoderm. Importantly, HAND1-low progenitors can be propagated in their multipotent state. This detailed mechanistic insight into human development has the potential to accelerate the delivery of effective disease modelling, including for congenital heart disease, and cell therapy-based regenerative medicine.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755634","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}

引用次数: 0

A bacterial network of T3SS effectors counteracts host pro-inflammatory responses and cell death to promote infection. 由 T3SS 效应器组成的细菌网络可抵消宿主的促炎反应和细胞死亡，从而促进感染。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-24 DOI: 10.1038/s44318-025-00412-5

Hui Wen Yeap, Ghin Ray Goh, Safwah Nasuha Rosli, Hai Shin Pung, Cristina Giogha, Vik Ven Eng, Jaclyn S Pearson, Elizabeth L Hartland, Kaiwen W Chen

{"title":"A bacterial network of T3SS effectors counteracts host pro-inflammatory responses and cell death to promote infection.","authors":"Hui Wen Yeap, Ghin Ray Goh, Safwah Nasuha Rosli, Hai Shin Pung, Cristina Giogha, Vik Ven Eng, Jaclyn S Pearson, Elizabeth L Hartland, Kaiwen W Chen","doi":"10.1038/s44318-025-00412-5","DOIUrl":"10.1038/s44318-025-00412-5","url":null,"abstract":"Innate immune signalling and cell death pathways are highly interconnected processes involving receptor-interacting protein kinases (RIPKs) as mediators of potent anti-microbial responses. However, these processes are often antagonised by bacterial type III secretion system (T3SS) effectors, and the cellular mechanisms by which the host retaliates are not completely understood. Here, we demonstrate that during Citrobacter rodentium infection, murine macrophages and colonic epithelial cells exhibit RIPK1 kinase-dependent caspase-8 activation to counteract NleE effector-mediated suppression of pro-inflammatory signalling. While C. rodentium injects into the host cells a second effector, NleB, to block caspase-8 signalling, macrophages respond by triggering RIPK3-mediated necroptosis, whereupon a third T3SS effector, EspL, acts to inactivate necroptosis. We further show that NleB and EspL collaborate to suppress caspase-8 and NLRP3 inflammasome activation in macrophages. Our findings suggest that C. rodentium has evolved to express a complex network of effectors as an adaptation to the importance of cell death for anti-bacterial defence in the host-pathogen arms race.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701974","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}

引用次数: 0