EMBO Journal最新文献_第4页

Author Correction: Toxin-mediated depletion of NAD and NADP drives persister formation in a human pathogen. 作者更正：毒素介导的NAD和NADP的消耗驱动人类病原体的持久性形成。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-05-01 DOI: 10.1038/s44318-024-00354-4

Isabella Santi, Raphael Dias Teixeira, Pablo Manfredi, Hector Hernandez Gonzalez, Daniel C Spiess, Guillaume Mas, Alexander Klotz, Andreas Kaczmarczyk, Simon van Vliet, Nicola Zamboni, Sebastian Hiller, Urs Jenal

引用次数: 0

An asymmetric nautilus-like HflK/C assembly controls FtsH proteolysis of membrane proteins. 不对称的鹦鹉螺样HflK/C组装控制FtsH蛋白水解膜蛋白。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-05-01 Epub Date: 2025-03-13 DOI: 10.1038/s44318-025-00408-1

Alireza Ghanbarpour, Bertina Telusma, Barrett M Powell, Jia Jia Zhang, Isabella Bolstad, Carolyn Vargas, Sandro Keller, Tania A Baker, Robert T Sauer, Joseph H Davis

{"title":"An asymmetric nautilus-like HflK/C assembly controls FtsH proteolysis of membrane proteins.","authors":"Alireza Ghanbarpour, Bertina Telusma, Barrett M Powell, Jia Jia Zhang, Isabella Bolstad, Carolyn Vargas, Sandro Keller, Tania A Baker, Robert T Sauer, Joseph H Davis","doi":"10.1038/s44318-025-00408-1","DOIUrl":"10.1038/s44318-025-00408-1","url":null,"abstract":"The AAA protease FtsH associates with HflK/C subunits to form a megadalton-size complex that spans the inner membrane and extends into the periplasm of E. coli. How this bacterial complex and homologous assemblies in eukaryotic organelles recruit, extract, and degrade membrane-embedded substrates is unclear. Following the overproduction of protein components, recent cryo-EM structures showed symmetric HflK/C cages surrounding FtsH in a manner proposed to inhibit the degradation of membrane-embedded substrates. Here, we present structures of native protein complexes, in which HflK/C instead forms an asymmetric nautilus-shaped assembly with an entryway for membrane-embedded substrates to reach and be engaged by FtsH. Consistent with this nautilus-like structure, proteomic assays suggest that HflK/C enhances FtsH degradation of certain membrane-embedded substrates. Membrane curvature in our FtsH•HflK/C complexes is opposite that of surrounding membrane regions, a property that correlates with lipid scramblase activity and possibly with FtsH's function in the degradation of membrane-embedded proteins.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2501-2513"},"PeriodicalIF":9.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626663","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}

引用次数: 0

A versatile toolbox for determining IRES activity in cells and embryonic tissues. 用于测定细胞和胚胎组织中IRES活性的多功能工具箱。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-05-01 Epub Date: 2025-03-13 DOI: 10.1038/s44318-025-00404-5

Philipp Koch, Zijian Zhang, Naomi R Genuth, Teodorus Theo Susanto, Martin Haimann, Alena Khmelinskaia, Gun Woo Byeon, Saurabh Dey, Maria Barna, Kathrin Leppek

{"title":"A versatile toolbox for determining IRES activity in cells and embryonic tissues.","authors":"Philipp Koch, Zijian Zhang, Naomi R Genuth, Teodorus Theo Susanto, Martin Haimann, Alena Khmelinskaia, Gun Woo Byeon, Saurabh Dey, Maria Barna, Kathrin Leppek","doi":"10.1038/s44318-025-00404-5","DOIUrl":"10.1038/s44318-025-00404-5","url":null,"abstract":"Widespread control of gene expression through translation has emerged as a key level of spatiotemporal regulation of protein expression. A prominent mechanism by which ribosomes can confer gene regulation is via internal ribosomal entry sites (IRESes), whose functions have however, remained difficult to rigorously characterize. Here we present a set of technologies in embryos and cells, including IRES-mediated translation of circular RNA (circRNA) reporters, single-molecule messenger (m)RNA isoform imaging, PacBio long-read sequencing, and isoform-sensitive mRNA quantification along polysome profiles as a new toolbox for understanding IRES regulation. Using these techniques, we investigate a broad range of cellular IRES RNA elements including Hox IRESes. We show IRES-dependent translation in circRNAs, as well as the relative expression, localization, and translation of an IRES-containing mRNA isoform in specific embryonic tissues. We thereby provide a new resource of technologies to elucidate the roles of versatile IRES elements in gene regulation and embryonic development.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2695-2724"},"PeriodicalIF":9.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626659","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}

引用次数: 0

HAND1 level controls the specification of multipotent cardiac and extraembryonic progenitors from human pluripotent stem cells. HAND1水平控制着来自人类多能干细胞的多能心脏和胚胎外祖细胞的分化。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-05-01 Epub 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":"2541-2565"},"PeriodicalIF":9.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048643/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Spc105/Kre28 complex promotes mitotic error correction by outer kinetochore recruitment of Ipl1/Sli15. Spc105/Kre28复合体通过Ipl1/Sli15的外着丝点募集促进有丝分裂错误纠正。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-25 DOI: 10.1038/s44318-025-00437-w

Alexander Dudziak, Richard Pleuger, Jasmin Schmidt, Frederik Hamm, Sharvari Tendulkar, Karolin Jänen, Ingrid R Vetter, Sylvia Singh, Josef Fischböck, Franz Herzog, Stefan Westermann

{"title":"The Spc105/Kre28 complex promotes mitotic error correction by outer kinetochore recruitment of Ipl1/Sli15.","authors":"Alexander Dudziak, Richard Pleuger, Jasmin Schmidt, Frederik Hamm, Sharvari Tendulkar, Karolin Jänen, Ingrid R Vetter, Sylvia Singh, Josef Fischböck, Franz Herzog, Stefan Westermann","doi":"10.1038/s44318-025-00437-w","DOIUrl":"https://doi.org/10.1038/s44318-025-00437-w","url":null,"abstract":"Kinetochores link chromosomes to dynamic microtubules of the mitotic spindle. To ensure equal chromosome segregation, sister chromatids must achieve biorientation. The conserved kinase Aurora B phosphorylates outer kinetochore proteins on attachments lacking tension, allowing the re-establishment of new connections until biorientation is achieved. Aurora B localizes to the centromere as part of the chromosomal passenger complex (CPC), but the underlying recruitment pathways can be eliminated without disrupting biorientation. It therefore remains unclear how the kinase operates during error correction. Here, we identify the conserved Spc105/Kre28 complex as an outer kinetochore receptor of the Aurora kinase Ipl1 and its activator Sli15 in Saccharomyces cerevisiae. We show that mutations in the helix bundle domain of Spc105/Kre28 impair mitotic error correction, resembling the effects of ipl1 or sli15 mutants. The defects can be suppressed by the artificial recruitment of Ipl1. In biochemical experiments, Ipl1/Sli15 directly associates with Spc105/Kre28, and a conserved segment in the Sli15 central domain is crucially involved in the binding mechanism. These results have important implications for the mechanism of tension-dependent error correction during chromosome biorientation.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037702","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

Recurrent innovation of protein-protein interactions in the Drosophila piRNA pathway. 果蝇piRNA通路中蛋白质相互作用的反复创新。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-24 DOI: 10.1038/s44318-025-00439-8

Sebastian Riedelbauch, Sarah Masser, Sandra Fasching, Sung-Ya Lin, Harpreet Kaur Salgania, Mie Aarup, Anja Ebert, Mandy Jeske, Mia T Levine, Ulrich Stelzl, Peter Andersen

{"title":"Recurrent innovation of protein-protein interactions in the Drosophila piRNA pathway.","authors":"Sebastian Riedelbauch, Sarah Masser, Sandra Fasching, Sung-Ya Lin, Harpreet Kaur Salgania, Mie Aarup, Anja Ebert, Mandy Jeske, Mia T Levine, Ulrich Stelzl, Peter Andersen","doi":"10.1038/s44318-025-00439-8","DOIUrl":"https://doi.org/10.1038/s44318-025-00439-8","url":null,"abstract":"Despite being essential for fertility, genome-defense-pathway genes often evolve rapidly. However, little is known about the molecular basis of this adaptation. Here, we characterized the evolution of a protein interaction network within the PIWI-interacting small RNA (piRNA) genome-defense pathway in Drosophila at unprecedented scale and evolutionary resolution. We uncovered the pervasive rapid evolution of a protein interaction network anchored at the heterochromatin protein 1 (HP1) paralog Rhino. Through cross-species high-throughput yeast-two-hybrid screening, we identified three distinct evolutionary protein interaction trajectories across ~40 million years of Drosophila evolution. While several protein interactions are fully conserved, indicating functional conservation despite rapid amino acid-sequence change, other interactions are preserved through coevolution and were detected only between proteins within or from closely related species. We also identified species-restricted protein interactions, revealing insight into the mechanistic diversity and ongoing molecular innovation in Drosophila piRNA production. In sum, our analyses reveal principles of interaction evolution in an adaptively evolving protein-protein interaction network, and support intermolecular interaction innovation as a central molecular mechanism of evolutionary adaptation in protein-coding genes.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056256","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

Autophagosomes anchor an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling. 自噬体锚定一个依赖akap11的调节检查点，形成神经元PKA信号。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-22 DOI: 10.1038/s44318-025-00436-x

Ashley Segura-Roman, Y Rose Citron, Myungsun Shin, Nicole Sindoni, Alex Maya-Romero, Simon Rapp, Claire Goul, Joseph D Mancias, Roberto Zoncu

{"title":"Autophagosomes anchor an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling.","authors":"Ashley Segura-Roman, Y Rose Citron, Myungsun Shin, Nicole Sindoni, Alex Maya-Romero, Simon Rapp, Claire Goul, Joseph D Mancias, Roberto Zoncu","doi":"10.1038/s44318-025-00436-x","DOIUrl":"https://doi.org/10.1038/s44318-025-00436-x","url":null,"abstract":"Protein Kinase A (PKA) is regulated spatially and temporally via scaffolding of its catalytic (Cα) and regulatory (RI/RII) subunits by the A-kinase-anchoring proteins (AKAP). By binding to an AKAP11 scaffold, PKA engages in poorly understood interactions with autophagy, a key degradation pathway for neuronal cell homeostasis. Mutations in AKAP11 promote schizophrenia and bipolar disorders (SZ-BP) through unknown mechanisms. Here, through proteomic-based analyses of immunopurified lysosomes, we identify the Cα-RIα-AKAP11 holocomplex as a prominent autophagy-associated protein-kinase complex. AKAP11 scaffolds Cα-RIα interaction with the autophagic machinery via its LC3-interacting region (LIR), enabling both PKA regulation by upstream signals, and its autophagy-dependent degradation. We identify Ser83 on the RIα linker-hinge region as an AKAP11-dependent phospho-residue that modulates RIα-Cα binding to the autophagosome and cAMP-induced PKA activation. Decoupling AKAP11-PKA from autophagy alters downstream phosphorylation events, supporting an autophagy-dependent checkpoint for PKA signaling. Ablating AKAP11 in induced pluripotent stem cell-derived neurons reveals dysregulation of multiple pathways for neuronal homeostasis. Thus, the autophagosome is a platform that modulates PKA signaling, providing a possible mechanistic link to SZ/BP pathophysiology.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038125","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

Drosophila Alms1 proteins regulate centriolar cartwheel assembly by enabling Plk4-Ana2 amplification loop. 果蝇 Alms1 蛋白通过启用 Plk4-Ana2 扩增环路来调控中心极车轮组装。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-28 DOI: 10.1038/s44318-025-00382-8

Marine Brunet, Joëlle Thomas, Jean-André Lapart, Léo Krüttli, Marine H Laporte, Maria Giovanna Riparbelli, Giuliano Callaini, Bénédicte Durand, Véronique Morel

{"title":"Drosophila Alms1 proteins regulate centriolar cartwheel assembly by enabling Plk4-Ana2 amplification loop.","authors":"Marine Brunet, Joëlle Thomas, Jean-André Lapart, Léo Krüttli, Marine H Laporte, Maria Giovanna Riparbelli, Giuliano Callaini, Bénédicte Durand, Véronique Morel","doi":"10.1038/s44318-025-00382-8","DOIUrl":"10.1038/s44318-025-00382-8","url":null,"abstract":"Centrioles play a central role in cell division by recruiting pericentriolar material (PCM) to form the centrosome. Alterations in centriole number or function lead to various diseases including cancer or microcephaly. Centriole duplication is a highly conserved mechanism in eukaryotes. Here, we show that the two Drosophila orthologs of the Alström syndrome protein 1 (Alms1a and Alms1b) are unexpected novel players of centriole duplication in fly. Using Ultrastructure Expansion Microscopy, we reveal that Alms1a is a PCM protein that is loaded proximally on centrioles at the onset of procentriole formation, whereas Alms1b caps the base of mature centrioles. We demonstrate that chronic loss of Alms1 proteins (with RNA null alleles) affects PCM maturation, whereas their acute loss (in RNAi KD) completely disrupts procentriole formation before Sas-6 cartwheel assembly. We establish that Alms1 proteins are required for the amplification of the Plk4-Ana2 pool at the duplication site and the subsequent Sas-6 recruitment. Thus, Alms1 proteins are novel critical but highly buffered regulators of PCM and cartwheel assembly in flies.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2366-2395"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532030","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}

引用次数: 0

The MAST kinase KIN-4 carries out mitotic entry functions of Greatwall in C. elegans. MAST激酶KIN-4在秀丽隐杆线虫中执行Greatwall的有丝分裂进入功能。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-17 DOI: 10.1038/s44318-025-00364-w

Ludivine Roumbo, Batool Ossareh-Nazari, Suzanne Vigneron, Ioanna Stefani, Lucie Van Hove, Véronique Legros, Guillaume Chevreux, Benjamin Lacroix, Anna Castro, Nicolas Joly, Thierry Lorca, Lionel Pintard

{"title":"The MAST kinase KIN-4 carries out mitotic entry functions of Greatwall in C. elegans.","authors":"Ludivine Roumbo, Batool Ossareh-Nazari, Suzanne Vigneron, Ioanna Stefani, Lucie Van Hove, Véronique Legros, Guillaume Chevreux, Benjamin Lacroix, Anna Castro, Nicolas Joly, Thierry Lorca, Lionel Pintard","doi":"10.1038/s44318-025-00364-w","DOIUrl":"10.1038/s44318-025-00364-w","url":null,"abstract":"MAST-like, or Greatwall (Gwl), an atypical protein kinase related to the evolutionarily conserved MAST kinase family, is crucial for cell cycle control during mitotic entry. Mechanistically, Greatwall is activated by Cyclin B-Cdk1 phosphorylation of a 550 amino acids-long insertion in its atypical activation segment. Subsequently, Gwl phosphorylates Endosulfine and Arpp19 to convert them into inhibitors of PP2A-B55 phosphatase, thereby preventing early dephosphorylation of M-phase targets of Cyclin B-Cdk1. Here, searching for an elusive Gwl-like activity in C. elegans, we show that the single worm MAST kinase, KIN-4, fulfills this function in worms and can functionally replace Greatwall in the heterologous Xenopus system. Compared to Greatwall, the short activation segment of KIN-4 lacks a phosphorylation site, and KIN-4 is active even when produced in E. coli. We also show that a balance between Cyclin B-Cdk1 and PP2A-B55 activity, regulated by KIN-4, is essential to ensure asynchronous cell divisions in the early worm embryo. These findings resolve a long-standing puzzle related to the supposed absence of a Greatwall pathway in C. elegans, and highlight a novel aspect of PP2A-B55 regulation by MAST kinases.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1943-1974"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442655","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}

引用次数: 0

Different Ras isoforms regulate synaptic plasticity in opposite directions. 不同的Ras亚型以相反的方向调节突触的可塑性。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-21 DOI: 10.1038/s44318-025-00390-8

Esperanza López-Merino, Alba Fernández-Rodrigo, Jessie G Jiang, Silvia Gutiérrez-Eisman, David Fernández de Sevilla, Alberto Fernández-Medarde, Eugenio Santos, Carmen Guerra, Mariano Barbacid, José A Esteban, Víctor Briz

{"title":"Different Ras isoforms regulate synaptic plasticity in opposite directions.","authors":"Esperanza López-Merino, Alba Fernández-Rodrigo, Jessie G Jiang, Silvia Gutiérrez-Eisman, David Fernández de Sevilla, Alberto Fernández-Medarde, Eugenio Santos, Carmen Guerra, Mariano Barbacid, José A Esteban, Víctor Briz","doi":"10.1038/s44318-025-00390-8","DOIUrl":"10.1038/s44318-025-00390-8","url":null,"abstract":"The small GTPase Ras is an intracellular signaling hub required for long-term potentiation (LTP) in the hippocampus and for memory formation. Genetic alterations in Ras signaling (i.e., RASopathies) are linked to cognitive disorders in humans. However, it remains unclear how Ras controls synaptic plasticity, and whether different Ras isoforms play overlapping or distinct roles in neurons. Using genetically modified mice, we show here that H-Ras (the most abundant isoform in the brain) does not promote LTP, but instead long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). Mechanistically, H-Ras is activated locally in spines during mGluR-LTD via c-Src, and is required to trigger Erk activation and de novo protein synthesis. Furthermore, H-Ras deletion impairs object recognition as well as social and spatial memory. Conversely, K-Ras is the isoform specifically required for LTP. This functional specialization correlates with a differential synaptic distribution of the two isoforms H-Ras and K-Ras, which may have important implications for RASopathies and cognitive function.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2106-2133"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473192","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}

引用次数: 0