The EMBO Journal最新文献

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FTO promotes weight gain via altering Kif1a splicing and axonal vesicle trafficking in AgRP neurons. FTO通过改变AgRP神经元的Kif1a剪接和轴突囊泡运输来促进体重增加。
The EMBO Journal Pub Date : 2025-07-09 DOI: 10.1038/s44318-025-00503-3
Daisuke Kohno,Reika Kawabata-Iwakawa,Sotaro Ichinose,Shigetomo Suyama,Kazuto Ohashi,Winda Ariyani,Tetsushi Sadakata,Hiromi Yokota-Hashimoto,Ryosuke Kobayashi,Takuro Horii,Vina Yanti Susanti,Ayumu Konno,Haruka Tsuneoka,Chiharu Yoshikawa,Sho Matsui,Akihiro Harada,Toshihiko Yada,Izuho Hatada,Hirokazu Hirai,Masahiko Nishiyama,Tsutomu Sasaki,Tadahiro Kitamura
{"title":"FTO promotes weight gain via altering Kif1a splicing and axonal vesicle trafficking in AgRP neurons.","authors":"Daisuke Kohno,Reika Kawabata-Iwakawa,Sotaro Ichinose,Shigetomo Suyama,Kazuto Ohashi,Winda Ariyani,Tetsushi Sadakata,Hiromi Yokota-Hashimoto,Ryosuke Kobayashi,Takuro Horii,Vina Yanti Susanti,Ayumu Konno,Haruka Tsuneoka,Chiharu Yoshikawa,Sho Matsui,Akihiro Harada,Toshihiko Yada,Izuho Hatada,Hirokazu Hirai,Masahiko Nishiyama,Tsutomu Sasaki,Tadahiro Kitamura","doi":"10.1038/s44318-025-00503-3","DOIUrl":"https://doi.org/10.1038/s44318-025-00503-3","url":null,"abstract":"N6-methyladenosine (m6A) is an abundant chemical RNA modification involved in the regulation of many biological processes. The m6A demethylase FTO (fat mass and obesity-associated protein) is known to affect body weight, but its systemic context and underlying mechanisms remain unclear. Here, we found that mice lacking or overexpressing Fto in agouti-related peptide-expressing (AgRP) neurons in the hypothalamus exhibited decreased and increased body weight, respectively. FTO demethylated m6A on mRNAs for proteins associated with membrane trafficking and alternative splicing in AgRP neurons. Downstream, FTO-modulated alternative splicing of the axonal motor protein Kif1a affected its hinge region, which is relevant to the structure and function of KIF1A. Notably, Kif1a knockdown in AgRP neurons suppressed the weight gain of mice overexpressing Fto. In addition, FTO increased the trafficking and secretion of dense-core vesicles containing neuropeptides NPY and AgRP from AgRP neurons. Collectively, these results reveal a novel regulatory FTO-KIF1A axis in the brain affecting appetite-stimulating AgRP neurons and systemic energy homeostasis, via FTO regulation of the epitranscriptome of AgRP neurons.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594402","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
Author Correction: The kinase TNIK is an essential activator of Wnt target genes. 作者更正:TNIK激酶是Wnt靶基因的重要激活因子。
The EMBO Journal Pub Date : 2025-07-09 DOI: 10.1038/s44318-025-00393-5
Tokameh Mahmoudi,Vivian S W Li,Ser Sue Ng,Nadia Taouatas,Robert G J Vries,Shabaz Mohammed,Albert J Heck,Hans Clevers
{"title":"Author Correction: The kinase TNIK is an essential activator of Wnt target genes.","authors":"Tokameh Mahmoudi,Vivian S W Li,Ser Sue Ng,Nadia Taouatas,Robert G J Vries,Shabaz Mohammed,Albert J Heck,Hans Clevers","doi":"10.1038/s44318-025-00393-5","DOIUrl":"https://doi.org/10.1038/s44318-025-00393-5","url":null,"abstract":"","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594400","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
Advances, challenges, and opportunities of human midbrain organoids for modelling of the dopaminergic system. 人类中脑类器官用于多巴胺能系统建模的进展、挑战和机遇。
The EMBO Journal Pub Date : 2025-07-02 DOI: 10.1038/s44318-025-00494-1
Alessandro Fiorenzano,Edoardo Sozzi,Rahel Kastli,Maria Roberta Iazzetta,Andreas Bruzelius,Paola Arlotta,Malin Parmar
{"title":"Advances, challenges, and opportunities of human midbrain organoids for modelling of the dopaminergic system.","authors":"Alessandro Fiorenzano,Edoardo Sozzi,Rahel Kastli,Maria Roberta Iazzetta,Andreas Bruzelius,Paola Arlotta,Malin Parmar","doi":"10.1038/s44318-025-00494-1","DOIUrl":"https://doi.org/10.1038/s44318-025-00494-1","url":null,"abstract":"Dopaminergic neurons in the ventral midbrain are critical for regulating movement, cognition, and emotion. Ventral midbrain organoids can be used to model both development and diseases of the dopaminergic system, especially Parkinson's disease. Here, we summarize recent advances and remaining challenges in developing such three-dimensional organoids from human pluripotent stem cells. We outline how ventral midbrain organoid systems have progressed from early three-dimensional culture models to sophisticated, engineered, multiregional systems that more accurately replicate the complex network of dopaminergic neurons. Furthermore, we examine how the development of organoid models from other brain regions, particularly the forebrain, provides complementary insights that can accelerate progress also in the field of midbrain organoids, towards the generation of more advanced in vitro systems for midbrain dopaminergic neurons and their circuitry. Such cutting-edge human stem cell-based models offer powerful platforms for investigating dopaminergic neuron generation, function, and connectivity, thereby enhancing disease modelling, drug discovery, and the development of targeted cell-based therapies.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547833","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
Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A. 鞘氨醇同时抑制核进口并通过结合进口蛋白和PPP2R1A激活PP2A。
The EMBO Journal Pub Date : 2025-06-30 DOI: 10.1038/s44318-025-00490-5
Vaishali Jayashankar,Peter Kubiniok,Alison N McCracken,Rebeca G Gentry,Kazumi H Eckenstein,Lorenzo Sernissi,Vito Vece,Jean-Baptiste Garsi,Sarah Y Valles,Sunhee Jung,Natalie C Hoffman,Arielle S Perrochon,Elizabeth M Selwan,Brendan T Finicle,Mary Pitman,DaWei Lin,Éric Bonneil,Ruijuan Xu,Cungui Mao,Peter Kaiser,David A Fruman,David Mobley,Cholsoon Jang,Stephen Hanessian,Pierre Thibault,Aimee L Edinger
{"title":"Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A.","authors":"Vaishali Jayashankar,Peter Kubiniok,Alison N McCracken,Rebeca G Gentry,Kazumi H Eckenstein,Lorenzo Sernissi,Vito Vece,Jean-Baptiste Garsi,Sarah Y Valles,Sunhee Jung,Natalie C Hoffman,Arielle S Perrochon,Elizabeth M Selwan,Brendan T Finicle,Mary Pitman,DaWei Lin,Éric Bonneil,Ruijuan Xu,Cungui Mao,Peter Kaiser,David A Fruman,David Mobley,Cholsoon Jang,Stephen Hanessian,Pierre Thibault,Aimee L Edinger","doi":"10.1038/s44318-025-00490-5","DOIUrl":"https://doi.org/10.1038/s44318-025-00490-5","url":null,"abstract":"Sphingosine and constrained analogs like FTY720 and SH-BC-893 restrain tumor growth through incompletely defined mechanisms that include protein phosphatase 2A (PP2A) activation. Here we show that these compounds directly bind not only the PP2A scaffolding subunit PPP2R1A, but also the structurally related karyopherins importin-β1 (KPNB1), transportin-1 (TNPO1), importin-5 (IPO5), and importin-7 (IPO7). Binding to sphingosine-like molecules triggers reversible unfolding of these target proteins, resulting in activation of PP2A and inhibition of importins. Although sphingosine engages these proteins, ceramide does not, suggesting that these two endogenous tumor-suppressive sphingolipids work through distinct mechanisms. Simultaneous PP2A activation and importin inhibition reduces nuclear levels of proteins that drive cancer progression and therapeutic resistance such as JUN, YAP, MYC, androgen receptor, hnRNPA1, and NF-κB under conditions where compounds that target PP2A or KPNB1 individually are inactive. These findings provide new insights into sphingolipid biology and highlight a possible path toward cancer therapeutics that could overcome drug resistance.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521429","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
Temperature-dependent modulation of light-induced circadian responses in Drosophila melanogaster. 黑腹果蝇光诱导昼夜节律反应的温度依赖性调节。
The EMBO Journal Pub Date : 2025-06-30 DOI: 10.1038/s44318-025-00499-w
Yue Tian,Hailiang Li,Wenjing Ye,Xin Yuan,Xuan Guo,Fang Guo
{"title":"Temperature-dependent modulation of light-induced circadian responses in Drosophila melanogaster.","authors":"Yue Tian,Hailiang Li,Wenjing Ye,Xin Yuan,Xuan Guo,Fang Guo","doi":"10.1038/s44318-025-00499-w","DOIUrl":"https://doi.org/10.1038/s44318-025-00499-w","url":null,"abstract":"Animals entrain their circadian rhythms to multiple external signals, such as light and temperature, which are integrated in master clock neurons to adjust circadian phases. However, the precise mechanisms underlying this process remain unclear. Here, we use in vivo two-photon calcium imaging while precisely controlling temperature to investigate how the Drosophila melanogaster circadian clock integrates light and temperature inputs in circadian neurons. We show that light responses modulate the circadian clock in central pacemaker neurons, with temperature acting as a fine-tuning mechanism to achieve optimal adaptation. Our results suggest that temperature-sensitive dorsal clock neurons DN1as regulate the light-induced firing of s-LNv circadian pacemaker neurons and release of the neuropeptide PDF through inhibitory glutamatergic signaling. Specifically, higher temperatures suppress s-LNv firing upon light exposure, while lower temperatures enhance this response. Behavioral analyses further indicate that lower temperatures accelerate phase adjustment, whereas higher temperatures decelerate them in response to new light-dark cycles. This novel mechanism of temperature-dependent modulation of circadian phase adjustment provides new insights into the adaptive strategies of animals for survival in fluctuating environments.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521430","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
WIP1 mutations suppress DNA damage triggered bypass of the mitotic timer. WIP1突变抑制DNA损伤触发的有丝分裂定时器旁路。
The EMBO Journal Pub Date : 2025-06-23 DOI: 10.1038/s44318-025-00495-0
Tomoaki Sobajima,Luke J Fulcher,Caleb Batley,Susanna J Alsop,Jonah Veakins,Francis A Barr
{"title":"WIP1 mutations suppress DNA damage triggered bypass of the mitotic timer.","authors":"Tomoaki Sobajima,Luke J Fulcher,Caleb Batley,Susanna J Alsop,Jonah Veakins,Francis A Barr","doi":"10.1038/s44318-025-00495-0","DOIUrl":"https://doi.org/10.1038/s44318-025-00495-0","url":null,"abstract":"Prolonged mitosis results in the destruction of MDM2, initiating a p53-dependent G1 cell-cycle arrest in the absence of DNA damage. Here, we investigate how DNA damage earlier in the cell cycle affects this mitotic-timer response. We find that G2-DNA damage triggers highly penetrant bypass of mitosis and of the mitotic timer, generating tetraploid cells arrested in G1. Collapse of G2 to G1 after DNA damage is initiated by p21-mediated CDK2 inhibition and rendered irreversible by the destruction of G2/M-cyclins A and B. This behaviour is altered in cells with cancer-associated mutations in the p53-phosphatase WIP1 (PPM1D), which increase the threshold for DNA-damage signalling, enabling DNA-damaged G2 cells to enter mitosis with elevated levels of MDM2, thereby suppressing mitotic-timer-dependent G1 cell-cycle arrest. Importantly, neither WIP1 mutations nor knockout prevent p53-dependent G1-arrest in response to prolonged mitosis in the absence of DNA damage. Prolonged mitosis and G2-DNA damage thus promote p53-dependent G1 cell-cycle exit through discrete routes with differential requirements for WIP1 and genotoxic stress.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370188","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
Epiblast-derived CX3CR1+ progenitors generate cardiovascular cells during cardiogenesis. 内皮细胞衍生的CX3CR1+祖细胞在心脏发生过程中产生心血管细胞。
The EMBO Journal Pub Date : 2025-06-23 DOI: 10.1038/s44318-025-00488-z
Kyuwon Cho,Mark Andrade,S Khodayari Khodayari,Christine Lee,Seongho Bae,Sangsung Kim,Jin Eyun Kim,Young-Sup Yoon
{"title":"Epiblast-derived CX3CR1+ progenitors generate cardiovascular cells during cardiogenesis.","authors":"Kyuwon Cho,Mark Andrade,S Khodayari Khodayari,Christine Lee,Seongho Bae,Sangsung Kim,Jin Eyun Kim,Young-Sup Yoon","doi":"10.1038/s44318-025-00488-z","DOIUrl":"https://doi.org/10.1038/s44318-025-00488-z","url":null,"abstract":"CX3CR1+ cells generate tissue macrophages in the developing heart and play cardioprotective roles in response to ischemic injuries in the adult heart. However, the origin and fate of CX3CR1+ cells during cardiogenesis remain unclear. Here, we performed genetic lineage tracing of CX3CR1+ cells and their progeny (termed Cx3cr1 lineage cells) in the mouse and demonstrated that they emerge from a subset of epiblast cells at embryonic day E6.5 and contribute to the parietal endoderm cells at E7.0. At E8.0-9.5 of development, Cx3cr1 lineage cells produced cardiomyocytes and endothelial cells via both de novo differentiation and fusion with pre-existing cardiomyocytes or endothelial cells, respectively. Cx3cr1 lineage cells persisted in the adult heart, comprising ~13% of cardiomyocytes and ~31% of endothelial cells. Additionally, CX3CR1+ cells differentiated from mouse embryonic stem cells generated cardiomyocytes, endothelial cells, and macrophages in vitro, ex vivo, and in vivo. Single-cell RNA sequencing revealed that Cx3cr1+ cells represent an intermediate cell population transitioning from embryonic stem cells to mesoderm. Taken together, embryonic CX3CR1+ cells constitute a multipotent epiblast-derived progenitor population that contributes not only to the formation of macrophages, but also of cardiomyocytes and endothelial cells.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370187","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
Adipose tissue-secreted Spz5 promotes distal tumor progression via Toll-6-mediated Hh pathway activation in Drosophila. 在果蝇中,脂肪组织分泌的Spz5通过toll -6介导的Hh通路激活促进肿瘤远端进展。
The EMBO Journal Pub Date : 2025-06-23 DOI: 10.1038/s44318-025-00489-y
Du Kong,Xiaoqin Li,Sihua Zhao,Chenliang Wang,Zixin Cai,Sha Song,Yifan Guo,Xiaoyu Kuang,Xianping Wang,Wenhan Liu,Peng Liu,Xiaowei Guo,Wenyan Xu,Yirong Wang,Bin Zhao,Bin Jin,Li He,Xianjue Ma
{"title":"Adipose tissue-secreted Spz5 promotes distal tumor progression via Toll-6-mediated Hh pathway activation in Drosophila.","authors":"Du Kong,Xiaoqin Li,Sihua Zhao,Chenliang Wang,Zixin Cai,Sha Song,Yifan Guo,Xiaoyu Kuang,Xianping Wang,Wenhan Liu,Peng Liu,Xiaowei Guo,Wenyan Xu,Yirong Wang,Bin Zhao,Bin Jin,Li He,Xianjue Ma","doi":"10.1038/s44318-025-00489-y","DOIUrl":"https://doi.org/10.1038/s44318-025-00489-y","url":null,"abstract":"Interorgan communication is vital for tissue homeostasis and health in multicellular organisms, and its disruption can lead to diseases such as cancer. Adipose tissue acts as a key endocrine center, secreting cytokines that influence remote organs. Despite clear links between obesity and increased cancer risk, the underlying mechanisms are unclear. Here, utilizing a Drosophila genetic model combining Gal4-UAS and QF-QUAS tissue-specific transgene expression systems, we reveal that adipose-secreted Spz5 ligand promotes distal epithelial tumor overgrowth and invasion. Mechanistically, Spz5 binds to tumor cell Toll-6 receptors, triggering the degradation of the endocytic adaptor protein AP-2α via Mib1-mediated ubiquitination. Consequently, impaired endocytosis leads to Smoothened (Smo) accumulation on the cell membrane and subsequent activation of the Hedgehog (Hh) pathway. This abnormal Hh activation synergizes with the oncogenic Yorkie (Yki) to drive tumor growth and invasion. Furthermore, tumor-derived Unpaired ligands (Upds) activate the JAK-STAT pathway in the fat bodies, which leads to Hippo pathway-dependent upregulation of spz5 expression. Thus, our study provides insights into the complex regulatory mechanisms by which systemic interorgan communication influences tumor progression.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"107 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370237","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
Copine-6 is a TRPM3 escort protein controlling the sensitivity of sensory neurons to noxious heat. Copine-6是一种TRPM3护送蛋白,控制感觉神经元对有害热量的敏感性。
The EMBO Journal Pub Date : 2025-06-19 DOI: 10.1038/s44318-025-00487-0
Yiting Gao,Shengxiang Yan,Zhongyang Zhang,Jieyao Zhang,Meng Yang,Shihab Shah,Sofia Figoli,Qi Jing,Haixia Gao,Nikita Gamper
{"title":"Copine-6 is a TRPM3 escort protein controlling the sensitivity of sensory neurons to noxious heat.","authors":"Yiting Gao,Shengxiang Yan,Zhongyang Zhang,Jieyao Zhang,Meng Yang,Shihab Shah,Sofia Figoli,Qi Jing,Haixia Gao,Nikita Gamper","doi":"10.1038/s44318-025-00487-0","DOIUrl":"https://doi.org/10.1038/s44318-025-00487-0","url":null,"abstract":"Copine-6 is a calcium-sensitive phospholipid-binding protein of the evolutionarily conserved Copine family. In the central nervous system, Copine-6 regulates function of some neurotransmitter receptors and structural plasticity of dendritic spines, influencing learning and memory. Copine-6 is expressed in peripheral somatosensory neurons, but its role in somatosensation remains unclear. Here we demonstrate that Copine-6 plays a prominent role in thermosensation. Copine-6 is highly expressed in a subpopulation of dorsal root ganglia (DRG) neurons that also express thermosensitive TRPM3 channels. Genetic deletion or downregulation of Copine-6 in the DRG in vivo selectively impairs sensitivity to noxious heat, without affecting other sensory modalities, and significantly reduced TRPM3 currents in DRG neurons. Copine-6 interacts with TRPM3 via its von Willebrand factor A (vWA) domain, promoting TRPM3 translocation to the plasma membrane. Thus, Copine-6-dependent TRPM3 trafficking determines noxious-heat sensitivity range of the nerve fibers; moreover, Copine-6 is an accessible target for the treatment of heat hypersensitivity in chronic inflammatory and neuropathic pain.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"89 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328834","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
Lysine myristoylation mediates long-term potentiation via membrane enrichment of synaptic plasticity effectors. 赖氨酸肉豆蔻酰化通过突触可塑性效应物的膜富集介导长期增强。
The EMBO Journal Pub Date : 2025-06-17 DOI: 10.1038/s44318-025-00484-3
Benjamin Matthews,Sevannah A Steeves,Isaac O Akefe,Noorya Yasmin Ahmed,Rachel S Gormal,Nathalie Dehorter,Tristan P Wallis,Frédéric A Meunier
{"title":"Lysine myristoylation mediates long-term potentiation via membrane enrichment of synaptic plasticity effectors.","authors":"Benjamin Matthews,Sevannah A Steeves,Isaac O Akefe,Noorya Yasmin Ahmed,Rachel S Gormal,Nathalie Dehorter,Tristan P Wallis,Frédéric A Meunier","doi":"10.1038/s44318-025-00484-3","DOIUrl":"https://doi.org/10.1038/s44318-025-00484-3","url":null,"abstract":"Synaptic plasticity underlying long-term memory is associated with the generation of saturated free fatty acids (sFFAs) -particularly myristic acid- from membrane phospholipids by the phospholipase A1 isoform DDHD2. However, the mechanism through which myristic acid contributes to synaptic plasticity remains elusive. Here we demonstrate that DDHD2-derived myristic acid is rapidly converted to myristoyl CoA, which serves as the substrate for N-myristoyl transferases (NMT1/2), to promote post-translational lysine myristoylation of synaptic proteins. Chemically-induced long-term potentiation (cLTP) in cortical neurons increases both sFFAs and their CoA-conjugates, predominantly myristoyl CoA, and this response is blocked by the DDHD2 inhibitor KLH-45. KLH-45-mediated inhibition of DDHD2 or IMP-1088-mediated inhibition of NMT1/2 also disrupts cLTP-induced proteomic changes, impairs dendritic spine remodeling, and prevents LTP in hippocampal slices. Instrumental conditioning further induces proteomic changes in the hippocampus, which are abolished in learning-deficient DDHD2-/- knockout mice. In these mice, key synaptic proteins such as NMDA receptor subunit GluN1, MAP2, and GAS7 fail to undergo learning-induced changes, effectively linking DDHD2 function to learning-dependent proteome remodeling. Our findings reveal that de novo lysine myristoylation promotes synaptic plasticity and memory formation.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311615","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
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