EMBO Reports最新文献_第6页

FP10 - the Competitiveness Fund for Europe. FP10 -欧洲竞争力基金。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-05-01 Epub Date: 2025-04-24 DOI: 10.1038/s44319-025-00462-0

Liselotte Højgaard

引用次数: 0

tRNA lysidinylation is essential for the minimal translation system in the Plasmodium falciparum apicoplast. tRNA溶苷基化对于恶性疟原虫顶质体的最小翻译系统至关重要。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-05-01 Epub Date: 2025-03-20 DOI: 10.1038/s44319-025-00420-w

Rubayet Elahi, Sean T Prigge

{"title":"tRNA lysidinylation is essential for the minimal translation system in the Plasmodium falciparum apicoplast.","authors":"Rubayet Elahi, Sean T Prigge","doi":"10.1038/s44319-025-00420-w","DOIUrl":"10.1038/s44319-025-00420-w","url":null,"abstract":"For decades, researchers have sought to define minimal translation systems to uncover fundamental principles of life and advance biotechnology. tRNAs, essential components of this machinery, decode mRNA codons into amino acids. The apicoplast of malaria parasites contains 25 tRNA isotypes in its organellar genome-the lowest number found in known translation systems. Efficient translation in such minimal systems depends heavily on post-transcriptional tRNA modifications. One such modification, lysidine at the wobble position (C34) of tRNACAU, distinguishes between methionine (AUG) and isoleucine (AUA) codons. tRNA isoleucine lysidine synthetase (TilS) produces lysidine, which is nearly ubiquitous in bacteria and essential for cellular viability. Here, we report a TilS ortholog (PfTilS) targeted to the apicoplast of Plasmodium falciparum. We demonstrate that PfTilS activity is essential for parasite survival and apicoplast function, likely due to its role in protein translation. This study is the first to characterize TilS in an endosymbiotic organelle, contributing to research on eukaryotic organelles and minimal translational systems. Moreover, the absence of lysidine in humans highlights a potential target for antimalarial strategies.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"2300-2322"},"PeriodicalIF":6.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12069591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669293","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

Unlocking success : The power of change management in core facilities. 解锁成功：核心设施变革管理的力量。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-05-01 Epub Date: 2025-04-23 DOI: 10.1038/s44319-025-00445-1

Saskia Lippens, Katerina Hoskova, Ondrej Hradil, Jutta Steinkoetter, Henri G A M Van Luenen, Geert Van Minnebruggen, Danielle Hoyle

引用次数: 0

Beyond good and evil : The pursuit of philosophical and scientific truth in a time of moral ambiguity. 超越善恶：道德模糊时代对哲学和科学真理的追求。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-05-01 DOI: 10.1038/s44319-025-00465-x

G Paolo Dotto

引用次数: 0

Transcriptomic changes including p53 dysregulation prime DNMT3A mutant cells for transformation. 转录组学改变，包括p53失调，导致DNMT3A突变细胞转化。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-04-30 DOI: 10.1038/s44319-025-00450-4

Erin M Lawrence, Amali Cooray, Andrew J Kueh, Martin Pal, Lin Tai, Alexandra L Garnham, Connie S N Li-Wai-Suen, Hannah Vanyai, Quentin Gouil, James Lancaster, Sylvie Callegari, Lauren Whelan, Elizabeth Lieschke, Annabella Thomas, Andreas Strasser, Yang Liao, Wei Shi, Andrew H Wei, Marco J Herold

{"title":"Transcriptomic changes including p53 dysregulation prime DNMT3A mutant cells for transformation.","authors":"Erin M Lawrence, Amali Cooray, Andrew J Kueh, Martin Pal, Lin Tai, Alexandra L Garnham, Connie S N Li-Wai-Suen, Hannah Vanyai, Quentin Gouil, James Lancaster, Sylvie Callegari, Lauren Whelan, Elizabeth Lieschke, Annabella Thomas, Andreas Strasser, Yang Liao, Wei Shi, Andrew H Wei, Marco J Herold","doi":"10.1038/s44319-025-00450-4","DOIUrl":"https://doi.org/10.1038/s44319-025-00450-4","url":null,"abstract":"DNMT3A mutations are prevalent in haematologic malignancies. In our mouse model the murine homologue (R878H) of the human 'hotspot' R882H mutation is introduced into the mouse Dnmt3a locus. This results in globally reduced DNA methylation in all tissues. Mice with heterozygous R878H DNMT3A mutations develop γ-radiation induced thymic lymphoma more rapidly than control mice, suggesting a vulnerability to stress stimuli in Dnmt3aR878H/+ cells. In competitive transplantations, Dnmt3aR878H/+ Lin-Sca-1+Kit+ (LSK) haematopoietic stem/progenitor cells (HSPCs) have a competitive advantage over WT HSPCs, indicating a self-renewal phenotype at the expense of differentiation. RNA sequencing of Dnmt3aR878H/+ LSKs exposed to low dose γ-radiation shows downregulation of the p53 pathway compared to γ-irradiated WT LSKs. Accordingly, reduced PUMA expression is observed by flow cytometry in the bone marrow of γ-irradiated Dnmt3aR878H/+ mice due to impaired p53 signalling. These findings provide new insights into how DNMT3A mutations cause subtle changes in the transcriptome of LSK cells which contribute to their increased self-renewal and propensity for malignant transformation.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974773","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

Ganglioside GT1b prevents selective spinal synapse removal following peripheral nerve injury. 神经节苷脂GT1b防止周围神经损伤后选择性脊髓突触移除。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-04-30 DOI: 10.1038/s44319-025-00452-2

Jaesung Lee, Kyungchul Noh, Subeen Lee, Kwang Hwan Kim, Seohyun Chung, Hyoungsub Lim, Minkyu Hwang, Joon-Hyuk Lee, Won-Suk Chung, Sunghoe Chang, Sung Joong Lee

{"title":"Ganglioside GT1b prevents selective spinal synapse removal following peripheral nerve injury.","authors":"Jaesung Lee, Kyungchul Noh, Subeen Lee, Kwang Hwan Kim, Seohyun Chung, Hyoungsub Lim, Minkyu Hwang, Joon-Hyuk Lee, Won-Suk Chung, Sunghoe Chang, Sung Joong Lee","doi":"10.1038/s44319-025-00452-2","DOIUrl":"https://doi.org/10.1038/s44319-025-00452-2","url":null,"abstract":"After peripheral nerve injury, the structure of the spinal cord is actively regulated by glial cells, contributing to the chronicity of neuropathic pain. However, the mechanism by which peripheral nerve injury leads to synaptic imbalance remains elusive. Here, we use a pH-reporter system and find that nerve injury triggers a reorganization of excitatory synapses that is influenced by the accumulation of the ganglioside GT1b at afferent terminals. GT1b acts as a protective signal against nerve injury-induced spinal synapse elimination. Inhibition of GT1b-synthesis increases glial phagocytosis of excitatory pre-synapses and reduces excitatory synapses post-injury. In vitro analyses reveal a positive correlation between GT1b accumulation and the frequency of pre-synaptic calcium activity, with GT1b-mediated suppression of glial phagocytosis occurring through SYK dephosphorylation. Our study highlights GT1b's pivotal role in preventing synapse elimination after nerve injury and offers new insight into the molecular underpinning of activity-dependent synaptic stability and glial phagocytosis.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988105","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

Genetic disruption of the circadian gene Bmal1 in the intestinal epithelium reduces colonic inflammation. 肠上皮中昼夜节律基因Bmal1的遗传破坏可减少结肠炎症。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-04-30 DOI: 10.1038/s44319-025-00464-y

Shan Hua, Ze Zhang, Zhe Zhang, Liansheng Liu, Shicheng Yu, Yanhui Xiao, Yuan Liu, Siting Wei, Ying Xu, Ye-Guang Chen

{"title":"Genetic disruption of the circadian gene Bmal1 in the intestinal epithelium reduces colonic inflammation.","authors":"Shan Hua, Ze Zhang, Zhe Zhang, Liansheng Liu, Shicheng Yu, Yanhui Xiao, Yuan Liu, Siting Wei, Ying Xu, Ye-Guang Chen","doi":"10.1038/s44319-025-00464-y","DOIUrl":"https://doi.org/10.1038/s44319-025-00464-y","url":null,"abstract":"Disruption of the circadian clock is associated with the development of inflammatory bowel disease (IBD), but the underlying mechanisms remain unclear. Here, we observe that mice in the early active phase (Zeitgeber time 12, ZT12) of the circadian clock are more tolerant to dextran sodium sulfate (DSS)-induced colitis, compared to those in the early resting phase (ZT0). The expression of the circadian gene Bmal1 peaks in the early resting phase and declines in the early active phase. Bmal1 knockout in the intestinal epithelium reduces DSS-induced inflammatory symptoms. Mechanistically, BMAL1 promotes apoptosis by binding to apoptosis-related genes, including Bax, p53, and Bak1, and promotes their expression. Intriguingly, we observe circadian apoptotic rhythms in the homeostatic intestinal epithelium, while Bmal1 deletion reduces cell apoptosis. Consistently, reducing Bmal1 expression by the REV-ERBα agonist SR9009 has the best therapeutic efficacy against DSS-induced colitis at ZT0. Collectively, our data demonstrate that the Bmal1-centered circadian clock is involved in intestinal injury repair.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977545","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

mTOR controls ependymal cell differentiation by targeting the alternative cell cycle and centrosomal proteins. mTOR通过靶向细胞周期和中心体蛋白调控室管膜细胞分化。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-04-30 DOI: 10.1038/s44319-025-00460-2

Alexia Bankolé, Ayush Srivastava, Asm Shihavuddin, Khaled Tighanimine, Marion Faucourt, Vonda Koka, Solene Weill, Ivan Nemazanyy, Alissa J Nelson, Matthew P Stokes, Nathalie Delgehyr, Auguste Genovesio, Alice Meunier, Stefano Fumagalli, Mario Pende, Nathalie Spassky

{"title":"mTOR controls ependymal cell differentiation by targeting the alternative cell cycle and centrosomal proteins.","authors":"Alexia Bankolé, Ayush Srivastava, Asm Shihavuddin, Khaled Tighanimine, Marion Faucourt, Vonda Koka, Solene Weill, Ivan Nemazanyy, Alissa J Nelson, Matthew P Stokes, Nathalie Delgehyr, Auguste Genovesio, Alice Meunier, Stefano Fumagalli, Mario Pende, Nathalie Spassky","doi":"10.1038/s44319-025-00460-2","DOIUrl":"https://doi.org/10.1038/s44319-025-00460-2","url":null,"abstract":"Ependymal cells are multiciliated glial cells lining the ventricles of the mammalian brain. Their differentiation from progenitor cells involves cell enlargement and progresses through centriole amplification phases and ciliogenesis. These phases are accompanied by the sharp up-regulation of mTOR Complex 1 activity (mTORC1), a master regulator of macromolecule biosynthesis and cell growth, whose function in ependymal cell differentiation is unknown. We demonstrate that mTORC1 inhibition by rapamycin preserves the progenitor pool by reinforcing quiescence and preventing alternative cell cycle progression for centriole amplification. Overexpressing E2F4 and MCIDAS circumvents mTORC1-regulated processes, enabling centriole amplification despite rapamycin, and enhancing mTORC1 activity through positive feedback. Acute rapamycin treatment in multicentriolar cells during the late phases of differentiation causes centriole regrouping, indicating a direct role of mTORC1 in centriole dynamics. By phosphoproteomic and phosphomutant analysis, we reveal that the mTORC1-mediated phosphorylation of GAS2L1, a centrosomal protein that links actin and microtubule cytoskeletons, participates in centriole disengagement. This multilayered and sequential control of ependymal development by mTORC1, from the progenitor pool to centriolar function, has implications for pathophysiological conditions like aging and hydrocephalus-prone genetic diseases.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974770","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

Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism. 时间分辨线粒体屏幕识别氧化代谢的调节成分。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-04-29 DOI: 10.1038/s44319-025-00459-9

Marcos Zamora-Dorta, Sara Laine-Menéndez, David Abia, Pilar González-García, Luis C López, Paula Fernández-Montes, Enrique Calvo, Jesús Vázquez, José Antonio Enríquez, Eduardo Balsa

{"title":"Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.","authors":"Marcos Zamora-Dorta, Sara Laine-Menéndez, David Abia, Pilar González-García, Luis C López, Paula Fernández-Montes, Enrique Calvo, Jesús Vázquez, José Antonio Enríquez, Eduardo Balsa","doi":"10.1038/s44319-025-00459-9","DOIUrl":"https://doi.org/10.1038/s44319-025-00459-9","url":null,"abstract":"Defects in mitochondrial oxidative metabolism underlie many genetic disorders with limited treatment options. The incomplete annotation of mitochondrial proteins highlights the need for a comprehensive gene inventory, particularly for Oxidative Phosphorylation (OXPHOS). To address this, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings to identify novel regulators of mitochondrial function. Our study generates a gene catalog essential for mitochondrial metabolism and maps a dynamic network of mitochondrial pathways, focusing on OXPHOS complexes. Computational analysis identifies RTN4IP1 and ECHS1 as key OXPHOS genes linked to mitochondrial diseases in humans. RTN4IP1 is found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Its deletion impairs branched-chain amino acids (BCAA) catabolism, disrupting lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992446","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

DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition. DDB1的结合定义了S656类似物对细胞周期蛋白K降解的选择性，而不是CDK抑制。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-04-28 DOI: 10.1038/s44319-025-00448-y

Céline Moison, Rodrigo Mendoza-Sanchez, Deanne Gracias, Doris A Schuetz, Jean-François Spinella, Simon Girard, Bounkham Thavonekham, Jalila Chagraoui, Aurélie Durand, Simon Fortier, Tara MacRae, Eric Bonneil, Yannick Rose, Nadine Mayotte, Isabel Boivin, Pierre Thibault, Josée Hébert, Réjean Ruel, Anne Marinier, Guy Sauvageau

{"title":"DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition.","authors":"Céline Moison, Rodrigo Mendoza-Sanchez, Deanne Gracias, Doris A Schuetz, Jean-François Spinella, Simon Girard, Bounkham Thavonekham, Jalila Chagraoui, Aurélie Durand, Simon Fortier, Tara MacRae, Eric Bonneil, Yannick Rose, Nadine Mayotte, Isabel Boivin, Pierre Thibault, Josée Hébert, Réjean Ruel, Anne Marinier, Guy Sauvageau","doi":"10.1038/s44319-025-00448-y","DOIUrl":"https://doi.org/10.1038/s44319-025-00448-y","url":null,"abstract":"In efforts to identify additional therapeutic targets for Acute Myeloid Leukemia (AML), we performed a high-throughput screen that includes 56 primary specimens tested with 10,000 structurally diverse small molecules. One specific hit, called S656 acts as a molecular glue degrader (MGD), that mediates the CRL4-dependent proteolysis of cyclin K. Structurally, S656 features a moiety that binds to the ATP binding site of cyclin-dependent kinases (CDKs), allowing the recruitment of the CDK12-cyclin K complex, along with a binding site for DDB1 bridging the CRL4 complex. Structure activity relationship studies reveal that minimal modifications to the dimethylaniline moiety of S656 improve its cyclin K MGD function over CDK inhibition by promoting DDB1 engagement. This includes full occupation of the DDB1 pocket, preferably with hydrophobic terminal groups, and cation-π interaction with Arg928. Additionally, we demonstrate that despite structural diversity, cyclin K degraders exhibit similar functional activity in AML which is distinct from direct CDK12 inhibition.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997747","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