EMBO Reports最新文献_第2页

Oncogenic YAP sensitizes cells to CHK1 inhibition via CDK4/6 driven G1 acceleration. 致癌YAP通过CDK4/6驱动的G1加速使细胞对CHK1抑制敏感。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-04 DOI: 10.1038/s44319-025-00514-5

Dörthe Gertzmann, Cornelius Presek, Anna Lena Mattes, Marco Sänger, Marie Zoller, Christina Schülein-Völk, Carsten P Ade, Martin Eilers, Stefan Gaubatz

{"title":"Oncogenic YAP sensitizes cells to CHK1 inhibition via CDK4/6 driven G1 acceleration.","authors":"Dörthe Gertzmann, Cornelius Presek, Anna Lena Mattes, Marco Sänger, Marie Zoller, Christina Schülein-Völk, Carsten P Ade, Martin Eilers, Stefan Gaubatz","doi":"10.1038/s44319-025-00514-5","DOIUrl":"https://doi.org/10.1038/s44319-025-00514-5","url":null,"abstract":"Replication stress is a driver of genomic instability, contributing to carcinogenesis by causing DNA damage and mutations. While YAP, the downstream co-activator of the Hippo signaling pathway, plays a crucial role in regulating cell growth and differentiation, it is unclear whether it generates replication stress exploitable for therapy. Here, we report that oncogenic YAP shortens the G1 phase through increased CDK4/6 activity, leading to early S-phase entry. This causes origin underlicensing, an overall reduced rate of DNA replication, and, unusually, an accelerated speed of individual replication forks. CHK1 inhibition in cells expressing oncogenic YAP results in DNA damage during S-phase, which is not due to premature CDK1 activation or mitotic entry. Sensitivity to CHK1 inhibition depends on the YAP-TEAD interaction and involves a global increase in transcription and an increase in transcription-replication conflicts (TRCs). Replication stress from oncogenic YAP can be mitigated by restoring G1 length through partial CDK4/6 inhibition or by reducing YAP-induced hypertranscription. Our findings suggest a potential therapeutic strategy for targeting YAP-dependent cancers by exploiting their vulnerability to replication stress.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564695","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

Identification of a fungal antibacterial endopeptidase that cleaves peptidoglycan. 分离肽聚糖的真菌抗菌内肽酶的鉴定。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-04 DOI: 10.1038/s44319-025-00508-3

Silke Machata, Ute Bertsche, Franziska Hoffmann, Zaher M Fattal, Franziska Kage, Michal Flak, Alexander N J Iliou, Falk Hillmann, Ferdinand von Eggeling, Hortense Slevogt, Axel A Brakhage, Ilse D Jacobsen

{"title":"Identification of a fungal antibacterial endopeptidase that cleaves peptidoglycan.","authors":"Silke Machata, Ute Bertsche, Franziska Hoffmann, Zaher M Fattal, Franziska Kage, Michal Flak, Alexander N J Iliou, Falk Hillmann, Ferdinand von Eggeling, Hortense Slevogt, Axel A Brakhage, Ilse D Jacobsen","doi":"10.1038/s44319-025-00508-3","DOIUrl":"https://doi.org/10.1038/s44319-025-00508-3","url":null,"abstract":"Aspergillus fumigatus is a saprophytic fungus dwelling in soil and on decaying plant material, but also an opportunistic pathogen in immunocompromised patients. In its environmental niche, A. fumigatus faces competition from other microorganisms including bacteria. Here, we describe the discovery of the first secreted antibacterial protein in A. fumigatus. We identify a secreted fungal endopeptidase, designated CwhA, that cleaves peptidoglycan of Gram-positive bacteria at specific residues within the peptidoglycan stem peptide. Cleavage leads to bacterial lysis and the release of peptidoglycan cleavage products. Expression of cwhA is induced by the presence of bacteria. Furthermore, CwhA is highly abundant in murine lungs during invasive pulmonary aspergillosis and peptidoglycan cleavage products generated by CwhA stimulate cytokine production of human immune cells in vitro. Although CwhA does not affect human cells directly, this novel player in fungal-bacterial interactions could affect A. fumigatus infections by inhibiting Gram-positive bacteria in its vicinity, and possibly modulate the immune system.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564692","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

NAT10-mediated acetylation of NIK mRNA in B cells promotes IgA production. nat10介导的B细胞NIK mRNA乙酰化促进了IgA的产生。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-04 DOI: 10.1038/s44319-025-00509-2

Wan-Jun Jiang, Xin-Tao Mao, Wen-Ping Li, Nicole Jin, Yu Wang, Guiping Guan, Jin Jin, Yi-Yuan Li

引用次数: 0

Palmitoylated importin α regulates mitotic spindle orientation through interaction with NuMA. 棕榈酰化输入蛋白α通过与NuMA相互作用调节有丝分裂纺锤体取向。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-01 Epub Date: 2025-05-27 DOI: 10.1038/s44319-025-00484-8

Patrick James Sutton, Natalie Mosqueda, Christopher W Brownlee

{"title":"Palmitoylated importin α regulates mitotic spindle orientation through interaction with NuMA.","authors":"Patrick James Sutton, Natalie Mosqueda, Christopher W Brownlee","doi":"10.1038/s44319-025-00484-8","DOIUrl":"10.1038/s44319-025-00484-8","url":null,"abstract":"Regulation of cell division orientation is a fundamental process critical to differentiation and tissue homeostasis. Microtubules emanating from the mitotic spindle pole bind a conserved complex of proteins at the cell cortex which orients the spindle and ultimately the cell division plane. Control of spindle orientation is of particular importance in developing tissues, such as the developing brain. Misorientation of the mitotic spindle and thus subsequent division plane misalignment can contribute to improper segregation of cell fate determinants in developing neuroblasts, leading to a rare neurological disorder known as microcephaly. We demonstrate that the nuclear transport protein importin α, when palmitoylated, plays a critical role in mitotic spindle orientation through localizing factors, such as NuMA, to the cell cortex. We also observe craniofacial developmental defects in Xenopus laevis when importin α palmitoylation is abrogated, including smaller head and brains, a hallmark of spindle misorientation and microcephaly. These findings characterize not only a role for importin α in spindle orientation, but also a broader role for importin α palmitoylation which has significance for many cellular processes.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3280-3304"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157325","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

Inflammation and IL-4 regulate Parkinson's and Crohn's disease associated kinase LRRK2. 炎症和IL-4调节帕金森病和克罗恩病相关激酶LRRK2。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-01 Epub Date: 2025-05-20 DOI: 10.1038/s44319-025-00473-x

Dina Dikovskaya, Rebecca Pemberton, Matthew Taylor, Anna Tasegian, Purbasha Bhattacharya, Karolina Zeneviciute, Esther M Sammler, Andrew J M Howden, Dario R Alessi, Mahima Swamy

{"title":"Inflammation and IL-4 regulate Parkinson's and Crohn's disease associated kinase LRRK2.","authors":"Dina Dikovskaya, Rebecca Pemberton, Matthew Taylor, Anna Tasegian, Purbasha Bhattacharya, Karolina Zeneviciute, Esther M Sammler, Andrew J M Howden, Dario R Alessi, Mahima Swamy","doi":"10.1038/s44319-025-00473-x","DOIUrl":"10.1038/s44319-025-00473-x","url":null,"abstract":"Mutations in Leucine-Rich Repeat protein Kinase 2 (LRRK2) are associated with Parkinson's disease (PD) and Crohn's disease (CD), but the regulation of LRRK2 during inflammation remains relatively unexplored. Here we describe the development of a flow cytometry-based assay to assess LRRK2 activity in individual cells and the generation of an EGFP-Lrrk2 knock-in reporter mouse to analyse cell-specific LRRK2 expression. Using these tools, we measured LRRK2 levels and activity in murine splenic and intestinal immune cells and in human blood. Anti-CD3 induced inflammation increases LRRK2 expression and activity in B cells and monocytes, while in mature neutrophils, inflammation stimulates activity but reduces LRRK2 expression. A kinase-activating PD-associated LRRK2-R1441C mutation exacerbates inflammation-induced activation of LRRK2 specifically in monocytes and macrophages. We identify IL-4 as a novel T-cell-derived factor that upregulates LRRK2 expression and activity in B cells, replicating inflammatory effects observed in vivo. Our findings provide valuable new insights into the regulation of the LRRK2 pathway in immune cells, crucial for understanding LRRK2 and its therapeutic potential in inflammatory diseases such as CD.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3327-3356"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109822","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

Laminin-defined mechanical status modulates retinal pigment epithelium phagocytosis. 层粘连蛋白定义的机械状态调节视网膜色素上皮吞噬。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-01 Epub Date: 2025-05-19 DOI: 10.1038/s44319-025-00475-9

Aleksandra N Kozyrina, Teodora Piskova, Francesca Semeraro, Iris C Doolaar, Taspia Prapty, Tamás Haraszti, Maxime Hubert, Reinhard Windoffer, Rudolf E Leube, Ana-Sunčana Smith, Jacopo Di Russo

{"title":"Laminin-defined mechanical status modulates retinal pigment epithelium phagocytosis.","authors":"Aleksandra N Kozyrina, Teodora Piskova, Francesca Semeraro, Iris C Doolaar, Taspia Prapty, Tamás Haraszti, Maxime Hubert, Reinhard Windoffer, Rudolf E Leube, Ana-Sunčana Smith, Jacopo Di Russo","doi":"10.1038/s44319-025-00475-9","DOIUrl":"10.1038/s44319-025-00475-9","url":null,"abstract":"Epithelial cells exhibit strong interconnections that are crucial for tissue mechanical properties. In homeostasis, these properties, termed mechanical homeostasis, depend on the balance between intercellular tension and extracellular matrix (ECM) adhesion forces. While age-related ECM remodeling is linked to outer retinal disease, its fundamental role in mechanical homeostasis remains unclear. In our study, we quantified changes in the mechanical state of retinal pigment epithelium (RPE), revealing a correlation with gradients of basement membrane laminins and their integrin receptors, β1 and β4. This relationship is related to regional phagocytic demand for recycling photoreceptor outer segments. Using a reductionist approach, we found that laminin 332 and laminin 511 isoforms differentially influence engagement with β1 and β4 integrins at low densities. Notably, laminin 511 enhances RPE contractility by reducing the β4 to β1 integrin engagement ratio, which subsequently diminishes phagocytic efficiency. Our findings suggest that the ECM-defined mechanical status of RPE serves as a novel parameter for visual function.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3357-3383"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101598","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

CYLD-TRAF6 interaction promotes ADP-heptose-induced NF-κB signaling in H. pylori infection. CYLD-TRAF6相互作用在幽门螺杆菌感染中促进adp -庚糖诱导的NF-κB信号传导。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-01 Epub Date: 2025-05-22 DOI: 10.1038/s44319-025-00480-y

Michelle C C Lim, Gunter Maubach, Michael Naumann

{"title":"CYLD-TRAF6 interaction promotes ADP-heptose-induced NF-κB signaling in H. pylori infection.","authors":"Michelle C C Lim, Gunter Maubach, Michael Naumann","doi":"10.1038/s44319-025-00480-y","DOIUrl":"10.1038/s44319-025-00480-y","url":null,"abstract":"The inflammatory response associated with Helicobacter pylori (H. pylori) infection causes a multitude of alterations in the gastric microenvironment, leading to the slow and steady disruption of the gastric epithelial barrier. Activation of NF-κB during H. pylori infection is crucial to this inflammatory response. Here, we show that CYLD, which interacts constitutively with TRAF6, enhances H. pylori's ADP-heptose-induced activation of the classical NF-κB pathway in gastric epithelial cells. This activating effect of CYLD contrasts with the inhibitory effect of CYLD on receptor-mediated NF-κB activity. Mechanistically, CYLD counteracts the hydrolysis of ubiquitin chains from TRAF6 by deubiquitinylase A20 in a catalytically independent manner, thus supporting the auto-ubiquitinylation of TRAF6 upon activation of NF-κB in early H. pylori infection. In addition, the subsequent classical NF-κB-dependent de novo synthesis of A20 provides a negative feedback loop leading to shutdown not only of the classical but also of the alternative NF-κB pathway. Our findings highlight the regulatory relationship between CYLD and A20 in controlling classical as well as alternative NF-κB signaling in H. pylori infection.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3241-3263"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127016","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

Meating the moment : Challenges and opportunities for cellular agriculture to produce the foods of the future. 把握当下：细胞农业生产未来食物的挑战与机遇。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-01 Epub Date: 2025-06-06 DOI: 10.1038/s44319-025-00492-8

Matthew J McNulty, Andrew J Stout, David L Kaplan

引用次数: 0

Retraction Note: Myeloid-derived growth factor (MYDGF) protects bone mass through inhibiting osteoclastogenesis and promoting osteoblast differentiation. 备注：髓源性生长因子（MYDGF）通过抑制破骨细胞生成和促进成骨细胞分化来保护骨量。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-01 DOI: 10.1038/s44319-025-00479-5

Xiaoli Xu, Yixiang Li, Lingfeng Shi, Kaiyue He, Ying Sun, Yan Ding, Biying Meng, Jiajia Zhang, Lin Xiang, Jing Dong, Min Liu, Junxia Zhang, Lingwei Xiang, Guangda Xiang

引用次数: 0

An alternative mechanism by which If1 prevents ATP hydrolysis by the ATP synthase subcomplex in S. cerevisiae. 在酿酒酵母中If1阻止ATP合成酶亚复合物水解的另一种机制。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-07-01 Epub Date: 2025-06-09 DOI: 10.1038/s44319-025-00430-8

Orane Lerouley, Isabelle Larrieu, Tom Louis Ducrocq, Benoît Pinson, Marie-France Giraud, Arnaud Mourier

{"title":"An alternative mechanism by which If1 prevents ATP hydrolysis by the ATP synthase subcomplex in S. cerevisiae.","authors":"Orane Lerouley, Isabelle Larrieu, Tom Louis Ducrocq, Benoît Pinson, Marie-France Giraud, Arnaud Mourier","doi":"10.1038/s44319-025-00430-8","DOIUrl":"10.1038/s44319-025-00430-8","url":null,"abstract":"The mitochondrial F1F0-ATP synthase is crucial for maintaining the ATP/ADP balance which is critical for cell metabolism, ion homeostasis and cell proliferation. This enzyme, conserved across evolution, is found in the mitochondria or chloroplasts of eukaryotic cells and the plasma membrane of bacteria. In vitro studies have shown that the mitochondrial F1F0-ATP synthase is reversible, capable of hydrolyzing instead of synthesizing ATP. In vivo, its reversibility is inhibited by the endogenous peptide If1 (Inhibitory Factor 1), which specifically prevents ATP hydrolysis in a pH-dependent manner. Despite its presumed importance, the loss of If1 in various model organisms does not cause severe phenotypes, suggesting its role may be confined to specific stress or metabolic conditions yet to be discovered. Our analyses indicate that inhibitory peptides are crucial in mitigating mitochondrial depolarizing stress under glyco-oxidative metabolic conditions. Additionally, we found that the absence of If1 destabilizes the nuclear-encoded free F1 subcomplex. This mechanism highlights the role of If1 in preventing harmful ATP wastage, offering new insights into its function under physiological and pathological conditions.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3305-3326"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257582","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