EMBO Reports最新文献_第2页

LRRK2 interactions with microtubules are independent of LRRK2-mediated Rab phosphorylation. LRRK2与微管的相互作用不依赖于LRRK2介导的Rab磷酸化。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-05-27 DOI: 10.1038/s44319-025-00486-6

Tuyana Malankhanova, Zhiyong Liu, Enquan Xu, Nicole Bryant, Ki Woon Sung, Huizhong Li, Samuel Strader, Andrew B West

{"title":"LRRK2 interactions with microtubules are independent of LRRK2-mediated Rab phosphorylation.","authors":"Tuyana Malankhanova, Zhiyong Liu, Enquan Xu, Nicole Bryant, Ki Woon Sung, Huizhong Li, Samuel Strader, Andrew B West","doi":"10.1038/s44319-025-00486-6","DOIUrl":"https://doi.org/10.1038/s44319-025-00486-6","url":null,"abstract":"Deregulated microtubules are common defects associated with neurodegenerative diseases. Recent cryo-electron microscopy studies in cell lines overexpressing Parkinson's disease-associated LRRK2 suggest microtubule surfaces may regulate kinase activity by stabilizing different LRRK2 conformations. In macrophages with high endogenous LRRK2 expression, we find that nocodazole treatment destabilizes microtubules and impairs LRRK2-mediated Rab phosphorylation. GTP supplementation restores nocodazole-reduced Rab phosphorylation, linking LRRK2 kinase action to cellular GTP levels. Chemical microtubule stabilization, and kinetically trapping LRRK2 to microtubule surfaces, has negligible effects on Rab phosphorylation. In contrast, trapping LRRK2 to LAMP1-positive membranes upregulates LRRK2-mediated Rab phosphorylation. Proximity-labeling proteomics and colocalization studies show that LRRK2 robustly interacts with both polymerized and free tubulin transiently and independently of LRRK2 kinase activity. Endogenous LRRK2 complexed with type I inhibitors in neurons and macrophages fails to stably interact with microtubules, whereas bulky N-terminal tags fused to LRRK2 promotes stable microtubule binding in cell lines. Collectively, these results show that tubulin isoforms and microtubules are transient LRRK2-interacting proteins non-essential for LRRK2-mediated Rab phosphorylation.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157323","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

Dynamic SAS-6 phosphorylation aids centrosome duplication and elimination in C. elegans oogenesis. 动态SAS-6磷酸化有助于秀丽隐杆线虫卵发生过程中中心体的复制和消除。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-05-23 DOI: 10.1038/s44319-025-00485-7

Feifei Qi, Shanshan Yin, Xiangrui Yang, Ning Ju, Bohan Liu, Xing Zhang, Zixuan Zhu, Li Ji, Fuxin Zhang, Li Zhao, Ruoxi Wang, Min Liu, Liangran Zhang, Huijie Zhao, Jun Zhou, Jinmin Gao

{"title":"Dynamic SAS-6 phosphorylation aids centrosome duplication and elimination in C. elegans oogenesis.","authors":"Feifei Qi, Shanshan Yin, Xiangrui Yang, Ning Ju, Bohan Liu, Xing Zhang, Zixuan Zhu, Li Ji, Fuxin Zhang, Li Zhao, Ruoxi Wang, Min Liu, Liangran Zhang, Huijie Zhao, Jun Zhou, Jinmin Gao","doi":"10.1038/s44319-025-00485-7","DOIUrl":"https://doi.org/10.1038/s44319-025-00485-7","url":null,"abstract":"In most metazoans, centrosome elimination during oogenesis ensures accurate centriole inheritance in the zygote, yet the molecular mechanisms remain poorly understood. Here, we reveal a critical role for controlled SAS-6 phosphorylation in centrosome dynamics during oogenesis. Centrioles disassemble during late meiotic prophase, while the cartwheel protein SAS-6 exhibits dynamic behavior in early meiotic prophase. Purified SAS-6 undergoes phase separation in vitro, and overexpressed SAS-6 forms droplets in cells. Mass spectrometry and kinase assays reveal that SAS-6 is phosphorylated at its C-terminus in cells and in vivo, with CDK-1 identified as a direct kinase. This phosphorylation inhibits SAS-6 phase separation and weakens interactions between centriolar proteins. SAS-6 degradation confirms its role in centrosome stability, and CDK-1 activity is required for timely centriole disassembly. Phospho-mimetic and phospho-deficient mutants demonstrate that dynamic SAS-6 phosphorylation is essential for centrosome assembly and elimination. We propose that the disordered C-terminus of SAS-6 facilitates cartwheel stacking via multivalent weak interactions, promoting centriole stability. Phosphorylation disrupts these interactions, impairing centrosome duplication and promoting elimination during oogenesis.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132193","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

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 : 2025-05-22 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":"https://doi.org/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":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNase H1 and Sen1 ensure that transient TERRA R-loops promote the repair of short telomeres. RNase H1和Sen1确保瞬时TERRA r -环促进短端粒的修复。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-05-22 DOI: 10.1038/s44319-025-00469-7

Fabio Bento, Matteo Longaretti, Vanessa Borges Pires, Arianna Lockhart, Brian Luke

{"title":"RNase H1 and Sen1 ensure that transient TERRA R-loops promote the repair of short telomeres.","authors":"Fabio Bento, Matteo Longaretti, Vanessa Borges Pires, Arianna Lockhart, Brian Luke","doi":"10.1038/s44319-025-00469-7","DOIUrl":"https://doi.org/10.1038/s44319-025-00469-7","url":null,"abstract":"Telomere repeat-containing RNA (TERRA) is transcribed at telomeres and forms RNA-DNA hybrids. In budding yeast, the presence of RNA-DNA hybrids at short telomeres promotes homology-directed repair (HDR) and prevents accelerated replicative senescence. RNA-DNA hybrids at telomeres have also been demonstrated to prevent 5'end resection, an essential step for HDR. In accordance, we now demonstrate that, not only the presence, but also the removal, of RNA-DNA hybrids drives HDR at shortened telomeres during replicative senescence. Although RNase H2 is absent from short telomeres, it is quickly compensated for by the recruitment of RNase H1 and Sen1. The recruitment of RNase H1 is essential to allow for the loading of Rad51, consistent with the notion that RNA-DNA hybrids prevent Exo1-mediated end resection. In the absence of RNase H1 or Sen1 function, yeast cultures prematurely enter replicative senescence in the absence of telomerase. Furthermore, the delayed senescence phenotype observed when RNase H2 is deleted, depends on the presence of RNase H1 and Sen1. This study demonstrates the importance of transient RNA-DNA hybrids at short telomeres to regulate senescence.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127017","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

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 : 2025-05-20 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":"https://doi.org/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":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A career in science requires a thick skin. 从事科学工作需要脸皮厚。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-05-20 DOI: 10.1038/s44319-025-00477-7

David R Smith

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 : 2025-05-19 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":"https://doi.org/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":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An integrated anatomical, functional and evolutionary view of the Drosophila olfactory system. 果蝇嗅觉系统的综合解剖、功能和进化观点。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-05-19 DOI: 10.1038/s44319-025-00476-8

Richard Benton, Jérôme Mermet, Andre Jang, Keita Endo, Steeve Cruchet, Karen Menuz

{"title":"An integrated anatomical, functional and evolutionary view of the Drosophila olfactory system.","authors":"Richard Benton, Jérôme Mermet, Andre Jang, Keita Endo, Steeve Cruchet, Karen Menuz","doi":"10.1038/s44319-025-00476-8","DOIUrl":"10.1038/s44319-025-00476-8","url":null,"abstract":"The Drosophila melanogaster olfactory system is one of the most intensively studied parts of the nervous system in any animal. Composed of ~50 independent olfactory neuron classes, with several associated hygrosensory and thermosensory pathways, it has been subject to diverse types of experimental analyses. However, synthesizing the available information is limited by the incomplete data and inconsistent nomenclature found in the literature. In this work, we first \"complete\" the peripheral sensory map through the identification of a previously uncharacterized antennal sensory neuron population expressing Or46aB, and the definition of an exceptional \"hybrid\" olfactory neuron class comprising functional Or and Ir receptors. Second, we survey developmental, anatomical, connectomic, functional, and evolutionary studies to generate an integrated dataset and associated visualizations of these sensory neuron pathways, creating an unprecedented resource. Third, we illustrate the utility of the dataset to reveal relationships between different organizational properties of this sensory system, and the new questions these stimulate. Such examples emphasize the power of this resource to promote further understanding of the construction, function, and evolution of these neural circuits.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101587","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

Ca²⁺ waves and ethylene/JA crosstalk orchestrate wound responses in Arabidopsis roots. Ca2+波和乙烯/JA串扰协调拟南芥根系的伤口反应。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-05-19 DOI: 10.1038/s44319-025-00471-z

Xuemin Ma, M Shamim Hasan, Muhammad Shahzad Anjam, Sakil Mahmud, Sabarna Bhattacharyya, Ute C Vothknecht, Badou Mendy, Florian M W Grundler, Peter Marhavý

{"title":"Ca2+ waves and ethylene/JA crosstalk orchestrate wound responses in Arabidopsis roots.","authors":"Xuemin Ma, M Shamim Hasan, Muhammad Shahzad Anjam, Sakil Mahmud, Sabarna Bhattacharyya, Ute C Vothknecht, Badou Mendy, Florian M W Grundler, Peter Marhavý","doi":"10.1038/s44319-025-00471-z","DOIUrl":"https://doi.org/10.1038/s44319-025-00471-z","url":null,"abstract":"Wounding triggers complex and multi-faceted responses in plants. Among these, calcium (Ca2+) waves serve as an immediate and localized response to strong stimuli, such as nematode infection or laser ablation. Here, we investigate the propagation patterns of Ca2+ waves induced by laser ablation and observe that glutamate-receptor-like channels (GLR3.3/GLR3.6), the stretch-activated anion channel MSL10, and the mechanosensitive Ca2+-permeable channels MCA1/MCA2 influence this process. These channels contribute to ethylene-associated signaling pathways, potentially through the WRKY33-ACS6 regulatory network. Furthermore, our findings show that ACC/ethylene signaling modulates Ca2+ wave propagation following laser ablation. Ethylene perception and synthesis at the site of damage regulate the local jasmonate response, which displays tissue-specific patterns upon laser ablation. Overall, our data provide new insights into the molecular and cellular processes underlying plant responses to localized damage, highlighting the roles of specific ion channels and hormone signaling pathways in shaping these responses in Arabidopsis roots.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101593","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

How to clone a Dire Wolf? 如何克隆恐狼？

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-05-16 DOI: 10.1038/s44319-025-00474-w

Jacob Höglund

引用次数: 0