The EMBO Journal最新文献_第10页

Poxvirus dsDNA genomes differentially activate AIM2 or NLRP3 inflammasomes in human primary cells. 痘病毒dsDNA基因组在人原代细胞中不同地激活AIM2或NLRP3炎症小体。

The EMBO Journal Pub Date : 2026-01-20 DOI: 10.1038/s44318-025-00690-z

Yonas M Tesfamariam,Maria H Christensen,Stefan Diehl,Tabea Klein,Julius M Lingnau,Sabine Normann,Elena Hagelauer,Miriam Herbert,Sophie Reimer,Richa P Joshi,Pujan Engels,Steffen Pritzl,Pietro Fontana,Thomas Zillinger,Gunther Hartmann,Anna Eis-Hübinger,Martin C Lam,Klaus J Walgenbach,Felix Meissner,Hao Wu,Florian I Schmidt

{"title":"Poxvirus dsDNA genomes differentially activate AIM2 or NLRP3 inflammasomes in human primary cells.","authors":"Yonas M Tesfamariam,Maria H Christensen,Stefan Diehl,Tabea Klein,Julius M Lingnau,Sabine Normann,Elena Hagelauer,Miriam Herbert,Sophie Reimer,Richa P Joshi,Pujan Engels,Steffen Pritzl,Pietro Fontana,Thomas Zillinger,Gunther Hartmann,Anna Eis-Hübinger,Martin C Lam,Klaus J Walgenbach,Felix Meissner,Hao Wu,Florian I Schmidt","doi":"10.1038/s44318-025-00690-z","DOIUrl":"https://doi.org/10.1038/s44318-025-00690-z","url":null,"abstract":"The innate immune system is known for its ability to recognize cytosolic DNA as evidence of infection, but detailed studies of this process have been mostly limited to mice and cell lines. To investigate inflammasome responses in human primary cells, we used engineered viruses encoding the inflammasome reporter caspase-1CARD-EGFP. We show that released genomes of vaccinia virus and monkeypox virus trigger robust inflammasome assembly in human primary cells. To determine the involved inflammasome sensors, we generated nanobodies against AIM2. Three of them inhibit AIM2 inflammasome assembly by blocking the polymerization of the AIM2 Pyrin domain, most potently as bivalent nanobodies. Utilizing an engineered vaccinia virus expressing bivalent AIM2 nanobodies, we demonstrate that inflammasomes in primary human macrophages and keratinocytes are nucleated by AIM2, while CD14+ monocytes assemble NLRP3 inflammasomes. This finding resolves the discrepancy between the previously reported activation of AIM2 inflammasomes in mice and NLRP3 inflammasomes in humans, and provides the first evidence for cell-type-specific regulation of DNA-triggered inflammasome activation. The newly developed AIM2-specific nanobodies offer a precise tool to dissect and potentially target AIM2 inflammasome assembly in other disease contexts.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"93 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005509","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

The splice of life: how alternative splicing shapes regulatory and phenotypic evolution. 生命的剪接：选择性剪接如何塑造调控和表型进化。

The EMBO Journal Pub Date : 2026-01-16 DOI: 10.1038/s44318-025-00666-z

Carissa Emerson Hunter,Yi Xing

引用次数: 0

MYO5A-mediated stabilization promotes the acquisition of fusion competence in sealed autophagosomes. myo5a介导的稳定促进封闭自噬体融合能力的获得。

The EMBO Journal Pub Date : 2026-01-15 DOI: 10.1038/s44318-025-00686-9

Akshaya Nambiar,René Martin,Kamakshi Tomar,Hans-Joachim Knölker,Sandhya P Koushika,Subramaniam K,Ravi Manjithaya

{"title":"MYO5A-mediated stabilization promotes the acquisition of fusion competence in sealed autophagosomes.","authors":"Akshaya Nambiar,René Martin,Kamakshi Tomar,Hans-Joachim Knölker,Sandhya P Koushika,Subramaniam K,Ravi Manjithaya","doi":"10.1038/s44318-025-00686-9","DOIUrl":"https://doi.org/10.1038/s44318-025-00686-9","url":null,"abstract":"Autophagy requires precise regulation of autophagosome-lysosome fusion, yet the molecular details of this process remain incompletely understood. Here, we identify the class V myosin MYO5A as a critical regulator of autophagic flux. The genetic or pharmacological inhibition of MYO5A in Saccharomyces cerevisiae, mammalian cells, or Caenorhabditis elegans blocked autophagic flux by preventing autophagosome-lysosome fusion. MYO5A facilitates the maturation of autophagosomes into fusion-competent intermediates as its loss altered the localization of fusion machinery on autophagosomes and reduced the pool of stationary autophagosomes, a step that proved critical for subsequent fusion with lysosomes. Domain mapping and targeted mutagenesis revealed that two LIR motifs (PAYRVL and QAYIGL) within the coiled-coil and globular tail domains of MYO5A mediate its direct interaction with LC3 on autophagosomes. Live imaging in mammalian cells and C. elegans added support for this role, revealing how MYO5A regulates autophagic flux to ensure fusion. Together, these findings establish MYO5A as a regulator of autophagy and highlight its potential as a target for fine-tuning autophagic flux.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971932","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

A smartphone analogy to explore the origin of animals. 一个智能手机的比喻来探索动物的起源。

The EMBO Journal Pub Date : 2026-01-14 DOI: 10.1038/s44318-026-00692-5

Iñaki Ruiz-Trillo,Elena Casacuberta,Nicholas H Brown,Ricard Solé

引用次数: 0

Cancer in disguise: a parasite within. 伪装的癌症：体内的寄生虫。

The EMBO Journal Pub Date : 2026-01-13 DOI: 10.1038/s44318-025-00691-y

Marek Wagner,Shigeo Koyasu

引用次数: 0

Structural insights into the antibacterial function of the Pseudomonas putida effector Tke5. 恶臭假单胞菌效应物Tke5抑菌功能的结构分析。

The EMBO Journal Pub Date : 2026-01-12 DOI: 10.1038/s44318-025-00689-6

Carmen Velázquez,Maialen Zabala-Zearreta,Carmen Paredes,Cristina Civantos,Jon Altuna-Alvarez,Patricia Bernal,David Albesa-Jové

{"title":"Structural insights into the antibacterial function of the Pseudomonas putida effector Tke5.","authors":"Carmen Velázquez,Maialen Zabala-Zearreta,Carmen Paredes,Cristina Civantos,Jon Altuna-Alvarez,Patricia Bernal,David Albesa-Jové","doi":"10.1038/s44318-025-00689-6","DOIUrl":"https://doi.org/10.1038/s44318-025-00689-6","url":null,"abstract":"Pseudomonas putida is a plant-beneficial rhizobacterium that encodes multiple type-VI secretion systems (T6SS) to outcompete phytopathogens in the rhizosphere. Among its antibacterial effectors, Tke5 (a member of the BTH_I2691 protein family) is a potent pore-forming toxin that disrupts ion homeostasis without causing considerable membrane damage. Tke5 harbours an N-terminal MIX domain, which is required for T6SS-dependent secretion in other systems. Many MIX domain-containing effectors require T6SS adaptor proteins (Tap) for secretion, but their molecular mechanisms of adaptor-effector binding remain elusive. Here, we report the 2.8 Å cryo-EM structure of the Tap3-Tke5 complex of P. putida strain KT2440, providing structural and functional insights into how effector Tke5 is recruited by its cognate adaptor protein Tap3. Functional dissection shows that the α-helical region of Tke5 is sufficient to kill intoxicated bacteria, while its β-rich region likely contributes to target membrane specificity. These findings delineate a mechanism of BTH_I2691 proteins for Tap recruitment and toxin activity, contributing to our understanding of a widespread yet understudied toxin family.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955989","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

The mechanism of cell-cycle-dependent proteasomal degradation of archaeal ESCRT-III homolog CdvB in Sulfolobus. 古细菌ESCRT-III同源CdvB细胞周期依赖性蛋白酶体降解的机制。

The EMBO Journal Pub Date : 2026-01-09 DOI: 10.1038/s44318-025-00688-7

Yin-Wei Kuo,Jovan Traparić,Sherman Foo,Buzz Baum

{"title":"The mechanism of cell-cycle-dependent proteasomal degradation of archaeal ESCRT-III homolog CdvB in Sulfolobus.","authors":"Yin-Wei Kuo,Jovan Traparić,Sherman Foo,Buzz Baum","doi":"10.1038/s44318-025-00688-7","DOIUrl":"https://doi.org/10.1038/s44318-025-00688-7","url":null,"abstract":"Protein degradation orders events in the cell division cycle in eukaryotes, bacteria, and archaea. In eukaryotes, chromosome segregation and mitotic exit are triggered by proteasome-dependent degradation of securin and cyclin B, respectively. Recent findings show that the archaeal proteasome also targets substrates, including CdvB, for degradation in a cell-cycle-dependent manner in Sulfolobus acidocaldarius-an experimentally tractable archaeal relative of eukaryotes. Here, using CdvB as a model substrate to explore the mechanism of cyclic protein degradation, we demonstrate that the C-terminal broken-winged helix of CdvB, previously shown to bind CdvA, is sufficient to render a fusion protein unstable as cells progress through division. We show that the rate of CdvB degradation accelerates during division in part due to a cell-cycle-dependent increase in expression of the proteasome-activating nucleotidase (PAN), under the control of a cyclically expressed novel transcription factor \"CCTF1\" that represses PAN expression. Taken together, these findings reveal mechanisms by which archaea, despite lacking cyclin-dependent kinases, control proteasome-mediated degradation to order events during cell division.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937897","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

Reactive oxygen species in the rhizosphere orchestrate the recruitment of beneficial bacteria. 根际活性氧协调有益菌的招募。

The EMBO Journal Pub Date : 2026-01-09 DOI: 10.1038/s44318-025-00685-w

Xijie Guo,Hengyi Dai,Zhiyi Jia,Ying Peng,Luotian Lu,Yaxing Su,Jianwei Li,Qinghong Li,Zeming Huang,Yucheng Wang,Fan Qi,Dayong Li,Xiaofei Lv,Yan Liang,Bin Ma

{"title":"Reactive oxygen species in the rhizosphere orchestrate the recruitment of beneficial bacteria.","authors":"Xijie Guo,Hengyi Dai,Zhiyi Jia,Ying Peng,Luotian Lu,Yaxing Su,Jianwei Li,Qinghong Li,Zeming Huang,Yucheng Wang,Fan Qi,Dayong Li,Xiaofei Lv,Yan Liang,Bin Ma","doi":"10.1038/s44318-025-00685-w","DOIUrl":"https://doi.org/10.1038/s44318-025-00685-w","url":null,"abstract":"Respiratory burst oxidase homolog D (RBOHD)-dependent reactive oxygen species (ROS) in Arabidopsis are well known to suppress pathogen colonization, but their influence on beneficial microbes remains unclear. Here, we found that the beneficial rhizobacterium Pseudomonas anguilliseptica was significantly less enriched in the rhizosphere of rbohD mutants than in that of wild-type plants. Conversely, elevated rhizosphere ROS levels, either triggered by pretreatment with pathogenic Dickeya solani bacteria or caused by mutations in ROS scavenging genes (e.g., in apx1 and cat2 mutants), promoted the rhizosphere recruitment of P. anguilliseptica. This promoting effect was abolished by catalase treatment. In situ microfluidic chemotaxis assays further revealed that P. anguilliseptica exhibits a chemotactic response to low concentrations of hydrogen peroxide ( ≤ 500 nM), accompanied by upregulated expression of chemotaxis- and motility-related genes. Notably, inoculation of P. anguilliseptica effectively suppressed D. solani-induced disease symptoms, and this protective effect was attenuated by catalase treatment. Collectively, these findings reveal a previously unrecognized role of ROS in recruitment beneficial microbiota to enhance plant growth and suppress disease symptoms.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937898","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

Fast label-free live imaging with FlowVision reveals key principles of cancer cell arrest on endothelial monolayers. 快速无标签实时成像与FlowVision揭示癌细胞在内皮单层阻滞的关键原理。

The EMBO Journal Pub Date : 2026-01-06 DOI: 10.1038/s44318-025-00678-9

Gautier Follain,Sujan Ghimire,Joanna W Pylvänäinen,Monika Vaitkevičiūtė,Iván Hidalgo-Cenalmor,Diana Wurzinger,Camilo Guzmán,James R W Conway,Michal Dibus,Jouni Härkönen,Sanna Oikari,Kirsi Rilla,Marko Salmi,Johanna Ivaska,Guillaume Jacquemet

{"title":"Fast label-free live imaging with FlowVision reveals key principles of cancer cell arrest on endothelial monolayers.","authors":"Gautier Follain,Sujan Ghimire,Joanna W Pylvänäinen,Monika Vaitkevičiūtė,Iván Hidalgo-Cenalmor,Diana Wurzinger,Camilo Guzmán,James R W Conway,Michal Dibus,Jouni Härkönen,Sanna Oikari,Kirsi Rilla,Marko Salmi,Johanna Ivaska,Guillaume Jacquemet","doi":"10.1038/s44318-025-00678-9","DOIUrl":"https://doi.org/10.1038/s44318-025-00678-9","url":null,"abstract":"The rapid, transient, and unpredictable nature of interactions between circulating cells and the endothelium challenges the investigation of these events under flow conditions. Here, we developed an imaging and image-analysis framework called FlowVision, which integrates fast, bright-field live-cell imaging with deep-learning-based image analysis to quantitatively track cell landing and arrest on an endothelial monolayer under physiological flow conditions. Using FlowVision, we find that pancreatic ductal adenocarcinoma (PDAC) cells exhibit variable adhesion strength and flow sensitivity. Remarkably, some PDAC cells demonstrate comparable endothelial engagement to leukocytes, preferentially arresting at endothelial junctions, providing them access to the underlying basal extracellular matrix. PDAC cells attach and form clusters in areas with high expression of the endothelial CD44 receptor. Targeting CD44 using siRNA, function-blocking antibodies, or degrading its ligand, hyaluronic acid (HA), strongly reduces PDAC cell attachment. Overall, our label-free live-imaging approach demonstrates that cancer and immune cells share both common and unique features in endothelial adhesion under flow, and allows identification of CD44 and HA as key mediators of PDAC cell arrest.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"183 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907596","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

A fibroblast-like endothelial cell state promotes atherosclerosis via C/EBPβ-activated TGF-β signaling. 成纤维细胞样内皮细胞状态通过C/ ebp β激活的TGF-β信号通路促进动脉粥样硬化。

The EMBO Journal Pub Date : 2026-01-06 DOI: 10.1038/s44318-025-00684-x

Linge Fan,Yingyi Zhu,Yi Li,Zixin Ji,Kefan Ma,Ying Zhang,Leiting Wei,Junbo Chen,Yuanqing Jiang,Dongwu Lai,Lingfeng Qin,Guosheng Fu,Michael Simons,Liang Xu,Luyang Yu,Cong Qiu

{"title":"A fibroblast-like endothelial cell state promotes atherosclerosis via C/EBPβ-activated TGF-β signaling.","authors":"Linge Fan,Yingyi Zhu,Yi Li,Zixin Ji,Kefan Ma,Ying Zhang,Leiting Wei,Junbo Chen,Yuanqing Jiang,Dongwu Lai,Lingfeng Qin,Guosheng Fu,Michael Simons,Liang Xu,Luyang Yu,Cong Qiu","doi":"10.1038/s44318-025-00684-x","DOIUrl":"https://doi.org/10.1038/s44318-025-00684-x","url":null,"abstract":"Endothelial cell (EC) dysfunction is a critical driver of chronic vascular inflammation and atherosclerosis. However, the molecular details of EC state dynamics during vascular disease progression remain ill-defined. Here, we used in-depth single-cell RNA sequencing to map transcriptional landscapes and molecular signatures of EC phenotypic plasticity during atherosclerosis in the mouse arota. This analysis identified a unique fibroblast-like EC population in atherosclerotic blood vessels, characterized by high expression of endothelial activation markers and extracellular matrix (ECM) remodeling, which increased with disease severity. Pseudotime trajectory analysis revealed that these fibroblast-like ECs represent terminal states of endothelial-mesenchymal transition (EndMT) during atherosclerosis. Further, the transcription factor C/EBPβ was identified as prominent driver of this phenotype transition as evidenced in vivo and in vitro. Mechanistically, inflammatory cytokines induce C/EBPβ, triggering TGF-β signaling and subsequent regulation of downstream genes via upregulation of TGF-β receptor type I (TGFBR1) through direct interaction with its promoter. Endothelial overexpression of C/EBPβ in vivo exacerbated atherosclerotic plaques, increased vascular inflammation, and elevated endothelial TGFBR1 levels. These findings highlight endothelial C/EBPβ as a novel regulator of TGF-β signaling and pathological fibroblast-like EC phenotypes during atherosclerosis, linking cytokine-driven inflammation with TGF-β-mediated endothelial dysfunction.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907597","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