Pub Date : 2026-01-16DOI: 10.1038/s44318-025-00666-z
Carissa Emerson Hunter,Yi Xing
Alternative splicing (AS) is a key mechanism for generating regulatory and phenotypic diversity in multicellular eukaryotes. Large-scale comparative transcriptomic studies have revealed that AS leads to lineage-specific and tissue-specific transcriptomic and proteomic changes, underscoring its contribution to the evolution of gene products and functions. In this review, we highlight the patterns and mechanisms of AS evolution across species, exploring how technological advancements are transforming our understanding of splicing evolution. Furthermore, we discuss mechanistic and functional insights from recent studies, including groundbreaking discoveries on how AS has shaped phenotypic evolution in mammals.
{"title":"The splice of life: how alternative splicing shapes regulatory and phenotypic evolution.","authors":"Carissa Emerson Hunter,Yi Xing","doi":"10.1038/s44318-025-00666-z","DOIUrl":"https://doi.org/10.1038/s44318-025-00666-z","url":null,"abstract":"Alternative splicing (AS) is a key mechanism for generating regulatory and phenotypic diversity in multicellular eukaryotes. Large-scale comparative transcriptomic studies have revealed that AS leads to lineage-specific and tissue-specific transcriptomic and proteomic changes, underscoring its contribution to the evolution of gene products and functions. In this review, we highlight the patterns and mechanisms of AS evolution across species, exploring how technological advancements are transforming our understanding of splicing evolution. Furthermore, we discuss mechanistic and functional insights from recent studies, including groundbreaking discoveries on how AS has shaped phenotypic evolution in mammals.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986233","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}
Pub Date : 2026-01-15DOI: 10.1038/s44318-025-00686-9
Akshaya Nambiar,René Martin,Kamakshi Tomar,Hans-Joachim Knölker,Sandhya P Koushika,Subramaniam K,Ravi Manjithaya
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.
{"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}
Pub Date : 2026-01-14DOI: 10.1038/s44318-026-00692-5
Iñaki Ruiz-Trillo,Elena Casacuberta,Nicholas H Brown,Ricard Solé
How animals evolved from their unicellular ancestor is a fundamental biological question. The fact that all animals are monophyletic-sharing a single common ancestor-implies their origin from unicellular eukaryotes was likely driven by rare and highly advantageous innovations. While the fossil record and initial genomic comparisons suggested animals originated by the rapid acquisition of many novel genes, new research on animal's closest unicellular relatives reveals most of those genes originated before animals evolved. Here we present a new model for animal origins, which shares similarities with the origin of one of the greatest technological innovations of our time: the smartphone. We show that the origin of both animals and smartphones was due to the integration and repurposing of pre-existing components driven by a novel "operating system", rather than the sudden emergence of many new parts. This model offers testable predictions and a new theoretical framework for understanding complex biological innovation.
{"title":"A smartphone analogy to explore the origin of animals.","authors":"Iñaki Ruiz-Trillo,Elena Casacuberta,Nicholas H Brown,Ricard Solé","doi":"10.1038/s44318-026-00692-5","DOIUrl":"https://doi.org/10.1038/s44318-026-00692-5","url":null,"abstract":"How animals evolved from their unicellular ancestor is a fundamental biological question. The fact that all animals are monophyletic-sharing a single common ancestor-implies their origin from unicellular eukaryotes was likely driven by rare and highly advantageous innovations. While the fossil record and initial genomic comparisons suggested animals originated by the rapid acquisition of many novel genes, new research on animal's closest unicellular relatives reveals most of those genes originated before animals evolved. Here we present a new model for animal origins, which shares similarities with the origin of one of the greatest technological innovations of our time: the smartphone. We show that the origin of both animals and smartphones was due to the integration and repurposing of pre-existing components driven by a novel \"operating system\", rather than the sudden emergence of many new parts. This model offers testable predictions and a new theoretical framework for understanding complex biological innovation.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"101 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968608","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}
Pub Date : 2026-01-13DOI: 10.1038/s44318-025-00691-y
Marek Wagner,Shigeo Koyasu
Cancer does not simply develop unchecked-it strategically exploits its host with parasitic precision. From immune evasion to tissue remodeling, cancer cells mirror the survival strategies of parasitic helminths. This resemblance suggests that malignant cells have co-opted deeply conserved, evolutionarily honed tactics used by parasites to persist within their hosts. By mimicking helminths, cancer cells may also engage type-2 immune responses, traditionally associated with anti-parasitic defense, as part of the host's attempt to control their expansion. Such parallels could also help explain why type-2 immunity, once considered tumor-promoting, has recently emerged as a potential source of tumoricidal activity. In this Perspective, we explore mechanistic parallels between cancer and helminth infection. Recognizing the parasitic nature of cancer cells not only challenges established models of oncogenesis but also reveals mechanisms that could be leveraged for therapy.
{"title":"Cancer in disguise: a parasite within.","authors":"Marek Wagner,Shigeo Koyasu","doi":"10.1038/s44318-025-00691-y","DOIUrl":"https://doi.org/10.1038/s44318-025-00691-y","url":null,"abstract":"Cancer does not simply develop unchecked-it strategically exploits its host with parasitic precision. From immune evasion to tissue remodeling, cancer cells mirror the survival strategies of parasitic helminths. This resemblance suggests that malignant cells have co-opted deeply conserved, evolutionarily honed tactics used by parasites to persist within their hosts. By mimicking helminths, cancer cells may also engage type-2 immune responses, traditionally associated with anti-parasitic defense, as part of the host's attempt to control their expansion. Such parallels could also help explain why type-2 immunity, once considered tumor-promoting, has recently emerged as a potential source of tumoricidal activity. In this Perspective, we explore mechanistic parallels between cancer and helminth infection. Recognizing the parasitic nature of cancer cells not only challenges established models of oncogenesis but also reveals mechanisms that could be leveraged for therapy.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961608","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}
Pub Date : 2026-01-12DOI: 10.1038/s44318-025-00689-6
Carmen Velázquez,Maialen Zabala-Zearreta,Carmen Paredes,Cristina Civantos,Jon Altuna-Alvarez,Patricia Bernal,David Albesa-Jové
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.
{"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}
Pub Date : 2026-01-09DOI: 10.1038/s44318-025-00688-7
Yin-Wei Kuo,Jovan Traparić,Sherman Foo,Buzz Baum
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.
{"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}
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.
{"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}
Pub Date : 2026-01-06DOI: 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
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.
{"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}
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.
{"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}
Pub Date : 2026-01-03DOI: 10.1038/s44318-025-00667-y
Carole Duchêne,Liping Wang,Susana M Coelho
The recent discovery of widespread giant virus sequences integrated into the genomes of diverse eukaryotes, and in particular marine lineages, has reignited interest in the molecular mechanisms underlying giant virus-host interactions. The brown alga Ectocarpus represents a compelling and historically rich model for such studies. As early as the 1970s, it was used to investigate latent infections by giant double-stranded DNA viruses, with elegant classical genetics and electron microscopy approaches revealing key aspects of virus-host life cycle coordination. However, progress was limited by the lack of molecular and genomic tools. In this review, we revisit these foundational studies through the lens of recent technological advances, including the development of genetic and genomic resources for brown algae. These tools now enable mechanistic insights into giant viral integration, latency, activation and host response. We highlight how Ectocarpus and related systems can illuminate both the evolutionary and ecological dimensions of virus-host dynamics, with a particular emphasis on the molecular and genetic mechanisms that mediate these complex interactions.
{"title":"Revisiting giant virus-host dynamics in brown algae: old stories and new perspectives.","authors":"Carole Duchêne,Liping Wang,Susana M Coelho","doi":"10.1038/s44318-025-00667-y","DOIUrl":"https://doi.org/10.1038/s44318-025-00667-y","url":null,"abstract":"The recent discovery of widespread giant virus sequences integrated into the genomes of diverse eukaryotes, and in particular marine lineages, has reignited interest in the molecular mechanisms underlying giant virus-host interactions. The brown alga Ectocarpus represents a compelling and historically rich model for such studies. As early as the 1970s, it was used to investigate latent infections by giant double-stranded DNA viruses, with elegant classical genetics and electron microscopy approaches revealing key aspects of virus-host life cycle coordination. However, progress was limited by the lack of molecular and genomic tools. In this review, we revisit these foundational studies through the lens of recent technological advances, including the development of genetic and genomic resources for brown algae. These tools now enable mechanistic insights into giant viral integration, latency, activation and host response. We highlight how Ectocarpus and related systems can illuminate both the evolutionary and ecological dimensions of virus-host dynamics, with a particular emphasis on the molecular and genetic mechanisms that mediate these complex interactions.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895367","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}
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