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}
Pub Date : 2026-01-03DOI: 10.1038/s44318-025-00672-1
Dale P Corkery,Deerada Wijayatunga,Benedita K L Feron,Laura K Herzog,Anastasia Knyazeva,Yao-Wen Wu
After damage from pathogenic, chemical or physical stress, endolysosomal membranes are repaired and resealed by the endosomal sorting complex required for transport (ESCRT) machinery, but how this membrane damage is sensed and translated into ESCRT recruitment is poorly understood. Here, we identify the two ATG8 E3-like ligases, ATG16L1 and TECPR1, as ion-dependent catalysts for ESCRT recruitment to damaged lysosomal membranes. Leakage from perforated lysosomes induces the proton sensitive V-ATPase-dependent recruitment of ATG16L1-ATG5-ATG12 complexes, or the calcium-sensitive sphingomyelin-dependent recruitment of TECPR1-ATG5-ATG12 complexes. In both cases, the E3-like complex-dependent ATG5-ATG12 conjugate is required for ESCRT recruitment to the damaged membrane, and stabilization of the ESCRT machinery. Collectively, this study establishes the ATG8 E3-like ligases as membrane damage sensors for ESCRT-mediated membrane repair.
{"title":"The ATG8 E3-like ligases sense lysosomal damage and initiate ESCRT-mediated membrane repair.","authors":"Dale P Corkery,Deerada Wijayatunga,Benedita K L Feron,Laura K Herzog,Anastasia Knyazeva,Yao-Wen Wu","doi":"10.1038/s44318-025-00672-1","DOIUrl":"https://doi.org/10.1038/s44318-025-00672-1","url":null,"abstract":"After damage from pathogenic, chemical or physical stress, endolysosomal membranes are repaired and resealed by the endosomal sorting complex required for transport (ESCRT) machinery, but how this membrane damage is sensed and translated into ESCRT recruitment is poorly understood. Here, we identify the two ATG8 E3-like ligases, ATG16L1 and TECPR1, as ion-dependent catalysts for ESCRT recruitment to damaged lysosomal membranes. Leakage from perforated lysosomes induces the proton sensitive V-ATPase-dependent recruitment of ATG16L1-ATG5-ATG12 complexes, or the calcium-sensitive sphingomyelin-dependent recruitment of TECPR1-ATG5-ATG12 complexes. In both cases, the E3-like complex-dependent ATG5-ATG12 conjugate is required for ESCRT recruitment to the damaged membrane, and stabilization of the ESCRT machinery. Collectively, this study establishes the ATG8 E3-like ligases as membrane damage sensors for ESCRT-mediated membrane repair.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895368","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/s44318-025-00676-x
Wenjie Ren,Yuxin Huang,Min Hu,Yanyang Yang,Wen Yang,Hui Wang
Most cytosolic and nuclear eukaryotic Fe-S proteins acquire their critical Fe-S cofactor by interacting with the cytosolic Fe-S cluster assembly targeting complex (CTC). Despite the critical roles these Fe-S proteins play in fundamental biology, how they are specifically recognized by the CTC remains largely understudied. Here we identified a hidden consensus pentapeptide motif as a sequence signature dictating cluster acquisition in a majority of known human Fe-S proteins, particularly DNA/RNA processing enzymes for genome maintenance. The presence of this motif drives CTC-client engagement, while its defect impairs CTC recognition, iron incorporation, and enzymatic activities of these clients, ultimately compromising their cellular functions, such as in DNA repair. Furthermore, our studies revealed a conserved surface pocket of CTC dedicated to client recruitment in general. This single pocket recognizes two distinct sequence signatures in clients including the Pentapeptide motif and a previously reported C-tail motif. Subsequent structure-guided affinity-purification mass spectrometry (AP-MS) enabled us to investigate the pocket-dependent human CTC interactome, potentially unveiling unrecognized Fe-S proteins. Overall, our findings decipher the sequence signature-directed mechanism underlying CTC client recruitment and open an avenue for expanding the repertoire of Fe-S proteins.
{"title":"Client recruitment mechanism of the cytosolic Fe-S cluster assembly targeting complex.","authors":"Wenjie Ren,Yuxin Huang,Min Hu,Yanyang Yang,Wen Yang,Hui Wang","doi":"10.1038/s44318-025-00676-x","DOIUrl":"https://doi.org/10.1038/s44318-025-00676-x","url":null,"abstract":"Most cytosolic and nuclear eukaryotic Fe-S proteins acquire their critical Fe-S cofactor by interacting with the cytosolic Fe-S cluster assembly targeting complex (CTC). Despite the critical roles these Fe-S proteins play in fundamental biology, how they are specifically recognized by the CTC remains largely understudied. Here we identified a hidden consensus pentapeptide motif as a sequence signature dictating cluster acquisition in a majority of known human Fe-S proteins, particularly DNA/RNA processing enzymes for genome maintenance. The presence of this motif drives CTC-client engagement, while its defect impairs CTC recognition, iron incorporation, and enzymatic activities of these clients, ultimately compromising their cellular functions, such as in DNA repair. Furthermore, our studies revealed a conserved surface pocket of CTC dedicated to client recruitment in general. This single pocket recognizes two distinct sequence signatures in clients including the Pentapeptide motif and a previously reported C-tail motif. Subsequent structure-guided affinity-purification mass spectrometry (AP-MS) enabled us to investigate the pocket-dependent human CTC interactome, potentially unveiling unrecognized Fe-S proteins. Overall, our findings decipher the sequence signature-directed mechanism underlying CTC client recruitment and open an avenue for expanding the repertoire of Fe-S proteins.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895364","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/s44318-025-00673-0
Lorenzo Sassi,Andrea Martinez Marroquin,Salli Waked,Alessandra Ardizzoia,Vincenzo Costanzo
Homologous recombination (HR) is traditionally portrayed as a DNA double-strand break repair pathway. However, emerging evidence positions RAD51, its partners BRCA1, BRCA2, and other HR factors at the core of a broader genome-maintenance network that operates by a "prevent and protect" strategy extending beyond repair. Here, we review how RAD51 can shield DNA from nucleolytic processing mediated by MRE11 and related nucleases, promote fork reversal, suppress replicative DNA gaps accumulation, and bind abasic sites, averting their conversion into cytotoxic intermediates. These extended functions counteract endogenous replication stress as shown in BRCA1- or BRCA2-deficient contexts, where failure to prevent gaps, protect forks, and safeguard abasic DNA accelerates genomic instability. The functional impairment of HR proteins, which interface with base-excision repair and translesion synthesis, rewires these pathways, driving distinctive base-substitution mutational signatures of HR-defective tumors. Abasic sites, especially from methyl-cytosine metabolism, put replication forks at risk of breaking, amplifying the need for RAD51-mediated defense. Such redefinition of homologous recombination protein function as part of an anticipatory surveillance and protective system, rather than a repair-only module, bears important implications for understanding tumorigenesis, therapy resistance, and aging.
{"title":"The expanding roles of homologous recombination proteins in genome stability.","authors":"Lorenzo Sassi,Andrea Martinez Marroquin,Salli Waked,Alessandra Ardizzoia,Vincenzo Costanzo","doi":"10.1038/s44318-025-00673-0","DOIUrl":"https://doi.org/10.1038/s44318-025-00673-0","url":null,"abstract":"Homologous recombination (HR) is traditionally portrayed as a DNA double-strand break repair pathway. However, emerging evidence positions RAD51, its partners BRCA1, BRCA2, and other HR factors at the core of a broader genome-maintenance network that operates by a \"prevent and protect\" strategy extending beyond repair. Here, we review how RAD51 can shield DNA from nucleolytic processing mediated by MRE11 and related nucleases, promote fork reversal, suppress replicative DNA gaps accumulation, and bind abasic sites, averting their conversion into cytotoxic intermediates. These extended functions counteract endogenous replication stress as shown in BRCA1- or BRCA2-deficient contexts, where failure to prevent gaps, protect forks, and safeguard abasic DNA accelerates genomic instability. The functional impairment of HR proteins, which interface with base-excision repair and translesion synthesis, rewires these pathways, driving distinctive base-substitution mutational signatures of HR-defective tumors. Abasic sites, especially from methyl-cytosine metabolism, put replication forks at risk of breaking, amplifying the need for RAD51-mediated defense. Such redefinition of homologous recombination protein function as part of an anticipatory surveillance and protective system, rather than a repair-only module, bears important implications for understanding tumorigenesis, therapy resistance, and aging.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895363","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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