EMBO ReportsPub Date : 2025-03-07DOI: 10.1038/s44319-025-00411-x
Delia Ricolo, Francesca Tamba, Jordi Casanova
{"title":"Autocrine Wingless constricts the Drosophila embryonic gut by Ca<sup>+2</sup>-mediated repolarisation of mesoderm cells.","authors":"Delia Ricolo, Francesca Tamba, Jordi Casanova","doi":"10.1038/s44319-025-00411-x","DOIUrl":"https://doi.org/10.1038/s44319-025-00411-x","url":null,"abstract":"<p><p>Wg/Wnt signalling-a highly conserved transduction pathway-has most commonly been found to be involved in patterning, cell fate, or cell proliferation, but less so in shaping organs or body parts. A remarkable case of the latter is the role of Wg signalling in the midgut of the Drosophila embryo. The Drosophila embryonic midgut is divided into four chambers that arise by the formation of three constrictions at distinct sites along the midgut. In particular, Wg is responsible for the middle constriction, a role first described more than 30 years ago. However, while some partial data have been obtained regarding the formation of this gut constriction, an overall picture of the process is lacking. Here we unveil that Wg signalling leads to this constriction by inducing ClC-a transcription in a subset of mesodermal cells. ClC-a, encodes a chloride channel, which in turn prompts a Ca<sup>+2</sup> pulse in these cells. Consequently, the mesoderm cells, which already showed some polarity, repolarise and in so doing so they reshape the microtubule organisation, therefore inducing the constriction of the cells.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585191","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}
EMBO ReportsPub Date : 2025-03-07DOI: 10.1038/s44319-025-00406-8
Ben Hur Marins Mussulini, Klaudia K Maruszczak, Piotr Draczkowski, Mayra A Borrero-Landazabal, Selvaraj Ayyamperumal, Artur Wnorowski, Michal Wasilewski, Agnieszka Chacinska
{"title":"MIA40 suppresses cell death induced by apoptosis-inducing factor 1.","authors":"Ben Hur Marins Mussulini, Klaudia K Maruszczak, Piotr Draczkowski, Mayra A Borrero-Landazabal, Selvaraj Ayyamperumal, Artur Wnorowski, Michal Wasilewski, Agnieszka Chacinska","doi":"10.1038/s44319-025-00406-8","DOIUrl":"https://doi.org/10.1038/s44319-025-00406-8","url":null,"abstract":"<p><p>Mitochondria harbor respiratory complexes that perform oxidative phosphorylation. Complex I is the first enzyme of the respiratory chain that oxidizes NADH. A dysfunction in complex I can result in higher cellular levels of NADH, which in turn strengthens the interaction between apoptosis-inducing factor 1 (AIFM1) and Mitochondrial intermembrane space import and assembly protein 40 (MIA40) in the mitochondrial intermembrane space. We investigated whether MIA40 modulates the activity of AIFM1 upon increased NADH/NAD+ balance. We found that in model cells characterized by an increase in NADH the AIFM1-MIA40 interaction is strengthened and these cells demonstrate resistance to AIFM1-induced cell death. Either silencing of MIA40, rescue of complex I, or depletion of NADH through the expression of yeast NADH-ubiquinone oxidoreductase-2 sensitized NDUFA13-KO cells to AIFM1-induced cell death. These findings indicate that the complex of MIA40 and AIFM1 suppresses AIFM1-induced cell death in a NADH-dependent manner. This study identifies an effector complex involved in regulating the programmed cell death that accommodates the metabolic changes in the cell and provides a molecular explanation for AIFM1-mediated chemoresistance of cancer cells.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585192","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}
EMBO ReportsPub Date : 2025-03-07DOI: 10.1038/s44319-025-00403-x
Miao Chen, Jun Li, Weiran Shan, Jianjun Yang, Zhiyi Zuo
{"title":"Auditory fear memory retrieval requires BLA-LS and LS-VMH circuitries via GABAergic and dopaminergic neurons.","authors":"Miao Chen, Jun Li, Weiran Shan, Jianjun Yang, Zhiyi Zuo","doi":"10.1038/s44319-025-00403-x","DOIUrl":"https://doi.org/10.1038/s44319-025-00403-x","url":null,"abstract":"<p><p>Fear and associated learning and memory are critical for developing defensive behavior. Excessive fear and anxiety are important components of post-traumatic stress disorder. However, the neurobiology of fear conditioning, especially tone-related fear memory retrieval, has not been clearly defined, which limits specific intervention development for patients with excessive fear and anxiety. Here, we show that auditory fear memory retrieval stimuli activate multiple brain regions including the lateral septum (LS). Inhibition of the LS and the connection between basolateral amygdala (BLA) and LS or between LS and ventromedial nucleus of the hypothalamus (VMH) attenuates tone-related fear conditioning and memory retrieval. Inhibiting GABAergic neurons or dopaminergic neurons in the LS also attenuates tone-related fear conditioning. Our data further show that fear conditioning is inhibited by blocking orexin B signaling in the LS. Our results indicate that the neural circuitries BLA-LS and LS-VMH are critical for tone-related fear conditioning and memory retrieval, and that GABAergic neurons, dopaminergic neurons and orexin signaling in the LS participate in this auditory fear conditioning.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585190","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}
EMBO ReportsPub Date : 2025-03-03DOI: 10.1038/s44319-025-00407-7
M Emre Kus, Cagatay Sahin, Emre Kilic, Arda Askin, M Mert Ozgur, Gokhan Karahanogullari, Ahmet Aksit, Ryan M O'Connell, H Atakan Ekiz
{"title":"TCGEx: a powerful visual interface for exploring and analyzing cancer gene expression data.","authors":"M Emre Kus, Cagatay Sahin, Emre Kilic, Arda Askin, M Mert Ozgur, Gokhan Karahanogullari, Ahmet Aksit, Ryan M O'Connell, H Atakan Ekiz","doi":"10.1038/s44319-025-00407-7","DOIUrl":"10.1038/s44319-025-00407-7","url":null,"abstract":"<p><p>Analyzing gene expression data from the Cancer Genome Atlas (TCGA) and similar repositories often requires advanced coding skills, creating a barrier for many researchers. To address this challenge, we developed The Cancer Genome Explorer (TCGEx), a user-friendly, web-based platform for conducting sophisticated analyses such as survival modeling, gene set enrichment analysis, unsupervised clustering, and linear regression-based machine learning. TCGEx provides access to preprocessed TCGA data and immune checkpoint inhibition studies while allowing integration of user-uploaded data sets. Using TCGEx, we explore molecular subsets of human melanoma and identify microRNAs associated with intratumoral immunity. These findings are validated with independent clinical trial data on immune checkpoint inhibitors for melanoma and other cancers. In addition, we identify cytokine genes that can be used to predict treatment responses to various immune checkpoint inhibitors prior to treatment. Built on the R/Shiny framework, TCGEx offers customizable features to adapt analyses for diverse research contexts and generate publication-ready visualizations. TCGEx is freely available at https://tcgex.iyte.edu.tr , providing an accessible tool to extract insights from cancer transcriptomics data.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540592","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}
EMBO ReportsPub Date : 2025-03-03DOI: 10.1038/s44319-025-00388-7
Carmen Figueras-Novoa, Masato Akutsu, Daichi Murata, Anne Weston, Ming Jiang, Beatriz Montaner, Christelle Dubois, Avinash Shenoy, Rupert Beale
{"title":"Caspase cleavage of influenza A virus M2 disrupts M2-LC3 interaction and regulates virion production.","authors":"Carmen Figueras-Novoa, Masato Akutsu, Daichi Murata, Anne Weston, Ming Jiang, Beatriz Montaner, Christelle Dubois, Avinash Shenoy, Rupert Beale","doi":"10.1038/s44319-025-00388-7","DOIUrl":"10.1038/s44319-025-00388-7","url":null,"abstract":"<p><p>Influenza A virus (IAV) Matrix 2 protein (M2) is an ion channel, required for efficient viral entry and egress. M2 interacts with the small ubiquitin-like LC3 protein through a cytoplasmic C-terminal LC3-interacting region (LIR). Here, we report that M2 is cleaved by caspases, abolishing the M2-LC3 interaction. A crystal structure of the M2 LIR in complex with LC3 indicates the caspase cleavage tetrapeptide motif (<sub>82</sub>SAVD<sub>85</sub>) is an unstructured linear motif that does not overlap with the LIR. IAV mutant expressing a permanently truncated M2, mimicking caspase cleavage, exhibit defects in M2 plasma membrane transport, viral filament formation, and virion production. Our results reveal a dynamic regulation of the M2-LC3 interaction by caspases. This highlights the role of host proteases in regulating IAV exit, relating virion production with host cell state.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540591","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}
EMBO ReportsPub Date : 2025-03-01Epub Date: 2025-02-03DOI: 10.1038/s44319-025-00383-y
Melina Messing, Marine Theret, Michael R Hughes, Jiaqi Wu, Omar Husain Syed, Fang Fang Li, Yicong Li, Fabio M V Rossi, Kelly M McNagny
{"title":"Type-2 innate signals are dispensable for skeletal muscle regeneration and pathology linked to Duchenne muscular dystrophy.","authors":"Melina Messing, Marine Theret, Michael R Hughes, Jiaqi Wu, Omar Husain Syed, Fang Fang Li, Yicong Li, Fabio M V Rossi, Kelly M McNagny","doi":"10.1038/s44319-025-00383-y","DOIUrl":"10.1038/s44319-025-00383-y","url":null,"abstract":"<p><p>Immune responses play an integral role in skeletal muscle regeneration. In the genetically inherited muscle disease Duchenne muscular dystrophy (DMD), muscle regeneration is disrupted, leading to chronic inflammation, fibrosis, and early mortality. Previously, it has been suggested that type-2 innate immune cells, particularly eosinophils and their production of IL-4, play an essential role in effective muscle regeneration after acute injury. We here re-investigate the role of eosinophils in skeletal muscle repair using mice deficient in eosinophils (ΔdblGATA), or deficient in IL-4R/IL-13R signaling through STAT6 (Stat6-/-). We show that neither deficiency has an impact on skeletal muscle regeneration in response to acute injury as quantified by fiber size, immune cell infiltration, or muscle-resident stem cell proliferation. We also investigate the role of STAT6 signaling in mdx:Stat6-/- mice, a model of DMD and, again, find that ablation of STAT6 signaling has no effect on the rate or severity of fibrotic scar formation or disease progression. In contrast to previous models, our data suggest a negligible role for eosinophils and STAT6 signaling in skeletal muscle regeneration after acute or chronic injury.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1406-1421"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11894123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Next-generation biotechnology inspired by extremes : The potential of extremophile organisms for synthetic biology and for more efficient and sustainable biotechnology.","authors":"Shuang Zheng, Mingwei Shao, Wanze Wang, Guo-Qiang Chen","doi":"10.1038/s44319-025-00389-6","DOIUrl":"10.1038/s44319-025-00389-6","url":null,"abstract":"","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1191-1195"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-03-01Epub Date: 2025-02-10DOI: 10.1038/s44319-025-00385-w
Pinqi Zhang, Zhuqiang Zhang, Yiyi Wang, Wenlong Du, Xingrui Song, Weiyi Lai, Hailin Wang, Bing Zhu, Jun Xiong
{"title":"A CRISPR-Cas9 screen reveals genetic determinants of the cellular response to decitabine.","authors":"Pinqi Zhang, Zhuqiang Zhang, Yiyi Wang, Wenlong Du, Xingrui Song, Weiyi Lai, Hailin Wang, Bing Zhu, Jun Xiong","doi":"10.1038/s44319-025-00385-w","DOIUrl":"10.1038/s44319-025-00385-w","url":null,"abstract":"<p><p>Decitabine (DAC), a well-recognized DNA hypomethylating agent, has been applied to treat acute myeloid leukemia. However, clinic investigations revealed that DNA methylation reduction does not correlate with a clinical response, and relapse is prevalent. To gain a better understanding of its anti-tumor mechanism, we perform a temporally resolved CRISPR-Cas9 screen to identify factors governing the DAC response. We show that DNA damage generated by DNMT-DNA adducts and 5-aza-dUTP misincorporation through the dCMP deaminase DCTD act as drivers of DAC-induced acute cytotoxicity. The DNA damage that arises during the next S phase is dependent on DNA replication, unveiling a trans-cell cycle effect of DAC on genome stability. By exploring candidates for synthetic lethality, we unexpectedly uncover that KDM1A promotes survival after DAC treatment through interactions with ZMYM3 and CoREST, independent of its demethylase activity or regulation of viral mimicry. These findings emphasize the importance of DNA repair pathways in DAC response and provide potential biomarkers.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1528-1565"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-03-01Epub Date: 2025-01-31DOI: 10.1038/s44319-025-00380-1
Akshaya Seshadri, Anjana Badrinarayanan
{"title":"Exonuclease action of replicative polymerase gamma drives damage-induced mitochondrial DNA clearance.","authors":"Akshaya Seshadri, Anjana Badrinarayanan","doi":"10.1038/s44319-025-00380-1","DOIUrl":"10.1038/s44319-025-00380-1","url":null,"abstract":"<p><p>Mitochondrial DNA (mtDNA) replication is essential for mitochondrial function. This is carried out by a dedicated DNA polymerase gamma, with 5'-3' polymerase and 3'-5' proofreading/ exonuclease activity. Perturbations to either property can have pathological consequences. Predominant sources for replication stress are DNA lesions, such as those induced by oxidative damage. How mtDNA lesions affect the polymerase activity and mtDNA stability in vivo is not fully understood. To address this, we induce mtDNA-specific damage in S. cerevisiae. We observe that mtDNA damage results in significant mtDNA loss. This loss occurs independent of cell cycle progression or cell division, suggesting an active mechanism for damaged mtDNA clearance. We implicate the 3'-5' exonuclease activity of the mtDNA polymerase in this clearance, with rates of loss being affected by cellular dNTP levels. Overall, our findings reveal context-dependent, selective regulation of two critical but opposing functions of polymerase gamma to ensure mitochondrial genome integrity.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1385-1405"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11894172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-03-01Epub Date: 2025-02-13DOI: 10.1038/s44319-025-00372-1
Masahito Yoshihara, Andrea Coschiera, Jörg A Bachmann, Mariangela Pucci, Haonan Li, Shruti Bhagat, Yasuhiro Murakawa, Jere Weltner, Eeva-Mari Jouhilahti, Peter Swoboda, Pelin Sahlén, Juha Kere
{"title":"Transcriptional enhancers in human neuronal differentiation provide clues to neuronal disorders.","authors":"Masahito Yoshihara, Andrea Coschiera, Jörg A Bachmann, Mariangela Pucci, Haonan Li, Shruti Bhagat, Yasuhiro Murakawa, Jere Weltner, Eeva-Mari Jouhilahti, Peter Swoboda, Pelin Sahlén, Juha Kere","doi":"10.1038/s44319-025-00372-1","DOIUrl":"10.1038/s44319-025-00372-1","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) have identified thousands of variants associated with complex phenotypes, including neuropsychiatric disorders. To better understand their pathogenesis, it is necessary to identify the functional roles of these variants, which are largely located in non-coding DNA regions. Here, we employ a human mesencephalic neuronal cell differentiation model, LUHMES, with sensitive and high-resolution methods to discover enhancers (NET-CAGE), perform DNA conformation analysis (Capture Hi-C) to link enhancers to their target genes, and finally validate selected interactions. We expand the number of known enhancers active in differentiating human LUHMES neurons to 47,350, and find overlap with GWAS variants for Parkinson's disease and schizophrenia. Our findings reveal a fine-tuned regulation of human neuronal differentiation, even between adjacent developmental stages; provide a valuable resource for further studies on neuronal development, regulation, and disorders; and emphasize the importance of exploring the vast regulatory potential of non-coding DNA and enhancers.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1212-1237"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}