eLife最新文献

{"title":"HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes.","authors":"Hongchen Li, Xinchao Zhang, Xiaoben Liang, Shuyan Li, Ziyi Cui, Xinyu Zhao, Kai Wang, Bingbing Zha, Haijie Ma, Ming Xu, Lei Lv, Yanping Xu","doi":"10.7554/eLife.103663","DOIUrl":"10.7554/eLife.103663","url":null,"abstract":"<p><p>The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and <i>TET2</i> knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of the <i>FBP1</i> promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207935","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":"Immobilizing bacteria to prevent infections.","authors":"Patricia Reist Iscar, Petr Broz","doi":"10.7554/eLife.107383","DOIUrl":"10.7554/eLife.107383","url":null,"abstract":"<p><p>The interferon-induced GTPase GVIN1 prevents bacteria from spreading among cells by coating them and rendering them immobile.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208013","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":"Daptomycin forms a stable complex with phosphatidylglycerol for selective uptake to bacterial membrane.","authors":"Pragyansree Machhua, Vignesh Gopalakrishnan Unnithan, Yu Liu, Yiping Jiang, Lingfeng Zhang, Zhihong Guo","doi":"10.7554/eLife.93267","DOIUrl":"10.7554/eLife.93267","url":null,"abstract":"<p><p>Daptomycin is a potent lipopeptide antibiotic used in the treatment of life-threatening Gram-positive infections, but the molecular mechanism of its interaction with bacterial membrane remains unclear. Here, we show that this interaction is divided into two stages, of which the first is a fast and reversible binding of the drug to phospholipid membrane in milliseconds, and the second is a slow and irreversible insertion into membrane in minutes, only in the presence of the bacteria-specific lipid phosphatidylglycerol, to a saturating point where the ratio of the drug to phosphatidylglycerol is 1:2. Fluorescence-based titration showed that the antibiotic simultaneously binds two molecules of phosphatidylglycerol with a nanomolar binding affinity in the presence of calcium ion. The resulting stable complex is easily formed in a test tube and readily isolated from the membrane of drug-treated bacterial cells, strongly supporting a unique drug uptake mechanism in which daptomycin forms a stable multicomponent complex with calcium and phosphatidylglycerol. Revelation of this novel uptake mechanism provides fresh insights into the mode of action of daptomycin and paves the way to new strategies to attenuate resistance to the drug.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12129450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198491","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":"Chemogenetic stimulation of phrenic motor output and diaphragm activity.","authors":"Ethan S Benevides, Prajwal P Thakre, Sabhya Rana, Michael D Sunshine, Victoria N Jensen, Karim Oweiss, David D Fuller","doi":"10.7554/eLife.97846","DOIUrl":"10.7554/eLife.97846","url":null,"abstract":"<p><p>Impaired respiratory motor output contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We investigated if expressing designer receptors exclusively activated by designer drugs (DREADDs) in the mid-cervical spinal cord could effectively stimulate phrenic motor output to increase diaphragm activation. Two primary questions were addressed: (1) does effective DREADD-mediated diaphragm activation require focal expression in phrenic motoneurons (vs. non-specific mid-cervical expression), and (2) can this method produce a sustained increase in inspiratory tidal volume? Wild-type (C57Bl/6) and ChAT-Cre mice received bilateral intraspinal (C4) injections of an adeno-associated virus (AAV) encoding the hM3D(Gq) excitatory DREADD. In wild-type mice, this produced non-specific DREADD expression throughout the mid-cervical ventral horn. In ChAT-Cre mice, a Cre-dependent viral construct was used to drive neuronal DREADD expression in the C4 ventral horns, targeting phrenic motoneurons. Diaphragm electromyograms (EMG) were recorded in isoflurane-anesthetized spontaneously breathing mice at 4-9 weeks post-AAV delivery. The DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hr) increase in inspiratory EMG bursting in both groups; the relative increase was greater in ChAT-Cre mice. Additional experiments in ChAT-Cre rats were conducted to determine if spinal DREADD activation could increase inspiratory tidal volume during spontaneous breathing, assessed using whole-body plethysmography without anesthesia. Three to four months after intraspinal (C4) injection of AAV driving Cre-dependent hM3D(Gq) expression, intravenous J60 resulted in a sustained (>30 min) increase in tidal volume. Subsequently, phrenic nerve recordings performed under urethane anesthesia confirmed that J60 evoked a >200% increase in inspiratory output. We conclude that targeting mid-cervical spinal DREADD expression to the phrenic motoneuron pool enables ligand-induced, sustained increases in phrenic motor output and tidal volume. Further development of this technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12129449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198490","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":"Otoacoustic emissions but not behavioral measurements predict cochlear nerve frequency tuning in an avian vocal communication specialist.","authors":"Diana M Karosas, Leslie Gonzales, Yingxuan Wang, Christopher Bergevin, Laurel H Carney, Kenneth S Henry","doi":"10.7554/eLife.102911","DOIUrl":"10.7554/eLife.102911","url":null,"abstract":"<p><p>Frequency analysis by the cochlea forms a key foundation for all subsequent auditory processing. Stimulus-frequency otoacoustic emissions (SFOAEs) are a potentially powerful alternative to traditional behavioral experiments for estimating cochlear tuning without invasive testing, as is necessary in humans. Which methods accurately predict cochlear tuning remains controversial due to only a single animal study comparing SFOAE-based, behavioral, and cochlear frequency tuning in the same species. The budgerigar (<i>Melopsittacus undulatus</i>) is a parakeet species with human-like behavioral sensitivity to many sounds and the capacity to mimic speech. Intriguingly, previous studies of critical bands, psychophysical tuning curves, and critical ratios in budgerigars show that behavioral tuning sharpness increases dramatically with increasing frequency from 1 to 3.5 kHz, doubling once per octave with peak tuning sharpness from 3.5 to 4 kHz. The pattern contrasts with slower monotonic growth of behavioral tuning sharpness with increasing frequency in other animals, including most avian species, suggesting a possible auditory specialization in budgerigars. We measured SFOAE-based and cochlear-afferent tuning in budgerigars, for comparison to previously reported behavioral results. SFOAE-based and cochlear-afferent tuning sharpness both increased monotonically and relatively slowly for higher frequencies, in contrast to the behavioral pattern. SFOAE-based tuning in budgerigars accurately predicted cochlear frequency tuning, and both measures aligned with typical patterns of cochlear tuning in other species. Divergent behavioral tuning in budgerigars is unlikely attributable to the periphery and could reflect specializations for central processing of masked signals. Our findings highlight the value of SFOAEs for estimating cochlear tuning and caution against direct inference of peripheral tuning from behavioral critical bands, psychophysical tuning curves, and critical ratios.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12129448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198494","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":"Image-based identification and isolation of micronucleated cells to dissect cellular consequences.","authors":"Lucian DiPeso, Sriram Pendyala, Heather Z Huang, Douglas M Fowler, Emily M Hatch","doi":"10.7554/eLife.101579","DOIUrl":"10.7554/eLife.101579","url":null,"abstract":"<p><p>Recent advances in isolating cells based on visual phenotypes have transformed our ability to identify the mechanisms and consequences of complex traits. Micronucleus (MN) formation is a frequent outcome of genome instability, triggers extensive changes in genome structure and signaling coincident with MN rupture, and is almost exclusively defined by visual analysis. Automated MN detection in microscopy images has proved challenging, limiting discovery of the mechanisms and consequences of MN. In this study we describe two new MN segmentation modules: a rapid model for classifying micronucleated cells and their rupture status (VCS MN), and a robust model for accurate MN segmentation (MNFinder) from a broad range of cell lines. As proof-of-concept, we define the transcriptome of non-transformed human cells with intact or ruptured MN after chromosome missegregation by combining VCS MN with photoactivation-based cell isolation and RNASeq. Surprisingly, we find that neither MN formation nor rupture triggers a strong unique transcriptional response. Instead, transcriptional changes appear correlated with small increases in aneuploidy in these cell classes. Our MN segmentation modules overcome a significant challenge with reproducible MN quantification, and, joined with visual cell sorting, enable the application of powerful functional genomics assays to a wide-range of questions in MN biology.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12129451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198493","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":"Virus attacks fish by muscling its way into cells.","authors":"Ping-Ping Liu, Zhe Wei, Xian-Wei Wang","doi":"10.7554/eLife.107508","DOIUrl":"10.7554/eLife.107508","url":null,"abstract":"<p><p>Nervous necrosis virus typically enters host cells via endocytosis, but it can also enter via a process called macropinocytosis.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12129447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198496","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":"Ferroptosis-related genes mediate tumor microenvironment and prognosis in triple-negative breast cancer via integrated RNA-seq analysis.","authors":"Xuantong Gong, Lishuang Gu, Di Yang, Yu He, Qian Li, Hao Qin, Yong Wang","doi":"10.7554/eLife.100923","DOIUrl":"10.7554/eLife.100923","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC), an aggressive malignancy with limited tools to predict recurrence and drug sensitivity, exhibits ferroptotic heterogeneity across subtypes. However, the tumor microenvironment (TME) mediated by ferroptosis-related genes remains poorly characterized. This study integrates single-cell and bulk RNA sequencing data from the Gene Expression Omnibus to elucidate ferroptosis-driven TME features in TNBC, employing machine learning to develop prognostic and therapeutic response prediction models. At the single-cell level, T cells were classified into three subpopulations and macrophages into two subpopulations, with their infiltration degrees significantly correlated with clinical outcomes. A risk score model constructed based on these findings demonstrated robust predictive performance, validated in external cohorts with 3-, 4-, and 5-year area under the receiver operating characteristic curves of 0.65, 0.67, and 0.71, respectively. Notably, high-risk patients exhibited enhanced sensitivity to 27 therapeutic agents. By delineating ferroptosis-associated immune heterogeneity, this work provides a risk stratification tool to enhance prognostic precision and therapeutic decision-making in TNBC, while identifying genes offer actionable targets for TNBC precision medicine.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12129453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198492","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":"Post-fertilization transcription initiation in an ancestral LTR retrotransposon drives lineage-specific genomic imprinting of <i>ZDBF2</i>.","authors":"Hisato Kobayashi, Tatsushi Igaki, Soichiro Kumamoto, Keisuke Tanaka, Tomoya Takashima, So I Nagaoka, Shunsuke Suzuki, Masaaki Hayashi, Marilyn B Renfree, Manabu Kawahara, Shun Saito, Toshihiro Kobayashi, Hiroshi Nagashima, Hitomi Matsunari, Kazuaki Nakano, Ayuko Uchikura, Hiroshi Kiyonari, Mari Kaneko, Hiroo Imai, Kazuhiko Nakabayashi, Matthew Lorincz, Kazuki Kurimoto","doi":"10.7554/eLife.94502","DOIUrl":"10.7554/eLife.94502","url":null,"abstract":"<p><p>The imprinted gene <i>ZDBF2</i> is regulated through a unique mechanism involving a transient paternal transcript in early embryos, rather than persistent gametic DNA methylation. In humans and mice, this transcript-<i>CMKLR2-AS</i> (also known as <i>GPR1-AS</i>) or the long isoform of <i>Zdbf2</i> (<i>Liz/Zdbf2linc/Platr12</i>)-arises from the unmethylated paternal allele and initiates secondary epigenetic marks that maintain <i>ZDBF2</i> expression. Here, we investigate the evolutionary origin of this mechanism, and show that the first exon of human <i>GPR1-AS</i> overlaps with a MER21C long terminal repeat (LTR), a retrotransposon subfamily specific to Boreoeutherian mammals. Comparative analyses revealed that this MER21C insertion occurred in the common ancestor of Euarchontoglires, including primates, rodents, and rabbits. Although not annotated, the first exon of mouse <i>Liz</i> displays conserved features with the MER21C-overlapping exon in humans. In rabbit and nonhuman primate placentas, <i>GPR1-AS</i> orthologs with LTR-embedded first exons were also identified. In contrast, in non-Euarchontoglire mammals such as cow and tammar wallaby, <i>ZDBF2</i> is biallelically expressed, suggesting absence of imprinting. These findings suggest that <i>ZDBF2</i> imprinting emerged in Euarchontoglires via MER21C insertion. Together with our prior work on LTR-driven imprinting in oocytes, our findings demonstrate that post-fertilization activation of retrotransposons can also drive lineage-specific acquisition of imprinting.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12129452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198495","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":"Inhibition of mitochondrial protein import and proteostasis by a pro-apoptotic lipid.","authors":"Josep Fita-Torró, José Luis Garrido-Huarte, Lucía López-Gil, Agnès H Michel, Benoit Kornmann, Amparo Pascual-Ahuir, Markus Proft","doi":"10.7554/eLife.93621","DOIUrl":"10.7554/eLife.93621","url":null,"abstract":"<p><p>Mitochondria-mediated cell death is critically regulated by bioactive lipids derived from sphingolipid metabolism. The lipid aldehyde trans-2-hexadecenal (t-2-hex) induces mitochondrial dysfunction from yeast to humans. Here, we apply unbiased transcriptomic, functional genomics, and chemoproteomic approaches in the yeast model to uncover the principal mechanisms and biological targets underlying this lipid-induced mitochondrial inhibition. We find that loss of Hfd1 fatty aldehyde dehydrogenase function efficiently sensitizes cells for t-2-hex inhibition and apoptotic cell death. Excess of t-2-hex causes a profound transcriptomic response with characteristic hallmarks of impaired mitochondrial protein import, like activation of mitochondrial and cytosolic chaperones or proteasomal function and severe repression of translation. We confirm that t-2-hex stress induces rapid accumulation of mitochondrial pre-proteins and protein aggregates and subsequent activation of Hsf1- and Rpn4-dependent gene expression. By saturated transposon mutagenesis, we find that t-2-hex tolerance requires an efficient heat shock response and specific mitochondrial and ER functions and that mutations in ribosome, protein, and amino acid biogenesis are beneficial upon t-2-hex stress. We further show that genetic and pharmacological inhibition of protein translation causes t-2-hex resistance, indicating that loss of proteostasis is the predominant consequence of the pro-apoptotic lipid. Several TOM subunits, including the central Tom40 channel, are lipidated by t-2-hex in vitro and mutation of accessory subunits Tom20 or Tom70 confers t-2-hex tolerance. Moreover, the Hfd1 gene dose determines the strength of t-2-hex mediated inhibition of mitochondrial protein import, and Hfd1 co-purifies with Tom70. Our results indicate that the transport of mitochondrial precursor proteins through the outer mitochondrial membrane is sensitively inhibited by the pro-apoptotic lipid and thus represents a hotspot for pro- and anti-apoptotic signaling.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12124835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186811","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}