eLife最新文献

{"title":"Nuclear and cytosolic J-domain proteins provide synergistic control of Hsf1 at distinct phases of the heat shock response.","authors":"Carmen Ruger-Herreros, Lucia Svoboda, Gurranna Male, Aseem Shrivastava, Markus Höpfler, Katharina Jetzinger, Jiří Koubek, Günter Kramer, Fabian den Brave, Axel Mogk, David S Gross, Bernd Bukau","doi":"10.7554/eLife.107157","DOIUrl":"10.7554/eLife.107157","url":null,"abstract":"<p><p>The heat shock response (HSR) is the major defense mechanism against proteotoxic stress in the cytosol and nucleus of eukaryotic cells. Initiation and attenuation of the response are mediated by stress-dependent regulation of heat shock transcription factors (HSFs). <i>Saccharomyces cerevisiae</i> encodes a single HSF (Hsf1), facilitating the analysis of HSR regulation. Hsf1 is repressed by Hsp70 chaperones under non-stress conditions and becomes activated under proteotoxic stress, directly linking protein damage and its repair to the HSR. J-domain proteins (JDPs) are essential for targeting of Hsp70s to their substrates, yet the specific JDP(s) regulating Hsf1 and connecting protein damage to HSR activation remain unclear. Here, we show that the yeast nuclear JDP Apj1 primarily controls the attenuation phase of the HSR by promoting Hsf1's displacement from heat shock elements in target DNA. In <i>apj1Δ</i> cells, HSR attenuation is significantly impaired. Additionally, yeast cells lacking both Apj1 and the major JDP Ydj1 exhibit increased HSR activation even in non-stress conditions, indicating their distinct regulatory roles. Apj1's role in both nuclear protein quality control and Hsf1 regulation underscores its role in directly linking nuclear proteostasis to HSR regulation. Together, these findings establish the nucleus as key stress-sensing signaling hub.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191319","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":"Astrocytic modulation of population encoding in mouse visual cortex via GABA transporter 3 revealed by multiplexed CRISPR/Cas9 gene editing.","authors":"Jiho Park, Grayson O Sipe, Xin Tang, Prachi Ojha, Giselle Fernandes, Yi Ning Leow, Caroline Zhang, Yuma Osako, Arundhati Natesan, Gabrielle T Drummond, Rudolf Jaenisch, Mriganka Sur","doi":"10.7554/eLife.107298","DOIUrl":"10.7554/eLife.107298","url":null,"abstract":"<p><p>Astrocytes, which are increasingly recognized as pivotal constituents of brain circuits governing a wide range of functions, express GABA transporter 3 (Gat3), an astrocyte-specific GABA transporter responsible for maintenance of extra-synaptic GABA levels. Here, we examined the functional role of Gat3 in astrocyte-mediated modulation of neuronal activity and information encoding. First, we developed a multiplexed CRISPR construct applicable for effective genetic ablation of Gat3 in the visual cortex of adult mice. Using <i>in vivo</i> two-photon calcium imaging of visual cortex neurons in Gat3 knockout mice, we observed changes in spontaneous and visually driven single neuronal response properties such as response magnitudes and trial-to-trial variability. Gat3 knockout exerted a pronounced influence on population-level neuronal activity, altering the response dynamics of neuronal populations and impairing their ability to accurately represent stimulus information. These findings demonstrate that Gat3 in astrocytes profoundly shapes the sensory information encoding capacity of neurons and networks within the visual cortex.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191365","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":"Targeting chromatin remodeling complexes to treat uveal melanoma.","authors":"Jonas A Nilsson","doi":"10.7554/eLife.109262","DOIUrl":"10.7554/eLife.109262","url":null,"abstract":"<p><p>A novel compound that inhibits the BAF chromatin remodeling complex causes regression in an animal model of the incurable cancer uveal melanoma.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191326","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":"Pesticide-induced resurgence in brown planthoppers is mediated by action on a suite of genes that promote juvenile hormone biosynthesis and female fecundity.","authors":"Yang Gao, Shao-Cong Su, Ji-Yang Xing, Zhao-Yu Liu, Dick R Nässel, Chris Bass, Congfen Gao, Shun-Fan Wu","doi":"10.7554/eLife.91774","DOIUrl":"10.7554/eLife.91774","url":null,"abstract":"<p><p>Pesticide-induced resurgence, increases in pest insect populations following pesticide application, is a serious threat to the sustainable control of many highly damaging crop pests. Resurgence can result from pesticide-enhanced pest reproduction; however, the molecular mechanisms mediating this process remain unresolved. Here we show that brown planthopper (BPH) resurgence in rice crops following exposure to sublethal doses of the pesticide emamectin benzoate (EB) results from the coordinated action of a suite of genes that regulate juvenile hormone (JH) levels, resulting in increased JH titer in adult females and enhanced fecundity. We demonstrate that EB treatment at sublethal levels results in profound changes in female BPH fitness, including increased egg maturation and oviposition. This enhanced reproductive fitness results from the EB-mediated upregulation of key genes involved in the regulation of JH, including <i>JHAMT and Kr-h1</i> and the downregulation of allatostatin (<i>AstA</i>) and allatostatin receptor (<i>AstAR</i>) expression. AstA signaling is known to inhibit the production of JH in the corpora allata and hence EB exposure diminishes this inhibitory action. We find that the changes in gene expression following EB exposure are caused by the allosteric action of this insecticide on its molecular target, the glutamate-gated chloride channel (GluClα). Collectively, these results provide mechanistic insights into the regulation of negative pesticide-induced responses in insects and reveal some key actors involved in the JH-signaling pathway that underpin pesticide resurgence.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198664","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":"Telomeres control human telomerase (<i>TERT</i>) expression through non-telomeric TRF2.","authors":"Antara Sengupta, Soujanya Vinayagamurthy, Dristhi Soni, Rajlekha Deb, Ananda Kishore Mukherjee, Subhajit Dutta, Jushta Jaiswal, Mukta Yadav, Shalu Sharma, Sulochana Bagri, Shuvra Shekhar Roy, Priya Poonia, Ankita Singh, Divya Khanna, Amit Kumar Kumar Bhatt, Akshay Sharma, Suman Saurav, Rajender K Motiani, Shantanu Chowdhury","doi":"10.7554/eLife.104045","DOIUrl":"10.7554/eLife.104045","url":null,"abstract":"<p><p>The function of the human telomerase reverse transcriptase (referred hereafter as <i>TERT</i>) in the synthesis and maintenance of chromosome ends, or telomeres, is widely understood. Whether and how telomeres, on the other hand, influence <i>TERT</i> regulation is relatively less studied. We found <i>TERT</i> was transcriptionally altered depending on telomere length (TL). This resulted from TL-dependent binding of TRF2 between telomeres and the <i>TERT</i> promoter. <i>TERT</i> promoter-bound TRF2 was non-telomeric and did not involve the looping of telomeres to the <i>TERT</i> promoter. Cell lines from different tissue types fibrosarcoma (HT1080), colon cancer (HCT116), and breast cancer (MDA-MB-231), engineered for either telomere elongation/shortening, gave an increase/decrease in <i>TERT</i>, respectively. Mechanistically, we show <i>TERT</i> promoter-bound non-telomeric TRF2 recruits the canonical PRC2-complex, inducing repressor histone H3K27-trimethylation in a TL-dependent fashion. This was further supported by TL-dependent promoter activity from an exogenously inserted <i>TERT</i> reporter. Increase in TL over days followed by a gradual decline, resulted in activation followed by repression of <i>TERT</i> in a concerted manner, further implicating TL as a key factor for <i>TERT</i> regulation. Notably, on reprogramming primary fibroblasts to induced pluripotent stem cells (iPSCs), TRF2 loss from the <i>TERT</i> promoter was evident along with telomere elongation and <i>TERT</i> upregulation. Conversely, on telomere shortening in iPSCs, <i>TERT</i> promoter-bound TRF2 was restored with a marked reduction in <i>TERT,</i> further supporting the causal role of TL in <i>TERT</i> transcription. Mechanisms of tight control of <i>TERT</i> by TL shown here are likely to have major implications in telomere-related physiologies, particularly, cancer, ageing, and pluripotency.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198695","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":"Direct modulation of TRPM8 ion channels by rapamycin and analog macrolide immunosuppressants.","authors":"Balázs István Tóth, Bahar Bazeli, Annelies Janssens, Erika Lisztes, Márk Racskó, Balázs Kelemen, Mihály Herczeg, Tamás Milán Nagy, Katalin E Kövér, Argha Mitra, Attila Borics, Tamás Bíró, Thomas Voets","doi":"10.7554/eLife.97341","DOIUrl":"10.7554/eLife.97341","url":null,"abstract":"<p><p>Rapamycin (sirolimus), a macrolide compound isolated from the bacterium <i>Streptomyces hygroscopicus</i>, is widely used as oral medication for the prevention of transplant rejection and the treatment of lymphangioleiomyomatosis. It is also incorporated in coronary stent coatings to prevent restenosis and in topical preparations for the treatment of skin disorders. Rapamycin's in vivo activities are generally ascribed to its binding to the protein FKBP12, leading to potent inhibition of the mechanistic target of rapamycin kinase (mTOR) by the FKBP12-rapamycin complex. The specific rapamycin-induced interaction between domains from mTOR and FKBP12 is also frequently employed in cell biological research, for rapid chemically-induced protein dimerization strategies. Here, we show that rapamycin activates TRPM8, a cation channel expressed in sensory nerve endings that serves as the primary cold sensor in mammals. Using a combination of electrophysiology, Saturation Transfer Triple-Difference (STTD) NMR spectroscopy, and molecular docking-based targeted mutagenesis, we demonstrate that rapamycin directly binds to human TRPM8. We identify a rapamycin-binding site in the groove between voltage sensor-like domain and the pore domain, distinct from the interaction sites of cooling agents and known TRPM8 agonists menthol and icilin. Related macrolide immunosuppressants act as partial TRPM8 agonists, competing with rapamycin for the same binding site. These findings identify a novel molecular target for rapamycin and provide new insights into the mechanisms of TRPM8 activation, which may assist in the development of therapies targeting this ion channel. Moreover, our findings also indicate that caution is needed when using molecular approaches based on rapamycin-induced dimerization to study ion channel regulation.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191171","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":"Spatial frequency adaptation modulates population receptive field sizes.","authors":"Ecem Altan, Catherine A Morgan, Steven C Dakin, D Samuel Schwarzkopf","doi":"10.7554/eLife.100734","DOIUrl":"10.7554/eLife.100734","url":null,"abstract":"<p><p>The spatial tuning of neuronal populations in the early visual cortical regions is related to the spatial frequency (SF) selectivity of neurons. However, there has been no direct investigation into how this relationship is reflected in population receptive field (pRF) sizes despite the common application of pRF mapping in visual neuroscience. We hypothesised that adaptation to high/low SF would decrease the sensitivity of neurons with respectively small/large receptive field sizes, resulting in a change in pRF sizes as measured by functional magnetic resonance imaging (fMRI). To test this hypothesis, we first quantified the SF aftereffect using a psychophysical paradigm where human observers made SF judgments following adaptation to high/low SF noise patterns. We then incorporated the same adaptation technique into a standard pRF mapping procedure to investigate the spatial tuning of the early visual cortex following SF adaptation. Results showed that adaptation to a low/high SF resulted in smaller/larger pRFs, respectively, as hypothesised. Our results provide the most direct evidence to date that the spatial tuning of the visual cortex, as measured by pRF mapping, is related to the SF selectivity of visual neural populations. This has implications for various domains of visual processing, including size perception and visual acuity.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12470847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148343","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":"Steady-state neuron-predominant LINE-1 encoded ORF1p protein and LINE-1 RNA increase with aging in the mouse and human brain.","authors":"Tom Bonnifet, Sandra Sinnassamy, Olivia Massiani-Beaudoin, Philippe Mailly, Heloise Monnet, Damarys Loew, Berangere Lombard, Nicolas Servant, Rajiv L Joshi, Julia Fuchs","doi":"10.7554/eLife.100687","DOIUrl":"10.7554/eLife.100687","url":null,"abstract":"<p><p>Recent studies have established a reciprocal causal link between aging and the activation of transposable elements, characterized in particular by a de-repression of LINE-1 retrotransposons. These LINE-1 elements represent 21% of the human genome, but only a minority of these sequences retain the coding potential essential for their mobility. LINE-1 encoded proteins can induce cell toxicity implicated in aging and neurodegenerative diseases. However, our knowledge of the expression and localization of LINE-1-encoded proteins in the central nervous system is limited. Using a novel approach combining atlas-based brain mapping with deep-learning algorithms on large-scale pyramidal brain images, we unveil a heterogeneous, neuron-predominant, and widespread ORF1p expression throughout the murine brain at steady-state. In aged mice, ORF1p expression increases significantly, which is corroborated in human post-mortem dopaminergic neurons by an increase in young LINE-1 elements including those with open reading frames. Mass spectrometry analysis of endogenous mouse ORF1p revealed novel, neuron-specific protein interactors. These findings contribute to a comprehensive description of the dynamics of LINE-1 and ORF1p expression in the brain at steady-state and in aging and provide insights on ORF1p protein interactions in the brain.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136954","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":"Segment-specific axon guidance by Wnt/Fz signaling diversifies motor commands in <i>Drosophila</i> larvae.","authors":"Suguru Takagi, Shiina Takano, Tomohiro Kubo, Yusaku Hashimoto, Shu Morise, Xiangsunze Zeng, Akinao Nose","doi":"10.7554/eLife.98624","DOIUrl":"10.7554/eLife.98624","url":null,"abstract":"<p><p>Functional diversification of homologous neuronal microcircuits is a widespread feature observed across brain regions, as well as across species, while its molecular and developmental mechanisms remain largely unknown. We address this question in <i>Drosophila</i> larvae by focusing on segmentally homologous Wave command-like neurons, which diversify their wiring and function in a segment-specific manner. Anterior Wave (a-Wave) neurons extend axons anteriorly and connect to circuits inducing backward locomotion, whereas posterior Wave (p-Wave) neurons extend axons posteriorly and trigger forward locomotion. Here, we show that Frizzled receptors DFz2 and DFz4, together with the DWnt4 ligand, regulate the segment-specific Wave axon projection. <i>DFz2</i> knockdown (KD) not only reroutes Wave axons to posterior neuromeres but also biases its motor command to induce forward instead of backward locomotion as tactile response. Thus, segment-specific axon guidance diversifies the function of homologous command neurons in behavioral regulation. Since control of anterior-posterior (A-P) axon guidance by Wnt/Fz signaling is evolutionarily conserved, our results reveal a potentially universal molecular principle for formation and diversification of the command system in the nerve cord. Furthermore, this work indicates that sensorimotor transduction can be rerouted by manipulating a single gene in a single class of neurons, potentially facilitating the evolutionary flexibility in action selection.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136938","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":"The molecular infrastructure of glutamatergic synapses in the mammalian forebrain.","authors":"Julia Peukes, Charlie Lovatt, Conny Leistner, Jerome Boulanger, Dustin R Morado, Martin J G Fuller, Wanda Kukulski, Fei Zhu, Noboru H Komiyama, John A G Briggs, Seth G N Grant, René A W Frank","doi":"10.7554/eLife.100335","DOIUrl":"10.7554/eLife.100335","url":null,"abstract":"<p><p>Glutamatergic synapses form the vast majority of connections within neuronal circuits, but how these subcellular structures are molecularly organized within the mammalian brain is poorly understood. Conventional electron microscopy using chemically fixed, metal-stained tissue has identified a proteinaceous, membrane-associated thickening called the 'postsynaptic density' (PSD). Here, we combined mouse genetics and cryo-electron tomography to determine the 3D molecular architecture of fresh isolated and anatomically intact synapses in the adult forebrain. The native glutamatergic synapse did not consistently show a higher density of proteins at the postsynaptic membrane, thought to be characteristic of the PSD. Instead, a 'synaptoplasm' consisting of cytoskeletal elements, macromolecular complexes, and membrane-bound organelles extended throughout the pre- and post-synaptic compartments. Snapshots of active processes gave insights into membrane remodeling processes. Clusters of up to 60 ionotropic glutamate receptors were positioned inside and outside the synaptic cleft. Together, these information-rich tomographic maps present a detailed molecular framework for the coordinated activity of synapses in the adult mammalian brain.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136963","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}