Nature chemical biology最新文献

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-11-18 DOI: 10.1038/s41589-024-01785-0

Yiyun Song

{"title":"Assembly-activated aggregation","authors":"Yiyun Song","doi":"10.1038/s41589-024-01785-0","DOIUrl":"https://doi.org/10.1038/s41589-024-01785-0","url":null,"abstract":"The aberrant aggregation of the presynaptic protein α-synuclein (α-syn) is a hallmark of synucleinopathies, which include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Previous studies have suggested that α-syn can undergo liquid–liquid phase separation (LLPS) and transition from a liquid to a solid state, which contributes to aggregation and fibril formation. However, the factors that instigate α-syn LLPS have remained unclear. Now, Matsuo et al. have discovered that the cytoplasmic Ca2+ influx triggers the assembly of RNA G-quadruplexes (rG4s), which bind to α-syn and facilitate its LLPS and gelation.The team also developed a light-induced assembly system called optoG4. This system includes an RNA component with rG4-forming repeats and MS2 RNA hairpin repeats, and a protein component that combines the MS2-binding protein MCP with mCherry and CRY2, a protein capable of oligomerization upon exposure to blue light. Using the optoG4 system, the team were able to control the formation and dissolution of rG4 condensates in cultured neurons and in mice. They observed that rG4 assembly led to the aggregation of endogenous α-syn and induced Parkinson’s disease-like phenotypes, such as neuron death and motor dysfunction. Furthermore, oral administration of 5-aminolevulinic acid, a prodrug of protoporphyrin IX that binds to rG4, reduced α-syn aggregation and alleviated Parkinson’s disease-like phenotypes in mice treated with α-syn preformed fibrils.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"1155 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665441","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}

引用次数: 0

Guiding the pioneer 引导先锋

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-11-18 DOI: 10.1038/s41589-024-01786-z

Grant Miura

{"title":"Guiding the pioneer","authors":"Grant Miura","doi":"10.1038/s41589-024-01786-z","DOIUrl":"https://doi.org/10.1038/s41589-024-01786-z","url":null,"abstract":"Forkhead box protein A1 (FOXA1) is a pioneer transcription factor that binds to chromatin at a canonical DNA motif. This binding promotes the opening of chromatin, providing access to additional transcription factors. Targeting transcription factors such as FOXA1 with small molecules can serve as a useful tool to elucidate the rapid dynamics of transcriptional regulation, but remains difficult owing to a lack of definable binding pockets. Through a chemical screen using activity-based protein profiling with a library of electrophilic compounds, Won et al. identified WX-02-23 as a covalent binder of FOXA1 at a specific cysteine residue (C258) in the Wing2 region that is known to make contacts with the minor DNA groove. Binding of WX-02-23 to FOXA1 required the presence of DNA and enhanced FOXA1–DNA interactions. ChIP–seq (chromatin immunoprecipitation with sequencing) and ATAC-seq (assay for transposase-accessible chromatin using sequencing) analysis demonstrated that C258-dependent binding of WX-02-23 to FOXA1 can either increase or decrease FOXA1 binding throughout the genome, correlating with alterations in chromatin accessibility. The team found that WX-02-23 altered 10% of FOXA1 binding sites. Motif analysis revealed that these increased FOXA1 binding sites, mediated by WX-02-23, lack an ancillary 3 bp component of the canonical motif. They proposed that WX-02-23 may relax the DNA motif recognized by FOXA1 to expand its binding sites in cells. Quantitative NanoBRET assays confirmed that WX-02-23 increased FOXA1 binding to non-canonical motifs, which was also seen with a hotspot cancer mutation in the Wing2 region of FOXA1 (R261G). Although the structural basis for the effects of WX-02-23 on FOXA1 pioneering activity remain unclear, the identification of WX-02-23 offers a versatile tool to reveal new insights into FOXA1 biology and chromatin regulation.Original reference: Mol. Cell https://doi.org/10.1016/j.molcel.2024.09.024 (2024)","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"9 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665440","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}

引用次数: 0

A key to sperm–egg union 精卵结合的关键

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-11-18 DOI: 10.1038/s41589-024-01787-y

Gene Chong

{"title":"A key to sperm–egg union","authors":"Gene Chong","doi":"10.1038/s41589-024-01787-y","DOIUrl":"https://doi.org/10.1038/s41589-024-01787-y","url":null,"abstract":"The fusion of egg and sperm requires an egg surface protein, JUNO in mammals or Bouncer in fish, and several conserved sperm surface proteins, including IZUMO1, SPACA6, DCST1 and DCST2. The binding of JUNO and IZUMO1 is known but is not sufficient for fusion, and the specific roles of SPACA6 and DCST1/DCST2 remain unclear. Deneke, Blaha et al. have now identified a conserved sperm complex that includes IZUMO1 and interacts with JUNO/Bouncer to bridge the sperm and egg for fusion.To identify other sperm surface proteins that may bind to IZUMO1, SPACA6 and DCST1/DCST2, they performed an AlphaFold-Multimer screen of pairwise interactions between approximately 1,400 proteins known to be expressed in zebrafish testes. The top-scoring predicted interactions were between Izumo1 and Spaca6 and between Izumo1 and the protein Tmem81, with an unknown function in fertilization. AlphaFold-Multimer predicted a trimer between IZUMO1, SPACA6 and TMEM81, with JUNO able to access the binding site of IZUMO1. However, Bouncer was predicted to bind to a distinct site at an interface between Izumo1 and Spaca6, which was validated experimentally. Co-immunoprecipitation of IZUMO1, SPACA6 and TMEM81 confirmed the AlphaFold-Multimer prediction that these proteins interact, and mutations in various interfacial residues within the trimer led to sterility in zebrafish. To test the role of the newly identified protein TMEM81 in fertilization, the team generated Tmem81-knockout lines in zebrafish and mice; these animals turned out to be sterile with their sperm unable to fertilize eggs.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"17 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665436","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}

引用次数: 0

Open-ended molecular recording of sequential cellular events into DNA 以开放式分子方式将连续的细胞事件记录到 DNA 中

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-11-14 DOI: 10.1038/s41589-024-01764-5

Theresa B. Loveless, Courtney K. Carlson, Catalina A. Dentzel Helmy, Vincent J. Hu, Sara K. Ross, Matt C. Demelo, Ali Murtaza, Guohao Liang, Michelle Ficht, Arushi Singhai, Marcello J. Pajoh-Casco, Chang C. Liu

{"title":"Open-ended molecular recording of sequential cellular events into DNA","authors":"Theresa B. Loveless, Courtney K. Carlson, Catalina A. Dentzel Helmy, Vincent J. Hu, Sara K. Ross, Matt C. Demelo, Ali Murtaza, Guohao Liang, Michelle Ficht, Arushi Singhai, Marcello J. Pajoh-Casco, Chang C. Liu","doi":"10.1038/s41589-024-01764-5","DOIUrl":"https://doi.org/10.1038/s41589-024-01764-5","url":null,"abstract":"Genetically encoded DNA recorders noninvasively convert transient biological events into durable mutations in a cell’s genome, allowing for the later reconstruction of cellular experiences by DNA sequencing. We present a DNA recorder, peCHYRON, that achieves high-information, durable, and temporally resolved multiplexed recording of multiple cellular signals in mammalian cells. In each step of recording, prime editor, a Cas9-reverse transcriptase fusion protein, inserts a variable triplet DNA sequence alongside a constant propagator sequence that deactivates the previous and activates the next step of insertion. Insertions accumulate sequentially in a unidirectional order, editing can continue indefinitely, and high information is achieved by coexpressing a variety of prime editing guide RNAs (pegRNAs), each harboring unique triplet DNA sequences. We demonstrate that the constitutive expression of pegRNA collections generates insertion patterns for the straightforward reconstruction of cell lineage relationships and that the inducible expression of specific pegRNAs results in the accurate recording of exposures to biological stimuli.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"7 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142609979","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}

引用次数: 0

Spatiotemporal control of subcellular O-GlcNAc signaling using Opto-OGT 利用光学-OGT 对亚细胞 O-GlcNAc 信号进行时空控制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-11-14 DOI: 10.1038/s41589-024-01770-7

Qunxiang Ong, Ler Ting Rachel Lim, Cameron Goh, Yilie Liao, Sher En Chan, Crystal Jing Yi Lim, Valerie Kam, Jerome Yap, Tiffany Tseng, Reina Desrouleaux, Loo Chien Wang, Siok Ghee Ler, Siew Lan Lim, Sun-Yee Kim, Radoslaw M. Sobota, Anton M. Bennett, Weiping Han, Xiaoyong Yang

{"title":"Spatiotemporal control of subcellular O-GlcNAc signaling using Opto-OGT","authors":"Qunxiang Ong, Ler Ting Rachel Lim, Cameron Goh, Yilie Liao, Sher En Chan, Crystal Jing Yi Lim, Valerie Kam, Jerome Yap, Tiffany Tseng, Reina Desrouleaux, Loo Chien Wang, Siok Ghee Ler, Siew Lan Lim, Sun-Yee Kim, Radoslaw M. Sobota, Anton M. Bennett, Weiping Han, Xiaoyong Yang","doi":"10.1038/s41589-024-01770-7","DOIUrl":"https://doi.org/10.1038/s41589-024-01770-7","url":null,"abstract":"The post-translational modification of intracellular proteins through O-linked β-N-acetylglucosamine (O-GlcNAc) is a conserved regulatory mechanism in multicellular organisms. Catalyzed by O-GlcNAc transferase (OGT), this dynamic modification has an essential role in signal transduction, gene expression, organelle function and systemic physiology. Here, we present Opto-OGT, an optogenetic probe that allows for precise spatiotemporal control of OGT activity through light stimulation. By fusing a photosensitive cryptochrome protein to OGT, Opto-OGT can be robustly and reversibly activated with high temporal resolution by blue light and exhibits minimal background activity without illumination. Transient activation of Opto-OGT results in mTORC activation and AMPK suppression, which recapitulate nutrient-sensing signaling. Furthermore, Opto-OGT can be customized to localize to specific subcellular sites. By targeting OGT to the plasma membrane, we demonstrate the downregulation of site-specific AKT phosphorylation and signaling outputs in response to insulin stimulation. Thus, Opto-OGT is a powerful tool for defining the role of O-GlcNAcylation in cell signaling and physiology.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"18 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142609978","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}

引用次数: 0

Author Correction: Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis 作者更正：Evybactin 是一种 DNA 回旋酶抑制剂，可选择性杀死结核分枝杆菌

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-11-08 DOI: 10.1038/s41589-024-01779-y

Yu Imai, Glenn Hauk, Jeffrey Quigley, Libang Liang, Sangkeun Son, Meghan Ghiglieri, Michael F. Gates, Madeleine Morrissette, Negar Shahsavari, Samantha Niles, Donna Baldisseri, Chandrashekhar Honrao, Xiaoyu Ma, Jason J. Guo, James M. Berger, Kim Lewis

引用次数: 0

Author Correction: ML-enhanced peroxisome capacity enables compartmentalization of multienzyme pathway 作者更正：ML 增强的过氧化物酶体能力可实现多酶途径的区隔化

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-11-08 DOI: 10.1038/s41589-024-01784-1

Jordan J. Baker, Jie Shi, Shangying Wang, Elena M. Mujica, Simone Bianco, Sara Capponi, John E. Dueber

引用次数: 0

Engineering a xylose fermenting yeast for lignocellulosic ethanol production 改造木糖发酵酵母以生产木质纤维素乙醇

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-11-04 DOI: 10.1038/s41589-024-01771-6

Yi-Wen Zhang, Jun-Jie Yang, Feng-Hui Qian, Kate Brandon Sutton, Carsten Hjort, Wen-Ping Wu, Yu Jiang, Sheng Yang

{"title":"Engineering a xylose fermenting yeast for lignocellulosic ethanol production","authors":"Yi-Wen Zhang, Jun-Jie Yang, Feng-Hui Qian, Kate Brandon Sutton, Carsten Hjort, Wen-Ping Wu, Yu Jiang, Sheng Yang","doi":"10.1038/s41589-024-01771-6","DOIUrl":"https://doi.org/10.1038/s41589-024-01771-6","url":null,"abstract":"Lignocellulosic ethanol is produced by yeast fermentation of lignocellulosic hydrolysates generated by chemical pretreatment and enzymatic hydrolysis of plant cell walls. The conversion of xylose into ethanol in hydrolysates containing microbial inhibitors is a major bottleneck in biofuel production. We identified sodium salts as the primary yeast inhibitors, and evolved a Saccharomyces cerevisiae strain overexpressing xylose catabolism genes in xylose or glucose-mixed medium containing sodium salts. The fully evolved yeast strain can efficiently convert xylose in the hydrolysates to ethanol on an industrial scale. We elucidated that the amplification of xylA, XKS1 and pentose phosphate pathway-related genes TAL1, RPE1, TKL1, RKI1, along with mutations in NFS1, TRK1, SSK1, PUF2 and IRA1, are responsible and sufficient for the effective xylose utilization in corn stover hydrolysates containing high sodium salts. Our evolved or reverse-engineered yeast strains enable industrial-scale production of lignocellulosic ethanol and the genetic foundation we uncovered can also facilitate transfer of the phenotype to yeast cell factories producing chemicals beyond ethanol.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"126 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574668","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}

引用次数: 0

A multiplex single-cell RNA-Seq pharmacotranscriptomics pipeline for drug discovery 用于药物发现的多重单细胞 RNA-Seq 药物转录组学管道

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-10-31 DOI: 10.1038/s41589-024-01761-8

Alice Dini, Harlan Barker, Emilia Piki, Subodh Sharma, Juuli Raivola, Astrid Murumägi, Daniela Ungureanu

{"title":"A multiplex single-cell RNA-Seq pharmacotranscriptomics pipeline for drug discovery","authors":"Alice Dini, Harlan Barker, Emilia Piki, Subodh Sharma, Juuli Raivola, Astrid Murumägi, Daniela Ungureanu","doi":"10.1038/s41589-024-01761-8","DOIUrl":"https://doi.org/10.1038/s41589-024-01761-8","url":null,"abstract":"The gene-regulatory dynamics governing drug responses in cancer are yet to be fully understood. Here, we report a pipeline capable of producing high-throughput pharmacotranscriptomic profiling through live-cell barcoding using antibody–oligonucleotide conjugates. This pipeline combines drug screening with 96-plex single-cell RNA sequencing. We show the potential of this approach by exploring the heterogeneous transcriptional landscape of primary high-grade serous ovarian cancer (HGSOC) cells after treatment with 45 drugs, with 13 distinct classes of mechanisms of action. A subset of phosphatidylinositol 3-OH kinase (PI3K), protein kinase B (AKT) and mammalian target of rapamycin (mTOR) inhibitors induced the activation of receptor tyrosine kinases, such as the epithelial growth factor receptor (EGFR), and this was mediated by the upregulation of caveolin 1 (CAV1). This drug resistance feedback loop could be mitigated by the synergistic action of agents targeting PI3K–AKT–mTOR and EGFR for HGSOC with CAV1 and EGFR expression. Using this workflow could enable the personalized testing of patient-derived tumor samples at single-cell resolution.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"37 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555821","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}

引用次数: 0

Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion 抑制碳酸酐酶可通过增强 tau 的分泌改善 tau 的毒性

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-10-31 DOI: 10.1038/s41589-024-01762-7

Ana Lopez, Farah H. Siddiqi, Julien Villeneuve, Rodrigo Portes Ureshino, Hee-Yeon Jeon, Philippos Koulousakis, Sophie Keeling, William A. McEwan, Angeleen Fleming, David C. Rubinsztein

{"title":"Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion","authors":"Ana Lopez, Farah H. Siddiqi, Julien Villeneuve, Rodrigo Portes Ureshino, Hee-Yeon Jeon, Philippos Koulousakis, Sophie Keeling, William A. McEwan, Angeleen Fleming, David C. Rubinsztein","doi":"10.1038/s41589-024-01762-7","DOIUrl":"https://doi.org/10.1038/s41589-024-01762-7","url":null,"abstract":"Tauopathies are neurodegenerative diseases that manifest with intracellular accumulation and aggregation of tau protein. These include Pick’s disease, progressive supranuclear palsy, corticobasal degeneration and argyrophilic grain disease, where tau is believed to be the primary disease driver, as well as secondary tauopathies, such as Alzheimer’s disease. There is a need to develop effective pharmacological therapies. Here we tested >1,400 clinically approved compounds using transgenic zebrafish tauopathy models. This revealed that carbonic anhydrase (CA) inhibitors protected against tau toxicity. CRISPR experiments confirmed that CA depletion mimicked the effects of these drugs. CA inhibition promoted faster clearance of human tau by promoting lysosomal exocytosis. Importantly, methazolamide, a CA inhibitor used in the clinic, also reduced total and phosphorylated tau levels, increased neuronal survival and ameliorated neurodegeneration in mouse tauopathy models at concentrations similar to those seen in people. These data underscore the feasibility of in vivo drug screens using zebrafish models and suggest serious consideration of CA inhibitors for treating tauopathies.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"6 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555822","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}

引用次数: 0