Nature chemical biology最新文献

Intracrine FFA4 signaling controls lipolysis at lipid droplets 卵巢内FFA4信号控制脂滴的脂解

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-08-05 DOI: 10.1038/s41589-025-01982-5

Shannon L. O’Brien, Emma Tripp, Natasja Barki, Elodie Blondel-Tepaz, Gabrielle Smith, Adam Boufersaoui, Jennie Roberts, Jeremy A. Pike, Joao Correia, Tamara Miljus, Michel Bouvier, Daniel A. Tennant, Brian D. Hudson, Zachary Gerhart-Hines, Graeme Milligan, Thue W. Schwartz, Davide Calebiro

{"title":"Intracrine FFA4 signaling controls lipolysis at lipid droplets","authors":"Shannon L. O’Brien, Emma Tripp, Natasja Barki, Elodie Blondel-Tepaz, Gabrielle Smith, Adam Boufersaoui, Jennie Roberts, Jeremy A. Pike, Joao Correia, Tamara Miljus, Michel Bouvier, Daniel A. Tennant, Brian D. Hudson, Zachary Gerhart-Hines, Graeme Milligan, Thue W. Schwartz, Davide Calebiro","doi":"10.1038/s41589-025-01982-5","DOIUrl":"https://doi.org/10.1038/s41589-025-01982-5","url":null,"abstract":"G-protein-coupled receptors (GPCRs) can signal from intracellular compartments but the occurrence and relevance of this phenomenon for metabolite-sensing GPCRs is largely unknown. Here, we investigate free fatty acid receptor 4 (FFA4), a metabolite-sensing GPCR activated by medium-chain and long-chain fatty acids. Using live-cell imaging, bioluminescence resonance energy transfer, super-resolution microscopy and cell fractionation, we show that FFA4 localizes to intracellular membranes, particularly endoplasmic reticulum subdomains surrounding lipid droplets, in both immortalized adipocytes and mouse adipose tissue. Upon lipolysis, locally released fatty acids appear to rapidly activate this intracellular FFA4 pool, leading to Gi/o protein signaling and preferential reduction of cyclic adenosine monophosphate levels near lipid droplets. These mechanisms are required for efficient FFA4-mediated lipolysis regulation, as shown using tethered mini-Gαi/o proteins to locally inhibit Gi/o signaling. These findings reveal an unexpected ‘intracrine’ GPCR signaling modality involved in the local regulation of cell metabolism, with biological and pharmacological implications.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"78 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778518","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

Directed evolution of LaccID for cell surface proximity labeling and electron microscopy 用于细胞表面接近标记和电子显微镜的LaccID定向进化

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-08-01 DOI: 10.1038/s41589-025-01973-6

Song-Yi Lee, Heegwang Roh, David Gonzalez-Perez, Mason R. Mackey, Daniel Hoces, Colleen N. McLaughlin, Chang Lin, Stephen R. Adams, Khanh Nguyen, Keun-Young Kim, David J. Luginbuhl, Liqun Luo, Namrata D. Udeshi, Steven A. Carr, Rogelio A. Hernández-López, Mark H. Ellisman, Miguel Alcalde, Alice Y. Ting

{"title":"Directed evolution of LaccID for cell surface proximity labeling and electron microscopy","authors":"Song-Yi Lee, Heegwang Roh, David Gonzalez-Perez, Mason R. Mackey, Daniel Hoces, Colleen N. McLaughlin, Chang Lin, Stephen R. Adams, Khanh Nguyen, Keun-Young Kim, David J. Luginbuhl, Liqun Luo, Namrata D. Udeshi, Steven A. Carr, Rogelio A. Hernández-López, Mark H. Ellisman, Miguel Alcalde, Alice Y. Ting","doi":"10.1038/s41589-025-01973-6","DOIUrl":"https://doi.org/10.1038/s41589-025-01973-6","url":null,"abstract":"Enzymes that oxidize aromatic substrates have been harnessed for cell-based technologies including proximity labeling and electron microscopy; however, they are associated with drawbacks such as the need for toxic H2O2. Here, we explore multicopper oxidases (laccases) as a new enzyme class for proximity labeling and electron microscopy in mammalian cells. LaccID was generated through 11 rounds of directed evolution from an ancestral fungal laccase and catalyzes one-electron oxidation of diverse aromatic substrates using O2 instead of toxic H2O2. Surprisingly, we found that LaccID is selectively active at the surface plasma membrane of both living and fixed cells. We use LaccID proximity labeling and mass spectrometry to map the changing surface proteome of T cells that engage with tumor cells through antigen-specific T cell receptors. In addition, we use LaccID as a genetically encodable tag for EM visualization of cell surface features in mammalian cell culture and in the fly brain. Our study paves the way for future cell-based applications of LaccID.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"150 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756344","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

Nde1 promotes Lis1 binding to full-length autoinhibited human dynein 1 Nde1促进Lis1与全长自抑制人动力蛋白1结合

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-08-01 DOI: 10.1038/s41589-025-01981-6

Jun Yang, Yuanchang Zhao, Pengxin Chai, Ahmet Yildiz, Kai Zhang

{"title":"Nde1 promotes Lis1 binding to full-length autoinhibited human dynein 1","authors":"Jun Yang, Yuanchang Zhao, Pengxin Chai, Ahmet Yildiz, Kai Zhang","doi":"10.1038/s41589-025-01981-6","DOIUrl":"https://doi.org/10.1038/s41589-025-01981-6","url":null,"abstract":"Cytoplasmic dynein 1 (dynein) is the primary motor responsible for the retrograde transport of intracellular cargoes along microtubules. Activation of dynein requires the opening its autoinhibited Phi conformation, a process driven by Lis1 and Nde1/Ndel1. Using biochemical reconstitution and cryo-electron microscopy, we demonstrate that Nde1 enhances Lis1 binding to autoinhibited dynein and facilitates Phi opening. We identify a key intermediate in this activation pathway where a single Lis1 dimer binds between Phi-like (PhiL) motor rings. In this ‘PhiL–Lis1’ complex, Lis1 interacts with one motor domain through canonical sites at the AAA+ (adenosine triphosphatases associated with diverse cellular activities) ring and stalk, and with AAA5, AAA6 and linker regions of the other motor domain. Mutagenesis and motility assays confirm the critical role of the PhiL–Lis1 interface in dynein activation. This intermediate forms rapidly in the presence of Nde1, although Nde1 is not part of PhiL–Lis1. These findings provide key insights into how Nde1 promotes Lis1-mediated Phi opening.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"33 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756342","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

Structure-guided phage display discovery of antibodies for (S)Tn-glycans in protein context 结构引导的噬菌体展示发现蛋白质环境中(S) n-聚糖的抗体

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-07-31 DOI: 10.1038/s41589-025-01971-8

Ramon Hurtado-Guerrero, Spyridon Gatos, Irene Ginés-Alcober, Javier Macías-León, Andrés Manuel González-Ramírez, Ilknur Kasapoglu, Billy Veloz, Ismael Compañón, Mattia Ghirardello, Pedro Merino, Francisco Corzana, Ola Blixt

{"title":"Structure-guided phage display discovery of antibodies for (S)Tn-glycans in protein context","authors":"Ramon Hurtado-Guerrero, Spyridon Gatos, Irene Ginés-Alcober, Javier Macías-León, Andrés Manuel González-Ramírez, Ilknur Kasapoglu, Billy Veloz, Ismael Compañón, Mattia Ghirardello, Pedro Merino, Francisco Corzana, Ola Blixt","doi":"10.1038/s41589-025-01971-8","DOIUrl":"https://doi.org/10.1038/s41589-025-01971-8","url":null,"abstract":"Developing high-affinity monoclonal antibodies (mAbs) against tumor-associated carbohydrate antigens such as Tn and STn on carrier proteins remains a major challenge in cancer therapy. These antigens, expressed as glycan–peptide epitopes (combotopes), require precise recognition for high specificity. Through structural studies, we found that VH domains of certain antibodies primarily recognize glycans, whereas VL domains bind peptide sequences. Using these insights, we developed a VH-focused and VL-diverse phage display library to discover mAbs with combotope-binding characteristics. Notably, structural analysis enabled us to convert Tn-specific mAbs into STn-specific mAbs through modification of VH complementarity-determining region 3, demonstrating the versatility of this approach. Our hypothesis was validated with glycoprotein targets MUC1 and CD43, yielding antibodies with high specificity and affinity. Furthermore, internalization studies using the parental antibody scaffold show efficient uptake by tumor cells, supporting its use in antibody–drug conjugates. This platform addresses the challenge of generating glycoform-specific antibodies for cancer therapy.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"13 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747442","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

GA-independent DELLA regulation by inositol pyrophosphate in a nonvascular land plant 非维管陆生植物中焦磷酸肌醇对ga不依赖的DELLA调控

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-07-31 DOI: 10.1038/s41589-025-01961-w

Priyanshi Rana, Anjana Edathil Kadangodan, Paulami Koley, Riya Ghosh, Naga Jyothi Pullagurla, Hemant Chandru Naik, Padmabati Mondal, Srimonta Gayen, Debabrata Laha

{"title":"GA-independent DELLA regulation by inositol pyrophosphate in a nonvascular land plant","authors":"Priyanshi Rana, Anjana Edathil Kadangodan, Paulami Koley, Riya Ghosh, Naga Jyothi Pullagurla, Hemant Chandru Naik, Padmabati Mondal, Srimonta Gayen, Debabrata Laha","doi":"10.1038/s41589-025-01961-w","DOIUrl":"https://doi.org/10.1038/s41589-025-01961-w","url":null,"abstract":"DELLA proteins integrate external and internal cues into a signaling network critical for land plant survival. In flowering plants, gibberellins (GAs) induce DELLA recognition to its receptor GID1, resulting in the polyubiquitylation and degradation of DELLA repressors. Notably, bryophytes lack the canonical GA receptor, despite the presence of genes encoding DELLA in these nonvascular land plants. Consequently, the underlying molecular mechanisms of DELLA regulation in bryophytes have remained largely elusive. Here, we report that MpVIH, responsible for the synthesis of inositol pyrophosphate messenger InsP8, negatively regulates DELLA in the liverwort Marchantia polymorpha to promote cell division and thallus development. Mechanistically, we elucidate that MpVIH-derived InsP8 binds to MpDELLA, promoting polyubiquitination and proteasomal degradation of the repressor. Lastly, our study provides evidence for the conservation of inositol pyrophosphate-controlled DELLA degradation in angiosperms. We, thus, identify a ‘noncanonical’ type of DELLA regulation by the inositol pyrophosphate messengers in land plants.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"716 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747448","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

Dissolving stress granules 溶解应力颗粒

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-07-25 DOI: 10.1038/s41589-025-01979-0

Alicia Dubinski, Christine Vande Velde

引用次数: 0

Mechanism of capsaicin entry into buried vanilloid sites in TRPV1 辣椒素进入TRPV1埋藏的香草蛋白位点的机制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-07-23 DOI: 10.1038/s41589-025-01966-5

Meng-Yang Sun, Yu-Jing Bian, Xiao-Ying Chen, Xue Zhang, Ming Li, Bo-Ying Zhou, Yang Yang, Yi-Zhe Huang, Rui Yang, Yu-Hao Gao, Wen-Wen Cui, Ya-Qi Wang, Si-Jia Zhu, Peng Cao, Chang-Zhu Li, Michael X. Zhu, Yun-Tao Lei, Fan Yang, Ye Yu

{"title":"Mechanism of capsaicin entry into buried vanilloid sites in TRPV1","authors":"Meng-Yang Sun, Yu-Jing Bian, Xiao-Ying Chen, Xue Zhang, Ming Li, Bo-Ying Zhou, Yang Yang, Yi-Zhe Huang, Rui Yang, Yu-Hao Gao, Wen-Wen Cui, Ya-Qi Wang, Si-Jia Zhu, Peng Cao, Chang-Zhu Li, Michael X. Zhu, Yun-Tao Lei, Fan Yang, Ye Yu","doi":"10.1038/s41589-025-01966-5","DOIUrl":"https://doi.org/10.1038/s41589-025-01966-5","url":null,"abstract":"The transient receptor potential vanilloid 1 (TRPV1) receptor is a promising target for nonopioid analgesics, yet hyperthermic side effects have hindered drug development. The prevailing perspective maintains that extracellular hydrophobic vanilloid ligands, such as capsaicin, traverse the cell membrane to reach the buried vanilloid site during TRPV1 activation. Here, we present an alternative mechanism based on computational and experimental approaches, which suggests a distinct hydrophobic pathway at the TRPV1–cell membrane interface as the principal route for ligand entry to the vanilloid site, rather than direct membrane penetration. Modifications to residues within this pathway greatly delayed capsaicin entry without directly modulating TRPV1 channel gating. A compound designed to occupy this pathway’s entrance exhibited analgesic effects without inducing hyperthermia. Cryo-electron microscopy confirmed binding to TRPV1 and its role in perturbing capsaicin entry. Thus, our findings unveil a unique and targetable route for capsaicin access to the TRPV1 vanilloid site.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"98 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684461","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

Publisher Correction: Nonheme Fe 1,3-nitrogen migratases for asymmetric noncanonical amino acid synthesis 出版者更正：非对称非规范氨基酸合成的非血红素Fe 1,3-氮迁移酶

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-07-21 DOI: 10.1038/s41589-025-02001-3

Liu-Peng Zhao, Huichong Liu, Binh Khanh Mai, Yu Zhang, Lida Cheng, Peng Liu, Yang Yang

引用次数: 0

Auxin branches out 生长素分支出来

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-07-17 DOI: 10.1038/s41589-025-01988-z

Grant Miura

{"title":"Auxin branches out","authors":"Grant Miura","doi":"10.1038/s41589-025-01988-z","DOIUrl":"https://doi.org/10.1038/s41589-025-01988-z","url":null,"abstract":"Plant roots require extensive branching to gather nutrients or water from the environment. When roots lose contact with soil and hit an air gap, an adaptive response called xerobranching suppresses lateral root branching until contact with water is re-established. Abscisic acid is a key hormone that mediates xerobranching by decreasing auxin levels and is produced under drought conditions. However, abscisic acid production occurs at a later stage of the xerobranching response, suggesting the requirement of an earlier signal. Given that reactive oxygen species (ROS) are involved in various plant stresses, Roy, Mehra et al. tested whether ROS signaling was involved in mediating the initial response of xerobranching. The expression of the ROS-producing enzymes respiratory burst oxidase homologs (RBOHs) was increased in the roots at the induction of xerobranching. In addition, the use of nuclear-localized H2O2 sensors showed rapid oxidation with xerobranching, indicative of a ROS burst in the nucleus that declined after root contact with water. rboh combinatorial homolog mutants exhibited continued lateral root growth in an air gap. The group also connected ROS signaling to auxin regulation, with the auxin transcriptional repressor IAA3 being a key intermediary. IAA3 contains a large number of modifiable cysteine residues, which mediate formation of multimers under non-reducing conditions. Mutation of four critical cysteine residues in IAA3, which were predicted to form disulfide bridges, blocked H2O2-mediated formation of multimers and resembled iaa3 mutants with extensive branching into air gaps. Loss of IAA3 multimer formation prevented interaction with the co-repressor TOPLESS, which prevented auxin target gene repression. Overall, the findings from Roy et al. have now identified a ROS–IAA3-mediated pathway that enables the early step of xerobranching.Original reference: Science https://doi.org/10.1126/science.adu1470 (2025)","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"71 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645385","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

Genes for Taxol 紫杉醇基因

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-07-17 DOI: 10.1038/s41589-025-01990-5

Francesco Zamberlan

{"title":"Genes for Taxol","authors":"Francesco Zamberlan","doi":"10.1038/s41589-025-01990-5","DOIUrl":"https://doi.org/10.1038/s41589-025-01990-5","url":null,"abstract":"Paclitaxel, known commercially as Taxol, is a chemotherapeutic diterpenoid compound widely used in anti-cancer therapy. Despite its low natural abundance, production of paclitaxel involves extraction of baccatin III, a precursor, from yew trees followed by chemical synthesis, as a complete chemical synthesis is not commercially viable and biomanufacturing routes are limited by the lack of knowledge of the complete paclitaxel biosynthetic pathway. Now, McClune, Liu et al. have reported a method to transcriptionally profile specific plant cell states to identify candidate genes involved in the paclitaxel biosynthetic pathway, enabling the de novo biosynthesis of baccatin III in the plant species Nicotiana benthamiana.The researchers first developed a multiplexed perturbation × single nuclei (mpXsn) transcriptomics method to simultaneously screen biosynthetic genes activated in yew plant tissues in response to factors such as hormones and microorganisms. This showed that Taxol genes co-expressed in separated sub-clusters or gene modules. Particularly, in the first module, the team found that an NTF2-like protein — now termed facilitator of taxane oxidation (FoTO1) — interacts with taxadiene 5α-hydroxylase (T5αH), responsible for the first oxidation step in the pathway, and enables yield increase in the crucial first step. Following the same approach, the team identified 7 further genes with related pathway functions, and then reconstituted the 17-gene biosynthesis of baccatin III and 3′-N-debenzoyl-2′-deoxypaclitaxel in N. benthamiana, obtaining yields comparable to those through extraction methods from yew tissues.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"5 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645250","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