Cell Chemical Biology最新文献_第2页

Ligand-induced assembly of antibody variable fragments for the chemical regulation of biological processes

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.01.007

Erik Rihtar , Tina Fink , Tina Lebar , Duško Lainšček , Živa Kolenc , Lucija Kadunc Polajnar , Roman Jerala

{"title":"Ligand-induced assembly of antibody variable fragments for the chemical regulation of biological processes","authors":"Erik Rihtar , Tina Fink , Tina Lebar , Duško Lainšček , Živa Kolenc , Lucija Kadunc Polajnar , Roman Jerala","doi":"10.1016/j.chembiol.2025.01.007","DOIUrl":"10.1016/j.chembiol.2025.01.007","url":null,"abstract":"<div><div>Precise control of biological processes by the application of small molecules can increase the safety and efficiency of therapies. Adverse side effects of small molecule signals and/or immunogenicity of regulatory domains hinder their biomedical utility. Here, we designed small molecule-responsive switches, based on the conditional reassembly of human antibody variable fragments, called Fv-CID switches. The principle was validated using high-affinity antibodies against nicotine and β-estradiol to construct chemically responsive transcription factors. Further, we developed an Fv-CID switch responsive to bio-inert, clinically approved compound fluorescein, which was used to control the activity of chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs) <em>in vivo</em>. This study provides a framework to regulate the expression of endogenous genes, combine multiple chemical signals, and regulate T cell-based immunotherapy in an animal cancer model using a clinically approved small molecule regulator that could be customized for regulating therapeutic proteins or cells.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 474-485.e5"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401350","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}

引用次数: 0

Disrupting neuron-tumor networking connections

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.006

Cheng-En Shen , Alesandra S. Echeandía Marrero , Yuan Pan

引用次数: 0

VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.002

Kyle Mangano , Robert G. Guenette , Spencer Hill , Shiqian Li , Jeffrey J. Liu , Cory M. Nadel , Suresh Archunan , Arghya Sadhukhan , Rajiv Kapoor , Seung Wook Yang , Kate S. Ashton , Patrick Ryan Potts

{"title":"VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation","authors":"Kyle Mangano , Robert G. Guenette , Spencer Hill , Shiqian Li , Jeffrey J. Liu , Cory M. Nadel , Suresh Archunan , Arghya Sadhukhan , Rajiv Kapoor , Seung Wook Yang , Kate S. Ashton , Patrick Ryan Potts","doi":"10.1016/j.chembiol.2025.02.002","DOIUrl":"10.1016/j.chembiol.2025.02.002","url":null,"abstract":"<div><div>In targeted protein degradation (TPD) a protein of interest is degraded by chemically induced proximity to an E3 ubiquitin ligase. One limitation of using TPD therapeutically is that most E3 ligases have broad tissue expression, which can contribute to toxicity via target degradation in healthy cells. Many pathogenic and oncogenic viruses encode E3 ligases (vE3s), which <em>de facto</em> have strictly limited expression to diseased cells. Here, we provide proof-of-concept for viral E3 pan-essential removing targeting chimeras (VIPER-TACs) that are bi-functional molecules that utilize viral E3 ubiquitin ligases to selectively degrade pan-essential proteins and eliminate diseased cells. We find that the human papillomavirus (HPV) ligase E6 can degrade the SARS1 pan-essential target protein in a model of HPV-positive cervical cancer to selectively kill E6 expressing cancer cells. Thus, VIPER-TACs have the capacity to dramatically increase the therapeutic window, alleviate toxicity concerns, and ultimately expand the potential target space for TPD.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 423-433.e9"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143547031","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

Dynamic PRDX S-acylation modulates ROS stress and signaling

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.01.009

Tian Qiu , Saara-Anne Azizi , Shubhashree Pani , Bryan C. Dickinson

{"title":"Dynamic PRDX S-acylation modulates ROS stress and signaling","authors":"Tian Qiu , Saara-Anne Azizi , Shubhashree Pani , Bryan C. Dickinson","doi":"10.1016/j.chembiol.2025.01.009","DOIUrl":"10.1016/j.chembiol.2025.01.009","url":null,"abstract":"<div><div>Peroxiredoxins (PRDXs) are a highly conserved family of peroxidases that serve as the primary scavengers of peroxides. Post-translational modifications play crucial roles modulating PRDX activities, tuning the balance between reactive oxygen species (ROS) signaling and stress. We previously reported that <em>S</em>-acylation occurs at the “peroxidatic” cysteine (Cp) site of PRDX5 and that it inhibits PRDX5 activity. Here, we show that the PRDX family more broadly is subject to <em>S</em>-acylation at the Cp site of all PRDXs and that PRDX <em>S</em>-acylation dynamically responds to cellular ROS levels. Using activity-based fluorescent imaging with DPP-Red, a red-shifted fluorescent indicator for acyl-protein thioesterase (APT) activity, we also discover that the instigation of ROS-stress via exogenous H<sub>2</sub>O<sub>2</sub> activates both the cytosolic and mitochondrial APTs, whereas epidermal growth factor (EGF)-stimulated endogenous H<sub>2</sub>O<sub>2</sub> deactivates the cytosolic APTs. These results indicate that APTs help tune H<sub>2</sub>O<sub>2</sub> signal transduction and ROS protection through PRDX <em>S</em>-deacylation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 511-519.e5"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486527","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

Mechanisms and functions of lysosomal lipid homeostasis

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.003

Michael Ebner , Florian Fröhlich , Volker Haucke

{"title":"Mechanisms and functions of lysosomal lipid homeostasis","authors":"Michael Ebner , Florian Fröhlich , Volker Haucke","doi":"10.1016/j.chembiol.2025.02.003","DOIUrl":"10.1016/j.chembiol.2025.02.003","url":null,"abstract":"<div><div>Lysosomes are the central degradative organelle of mammalian cells and have emerged as major intersections of cellular metabolite flux. Macromolecules derived from dietary and intracellular sources are delivered to the acidic lysosomal lumen where they are subjected to degradation by acid hydrolases. Lipids derived from lipoproteins, autophagy cargo, or autophagosomal membranes themselves constitute major lysosomal substrates. Dysregulation of lysosomal lipid processing, defective export of lipid catabolites, and lysosomal membrane permeabilization underly diseases ranging from neurodegeneration to metabolic syndromes and lysosomal storage disorders. Mammalian cells are equipped with sophisticated homeostatic control mechanisms that protect the lysosomal limiting membrane from excessive damage, prevent the spillage of luminal hydrolases into the cytoplasm, and preserve the lysosomal membrane composition in the face of constant fusion with heterotypic organelles such as endosomes and autophagosomes. In this review we discuss the molecular mechanisms that govern lysosomal lipid homeostasis and, thereby, lysosome function in health and disease.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 392-407"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560763","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}

引用次数: 0

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking 脂质供应通过调节多不饱和脂肪酸的运输影响癌细胞对铁蛋白沉积的敏感性

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2024.09.008

Kelly H. Sokol , Cameron J. Lee , Thomas J. Rogers , Althea Waldhart , Abigail E. Ellis , Sahithi Madireddy , Samuel R. Daniels , Rachel (Rae) J. House , Xinyu Ye , Mary Olesnavich , Amy Johnson , Benjamin R. Furness , Ryan D. Sheldon , Evan C. Lien

{"title":"Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking","authors":"Kelly H. Sokol , Cameron J. Lee , Thomas J. Rogers , Althea Waldhart , Abigail E. Ellis , Sahithi Madireddy , Samuel R. Daniels , Rachel (Rae) J. House , Xinyu Ye , Mary Olesnavich , Amy Johnson , Benjamin R. Furness , Ryan D. Sheldon , Evan C. Lien","doi":"10.1016/j.chembiol.2024.09.008","DOIUrl":"10.1016/j.chembiol.2024.09.008","url":null,"abstract":"<div><div>Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 408-422.e6"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487024","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}

引用次数: 0

Targeting biomolecular condensates: The rise of engineered chaperones

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.005

Yevheniia Bushman , Duhita A. Mirikar , Andrew.W. Truman

引用次数: 0

Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders 选择性极光激酶A降解物靶向神经母细胞瘤N-Myc

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.12.006

Jian Tang , Ramkumar Moorthy , Laura E. Hirsch , Özlem Demir , Zachary D. Baker , Jordan A. Naumann , Katherine F.M. Jones , Michael J. Grillo , Ella S. Haefner , Ke Shi , Michaella J. Levy , Harshita B. Gupta , Hideki Aihara , Reuben S. Harris , Rommie E. Amaro , Nicholas M. Levinson , Daniel A. Harki

{"title":"Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders","authors":"Jian Tang , Ramkumar Moorthy , Laura E. Hirsch , Özlem Demir , Zachary D. Baker , Jordan A. Naumann , Katherine F.M. Jones , Michael J. Grillo , Ella S. Haefner , Ke Shi , Michaella J. Levy , Harshita B. Gupta , Hideki Aihara , Reuben S. Harris , Rommie E. Amaro , Nicholas M. Levinson , Daniel A. Harki","doi":"10.1016/j.chembiol.2024.12.006","DOIUrl":"10.1016/j.chembiol.2024.12.006","url":null,"abstract":"<div><div>The N-Myc transcription factor, encoded by <em>MYCN</em>, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in <em>MYCN</em>-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels. A potent Aurora-A degrader, HLB-0532259 (compound <strong>4</strong>), was developed from an Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of Aurora-A, which elicits concomitant N-Myc degradation, with nanomolar potency and excellent selectivity. HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 352-362.e10"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935250","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

Dynamic sampling of a surveillance state enables DNA proofreading by Cas9 监控状态的动态取样使 Cas9 能够进行 DNA 校对

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.10.001

Viviane S. De Paula , Abhinav Dubey , Haribabu Arthanari , Nikolaos G. Sgourakis

{"title":"Dynamic sampling of a surveillance state enables DNA proofreading by Cas9","authors":"Viviane S. De Paula , Abhinav Dubey , Haribabu Arthanari , Nikolaos G. Sgourakis","doi":"10.1016/j.chembiol.2024.10.001","DOIUrl":"10.1016/j.chembiol.2024.10.001","url":null,"abstract":"<div><div>CRISPR-Cas9 has revolutionized genome engineering applications by programming its single-guide RNA, where high specificity is required. However, the precise molecular mechanism underscoring discrimination between on/off-target DNA sequences, relative to the guide RNA template, remains elusive. Here, using methyl-based NMR to study multiple holoenzymes assembled <em>in vitro</em>, we elucidate a discrete protein conformational state which enables recognition of DNA mismatches at the protospacer adjacent motif (PAM)-distal end. Our results delineate an allosteric pathway connecting a dynamic conformational switch at the REC3 domain, with the sampling of a catalytically competent state by the HNH domain. Our NMR data show that HiFi Cas9 (R691A) increases the fidelity of DNA recognition by stabilizing this \"surveillance state\" for mismatched substrates, shifting the Cas9 conformational equilibrium away from the active state. These results establish a paradigm of substrate recognition through an allosteric protein-based switch, providing unique insights into the molecular mechanism which governs Cas9 selectivity.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 267-279.e5"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519849","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

Anti-tumor immunotherapy using engineered bacterial outer membrane vesicles fused to lysosome-targeting chimeras mediated by transferrin receptor 利用工程细菌外膜囊泡与转铁蛋白受体介导的溶酶体靶向嵌合体融合抗肿瘤免疫治疗

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.12.008

Ling-Yan Su, Yang Tian, Qiang Zheng, Yu Cao, Mengyu Yao, Shuangping Wang, Wen Xu, Chuyu Xi, Andrea Clocchiatti, Guangjun Nie, Hejiang Zhou

引用次数: 0