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SynPull: An advanced method for studying neurodegeneration-related aggregates in synaptosomes using super-resolution microscopy
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2025.01.001
Shekhar Kedia , Emre Fertan , Yunzhao Wu , Yu P. Zhang , Georg Meisl , Jeff Y.L. Lam , Frances K. Wiseman , William A. McEwan , Annelies Quaegebeur , Maria Grazia Spillantini , John S.H. Danial , David Klenerman
{"title":"SynPull: An advanced method for studying neurodegeneration-related aggregates in synaptosomes using super-resolution microscopy","authors":"Shekhar Kedia ,&nbsp;Emre Fertan ,&nbsp;Yunzhao Wu ,&nbsp;Yu P. Zhang ,&nbsp;Georg Meisl ,&nbsp;Jeff Y.L. Lam ,&nbsp;Frances K. Wiseman ,&nbsp;William A. McEwan ,&nbsp;Annelies Quaegebeur ,&nbsp;Maria Grazia Spillantini ,&nbsp;John S.H. Danial ,&nbsp;David Klenerman","doi":"10.1016/j.chembiol.2025.01.001","DOIUrl":"10.1016/j.chembiol.2025.01.001","url":null,"abstract":"<div><div>Synaptic dysfunction is a primary hallmark of both Alzheimer’s and Parkinson’s disease, leading to cognitive and behavioral decline. While alpha-synuclein, beta-amyloid, and tau are involved in the physiological functioning of synapses, their pathological aggregation has been linked to synaptopathology. The methodology for studying the small-soluble protein aggregates formed by these proteins is limited. Here we describe SynPull, a method combining single-molecule pull-down, super-resolution microscopy, and advanced computational analyses to characterize the protein aggregates in human and mouse synaptosomes. We show that AT8-positive tau aggregates are the predominant aggregate type in synaptosomes from postmortem Alzheimer’s disease brain, although the aggregate size does not change in disease. Meanwhile, the relatively smaller amount of alpha-synuclein and beta-amyloid aggregates found in the synapses are larger than the extra-synaptic ones. Collectively, these results show the utility of SynPull to study pathological aggregates in neurodegeneration, elucidating the disease mechanisms causing synaptic dysfunction.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 338-351.e4"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027103","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
An engineered cereblon optimized for high-throughput screening and molecular glue discovery 为高通量筛选和分子胶发现而优化的工程脑龙
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.11.002
Henry J. Bailey , Jonathan Eisert , Rubina Kazi , Jan Gerhartz , Dominika Ewa Pieńkowska , Ina Dressel , Joshua Vollrath , Ivan Kondratov , Tetiana Matviyuk , Nataliya Tolmachova , Varun Jayeshkumar Shah , Giulio Giuliani , Thorsten Mosler , Thomas M. Geiger , Ana M. Esteves , Sandra P. Santos , Raquel L. Sousa , Tiago M. Bandeiras , Eva-Maria Leibrock , Ulrike Bauer , Ivan Dikic
{"title":"An engineered cereblon optimized for high-throughput screening and molecular glue discovery","authors":"Henry J. Bailey ,&nbsp;Jonathan Eisert ,&nbsp;Rubina Kazi ,&nbsp;Jan Gerhartz ,&nbsp;Dominika Ewa Pieńkowska ,&nbsp;Ina Dressel ,&nbsp;Joshua Vollrath ,&nbsp;Ivan Kondratov ,&nbsp;Tetiana Matviyuk ,&nbsp;Nataliya Tolmachova ,&nbsp;Varun Jayeshkumar Shah ,&nbsp;Giulio Giuliani ,&nbsp;Thorsten Mosler ,&nbsp;Thomas M. Geiger ,&nbsp;Ana M. Esteves ,&nbsp;Sandra P. Santos ,&nbsp;Raquel L. Sousa ,&nbsp;Tiago M. Bandeiras ,&nbsp;Eva-Maria Leibrock ,&nbsp;Ulrike Bauer ,&nbsp;Ivan Dikic","doi":"10.1016/j.chembiol.2024.11.002","DOIUrl":"10.1016/j.chembiol.2024.11.002","url":null,"abstract":"<div><div>The majority of clinical degraders utilize an immunomodulatory imide drug (IMiD)-based derivative that directs their target to the E3 ligase receptor cereblon (CRBN); however, identification of IMiD molecular glue substrates has remained underexplored. To tackle this, we design human CRBN constructs, which retain all features for ternary complex formation, while allowing generation of homogenous and cost-efficient expression in <em>E. coli</em>. Extensive profiling of the construct shows it to be the “best of both worlds” in terms of binding activity and ease of production. We next designed the “Enamine focused IMiD library” and demonstrated applicability of the construct to high-throughput screening, identifying binders with high potency, ligand efficiency, and specificity. Finally, we adapt our construct for proof of principle glue screening approaches enabling IMiD cellular interactome determination. Coupled with our IMiD binding landscape the methods described here should serve as valuable tools to assist discovery of next generation CRBN glues.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 363-376.e10"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718728","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
Biogenesis and roles of tRNA queuosine modification and its glycosylated derivatives in human health and diseases tRNA队列苷修饰及其糖基化衍生物在人类健康和疾病中的生物发生和作用
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.11.004
Tsutomu Suzuki , Atsuya Ogizawa , Kensuke Ishiguro , Asuteka Nagao
{"title":"Biogenesis and roles of tRNA queuosine modification and its glycosylated derivatives in human health and diseases","authors":"Tsutomu Suzuki ,&nbsp;Atsuya Ogizawa ,&nbsp;Kensuke Ishiguro ,&nbsp;Asuteka Nagao","doi":"10.1016/j.chembiol.2024.11.004","DOIUrl":"10.1016/j.chembiol.2024.11.004","url":null,"abstract":"<div><div>Various types of post-transcriptional modifications contribute to physiological functions by regulating the abundance and function of RNAs. In particular, tRNAs have the widest variety and largest number of modifications, with crucial roles in protein synthesis. Queuosine (Q) is a characteristic tRNA modification with a 7-deazaguanosine core structure bearing a bulky side chain with a cyclopentene group. Q and its derivatives are found in the anticodon of specific tRNAs in both bacteria and eukaryotes. In metazoan tRNAs, Q is further glycosylated with galactose or mannose. The functions of these glycosylated Qs remained unknown for nearly half a century since their discovery. Recently, our group identified the glycosyltransferases responsible for these tRNA modifications and elucidated their biological roles. We, here, review the biochemical and physiological functions of Q and its glycosylated derivatives as well as their associations with human diseases, including cancer and inflammatory and neurological diseases.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 227-238"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793567","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
Next steps for targeted protein degradation 定向降解蛋白质的下一步行动
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.10.004
Mackenzie W. Krone , Craig M. Crews
{"title":"Next steps for targeted protein degradation","authors":"Mackenzie W. Krone ,&nbsp;Craig M. Crews","doi":"10.1016/j.chembiol.2024.10.004","DOIUrl":"10.1016/j.chembiol.2024.10.004","url":null,"abstract":"<div><div>Targeted protein degradation (TPD) has greatly advanced as a therapeutic strategy in the past two decades, and we are on the cusp of rationally designed protein degraders reaching clinical approval. Offering pharmacological advantages relative to occupancy-driven protein inhibition, chemical methods for regulating biomolecular proximity have provided opportunities to tackle disease-related targets that were undruggable. Despite the pre-clinical success of designed degraders and existence of clinical therapies that serendipitously utilize TPD, expansion of the TPD toolbox is necessary to identify and characterize the next generation of molecular degraders. Here we highlight three areas for continued growth in the field that should be prioritized: expansion of TPD platform with greater spatiotemporal precision, increased throughput of degrader synthesis, and optimization of cooperativity in chemically induced protein complexes. The future is bright for TPD in medicine, and we expect that innovative approaches will increase therapeutic applications of proximity-induced pharmacology.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 219-226"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574666","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
Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation 靶向选择性PCK1和PGC-1α赖氨酸乙酰化的小分子通过增加乳酸氧化引起抗糖尿病作用
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2025.01.005
Beste Mutlu, Kfir Sharabi, Jee Hyung Sohn, Bo Yuan, Pedro Latorre-Muro, Xin Qin, Jin-Seon Yook, Hua Lin, Deyang Yu, João Paulo G. Camporez, Shingo Kajimura, Gerald I. Shulman, Sheng Hui, Theodore M. Kamenecka, Patrick R. Griffin, Pere Puigserver
{"title":"Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation","authors":"Beste Mutlu,&nbsp;Kfir Sharabi,&nbsp;Jee Hyung Sohn,&nbsp;Bo Yuan,&nbsp;Pedro Latorre-Muro,&nbsp;Xin Qin,&nbsp;Jin-Seon Yook,&nbsp;Hua Lin,&nbsp;Deyang Yu,&nbsp;João Paulo G. Camporez,&nbsp;Shingo Kajimura,&nbsp;Gerald I. Shulman,&nbsp;Sheng Hui,&nbsp;Theodore M. Kamenecka,&nbsp;Patrick R. Griffin,&nbsp;Pere Puigserver","doi":"10.1016/j.chembiol.2025.01.005","DOIUrl":"10.1016/j.chembiol.2025.01.005","url":null,"abstract":"","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Page 379"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981367","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
The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells 外排泵ABCC1/MRP1组成性地限制癌细胞中PROTAC的敏感性
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.11.009
Gernot Wolf , Conner Craigon , Shao Thing Teoh , Patrick Essletzbichler , Svenja Onstein , Diane Cassidy , Esther C.H. Uijttewaal , Vojtech Dvorak , Yuting Cao , Ariel Bensimon , Ulrich Elling , Alessio Ciulli , Giulio Superti-Furga
{"title":"The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells","authors":"Gernot Wolf ,&nbsp;Conner Craigon ,&nbsp;Shao Thing Teoh ,&nbsp;Patrick Essletzbichler ,&nbsp;Svenja Onstein ,&nbsp;Diane Cassidy ,&nbsp;Esther C.H. Uijttewaal ,&nbsp;Vojtech Dvorak ,&nbsp;Yuting Cao ,&nbsp;Ariel Bensimon ,&nbsp;Ulrich Elling ,&nbsp;Alessio Ciulli ,&nbsp;Giulio Superti-Furga","doi":"10.1016/j.chembiol.2024.11.009","DOIUrl":"10.1016/j.chembiol.2024.11.009","url":null,"abstract":"<div><div>Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for targeting “undruggable” proteins, and several PROTACs have reached the stage of clinical candidates. However, the roles of cellular transmembrane transporters in PROTAC uptake and efflux remain underexplored. Here, we utilized transporter-focused genetic screens to identify the ATP-binding cassette transporter ABCC1/MRP1 as a key PROTAC resistance factor. Unlike the previously identified inducible PROTAC exporter ABCB1/MDR1, ABCC1 is highly expressed among cancers of various origins and constitutively restricts PROTAC bioavailability. Moreover, in a genome-wide PROTAC resistance screen, we identified candidates involved in processes such as ubiquitination, mTOR signaling, and apoptosis as genetic factors involved in PROTAC resistance. In summary, our findings reveal ABCC1 as a crucial constitutively active efflux pump limiting PROTAC efficacy in various cancer cells, offering insights for overcoming drug resistance.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 291-306.e6"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917462","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
Ligand-induced assembly of antibody variable fragments for the chemical regulation of biological processes
IF 8.6 1区 生物学
Cell Chemical Biology Pub Date : 2025-02-13 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":"https://doi.org/10.1016/j.chembiol.2025.01.007","url":null,"abstract":"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.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"44 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-02-13","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
De novo designed Hsp70 activator dissolves intracellular condensates
IF 8.6 1区 生物学
Cell Chemical Biology Pub Date : 2025-02-07 DOI: 10.1016/j.chembiol.2025.01.006
Jason Z. Zhang, Nathan Greenwood, Jason Hernandez, Josh T. Cuperus, Buwei Huang, Bryan D. Ryder, Christine Queitsch, Jason E. Gestwicki, David Baker
{"title":"De novo designed Hsp70 activator dissolves intracellular condensates","authors":"Jason Z. Zhang, Nathan Greenwood, Jason Hernandez, Josh T. Cuperus, Buwei Huang, Bryan D. Ryder, Christine Queitsch, Jason E. Gestwicki, David Baker","doi":"10.1016/j.chembiol.2025.01.006","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.01.006","url":null,"abstract":"Protein quality control (PQC) is carried out in part by the chaperone Hsp70 in concert with adapters of the J-domain protein (JDP) family. The JDPs, also called Hsp40s, are thought to recruit Hsp70 into complexes with specific client proteins. However, the molecular principles regulating this process are not well understood. We describe the <em>de novo</em> design of Hsp70 binding proteins that either inhibit or stimulate Hsp70 ATPase activity. An ATPase stimulating design promoted the refolding of denatured luciferase <em>in vitro</em>, similar to native JDPs. Targeting of this design to intracellular condensates resulted in their nearly complete dissolution and revealed roles as cell growth promoting signaling hubs. The designs inform our understanding of chaperone structure-function relationships and provide a general and modular way to target PQC systems to regulate condensates and other cellular targets.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"141 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258446","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
Engineering electrogenetic interfaces for mammalian cell control 哺乳动物细胞控制的电基因界面工程学
IF 8.6 1区 生物学
Cell Chemical Biology Pub Date : 2025-01-28 DOI: 10.1016/j.chembiol.2025.01.003
Maysam Mansouri, Martin Fussenegger
{"title":"Engineering electrogenetic interfaces for mammalian cell control","authors":"Maysam Mansouri, Martin Fussenegger","doi":"10.1016/j.chembiol.2025.01.003","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.01.003","url":null,"abstract":"Human body cells and our daily electronic devices both communicate information within their distinct worlds by regulating the flow of electrons across specified membranes. While electronic devices depend on the flow of electrons generated by conductive materials to communicate within a digital network, biological systems use ion gradients, created in analog biochemical reactions, to trigger biological data transmission throughout multicellular systems. Electrogenetics is an emerging concept in synthetic biology in which electrons generated by digital electronic devices program customized electron-responsive biological units within living cells. In this paper, we outline endeavors to design direct electrogenetic interfaces to control cell behaviors in therapeutically engineered mammalian cells. We also discuss prospects for the world of electrogenetics, focusing on how to engineer the next generation of therapeutic cells controlled by electronic devices and the internet of the body.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"19 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050284","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
Covalent targeting of splicing in T cells T 细胞剪接的共价靶向作用
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2025-01-16 DOI: 10.1016/j.chembiol.2024.10.010
Kevin A. Scott , Hiroyuki Kojima , Nathalie Ropek , Charles D. Warren , Tiffany L. Zhang , Simon J. Hogg , Henry Sanford , Caroline Webster , Xiaoyu Zhang , Jahan Rahman , Bruno Melillo , Benjamin F. Cravatt , Jiankun Lyu , Omar Abdel-Wahab , Ekaterina V. Vinogradova
{"title":"Covalent targeting of splicing in T cells","authors":"Kevin A. Scott ,&nbsp;Hiroyuki Kojima ,&nbsp;Nathalie Ropek ,&nbsp;Charles D. Warren ,&nbsp;Tiffany L. Zhang ,&nbsp;Simon J. Hogg ,&nbsp;Henry Sanford ,&nbsp;Caroline Webster ,&nbsp;Xiaoyu Zhang ,&nbsp;Jahan Rahman ,&nbsp;Bruno Melillo ,&nbsp;Benjamin F. Cravatt ,&nbsp;Jiankun Lyu ,&nbsp;Omar Abdel-Wahab ,&nbsp;Ekaterina V. Vinogradova","doi":"10.1016/j.chembiol.2024.10.010","DOIUrl":"10.1016/j.chembiol.2024.10.010","url":null,"abstract":"<div><div>Despite significant interest in therapeutic targeting of splicing, few chemical probes are available for the proteins involved in splicing. Here, we show that elaborated stereoisomeric acrylamide EV96 and its analogues lead to a selective T cell state-dependent loss of interleukin 2-inducible T cell kinase (ITK) by targeting one of the core splicing factors SF3B1. Mechanistic investigations suggest that the state-dependency stems from a combination of differential protein turnover rates and extensive ITK mRNA alternative splicing. We further introduce the most comprehensive list to date of proteins involved in splicing and leverage cysteine- and protein-directed activity-based protein profiling with electrophilic scout fragments to demonstrate covalent ligandability for many classes of splicing factors and splicing regulators in T cells. Taken together, our findings show how chemical perturbation of splicing can lead to immune state-dependent changes in protein expression and provide evidence for the broad potential to target splicing factors with covalent chemistry.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 201-218.e17"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696958","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
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