Cell Chemical Biology最新文献

Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22 核糖体RNA转录通过核糖体蛋白RPL22调控剪接

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.05.012

Wenjun Fan , Hester Liu , Gregory C. Stachelek , Asma Begum , Catherine E. Davis , Tony E. Dorado , Glen Ernst , William C. Reinhold , Busra Ozbek , Qizhi Zheng , Angelo M. De Marzo , N.V. Rajeshkumar , James C. Barrow , Marikki Laiho

{"title":"Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22","authors":"Wenjun Fan , Hester Liu , Gregory C. Stachelek , Asma Begum , Catherine E. Davis , Tony E. Dorado , Glen Ernst , William C. Reinhold , Busra Ozbek , Qizhi Zheng , Angelo M. De Marzo , N.V. Rajeshkumar , James C. Barrow , Marikki Laiho","doi":"10.1016/j.chembiol.2025.05.012","DOIUrl":"10.1016/j.chembiol.2025.05.012","url":null,"abstract":"<div><div>Ribosome biosynthesis is a cancer vulnerability targeted by inhibiting RNA polymerase I (Pol I) transcription. We developed specific Pol I inhibitors that activate a ribotoxic stress pathway to uncover drivers of sensitivity. Integrating multi-omics and drug response data from a large cancer cell panel, we found that RPL22 frameshift mutations confer Pol I inhibitor sensitivity. Mechanistically, RPL22 interacts directly with 28S rRNA and mRNA splice junctions, acting as a splicing regulator. RPL22 deficiency, intensified by 28S rRNA sequestration, promotes splicing of its paralog RPL22L1 and the p53 negative regulator MDM4. Both chemical and genetic inhibition of rRNA synthesis broadly remodel mRNA splicing controlling hundreds of targets. Notably, RPL22-dependent alternative splicing is reversed by Pol I inhibition, revealing a non-canonical ribotoxic stress-initiated tumor suppressive pathway. This study uncovers a robust mechanism linking rRNA synthesis activity to splicing, coordinated by the ribosomal protein RPL22.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 908-925.e9"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311709","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

Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism 动力：线粒体NADPH促进氧化代谢

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.006

Riley J. Wedan , Sara M. Nowinski

引用次数: 0

RPL22 links ribosome biogenesis, RNA splicing, and sensitivity to RNA polymerase I inhibition RPL22连接核糖体生物发生，RNA剪接和对RNA聚合酶I抑制的敏感性

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.001

Kenyon Weis , Omar Abdel-Wahab

引用次数: 0

Site-resolved assessment of targeted protein degradation 靶向蛋白降解的位点分辨评估

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.002

Ricardo Moreno-Ballesteros , Thomas Pembridge , Gaurav Beniwal , Satpal Virdee

{"title":"Site-resolved assessment of targeted protein degradation","authors":"Ricardo Moreno-Ballesteros , Thomas Pembridge , Gaurav Beniwal , Satpal Virdee","doi":"10.1016/j.chembiol.2025.06.002","DOIUrl":"10.1016/j.chembiol.2025.06.002","url":null,"abstract":"<div><div>Induced proximity using small molecules, exemplified by targeted protein degradation (TPD), represents a highly promising therapeutic strategy with significant untapped potential. However, evaluating an induced proximity event that accurately reflects drug binding typically requires the challenging and costly development of specific ligands, which limits the advancement of medicines based on this modality. To overcome this bottleneck, we combine genetic code expansion with ultra-fast bioorthogonal chemistry to sensitize specific protein sites at single-residue resolution to a generic bioorthogonal proximity inducer (BPI) molecule. Mammalian cells expressing sensitized mutants of the ubiquitin E3 ligases VHL and CRBN exhibit neosubstrate degradation in the presence of a BPI equipped with a ligand targeting bromodomain and extraterminal (BET) proteins. Furthermore, we demonstrate E3-independent degradation through recruitment of an upstream E2 conjugating enzyme. We anticipate that this approach will have broad applicability, enabling comprehensive assessment of the scope of induced proximity.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 969-981.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547594","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 cereblon-based glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner 基于小脑的NEK7胶降解剂以上下文依赖的方式调节NLRP3炎性体

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.005

Aude Sylvain , Natacha Stoehr , Fupeng Ma , Artiom Cernijenko , Martin Schröder , Maryam Khoshouei , Melanie Vogelsanger , Michel Schoenboerner , Ashley Burke , Pasupuleti Rao , Jonathan M. Solomon , Joshiawa Paulk , Lei Xu , Janet Dawson , Damien Begue , Peggy Lefeuvre , Erik Ahrne , Andreas Hofmann , Callum J. Dickson , Philip Arabin , Zuni I. Bassi

{"title":"A cereblon-based glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner","authors":"Aude Sylvain , Natacha Stoehr , Fupeng Ma , Artiom Cernijenko , Martin Schröder , Maryam Khoshouei , Melanie Vogelsanger , Michel Schoenboerner , Ashley Burke , Pasupuleti Rao , Jonathan M. Solomon , Joshiawa Paulk , Lei Xu , Janet Dawson , Damien Begue , Peggy Lefeuvre , Erik Ahrne , Andreas Hofmann , Callum J. Dickson , Philip Arabin , Zuni I. Bassi","doi":"10.1016/j.chembiol.2025.06.005","DOIUrl":"10.1016/j.chembiol.2025.06.005","url":null,"abstract":"<div><div>Aberrant NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome activation is linked to many inflammatory diseases, driving the search for therapeutics inhibiting this pathway. NEK7 is proposed to mediate NLRP3 inflammasome assembly and activation by bridging adjacent NLRP3 subunits. Hence, reduction of NEK7 protein may block NLRP3 activation. We identified NK7-902, a potent and selective cereblon (CRBN) glue degrader of NEK7. NK7-902 degraded NEK7 in human immune cells and whole blood. However, full NEK7 degradation completely blocked NLRP3-dependent interleukin-1β (IL-1β) release <em>in vitro</em> only in certain donors and experimental conditions. Unlike most CRBN glue degraders, NK7-902 effectively degraded NEK7 in murine cells and inhibited IL-1β release in mouse <em>in vivo</em>. By contrast, oral administration of NK7-902 in cynomolgus monkey caused long-lasting NEK7 degradation but only transiently blocked IL-1β in blood. These findings suggest NEK7 contributes to but is not absolutely required for NLRP3 activation in monkeys and humans.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 955-968.e13"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586803","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

Silencing stress: Structural insights into ISR termination by the SIFI ubiquitin ligase 沉默压力：SIFI泛素连接酶对ISR终止的结构见解

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.007

Zeba Rizvi , Gabriel C. Lander

引用次数: 0

Plasmodium falciparum protein kinase 6 and hemozoin formation are inhibited by a type II human kinase inhibitor exhibiting antimalarial activity 一种具有抗疟活性的II型人激酶抑制剂可抑制恶性疟原虫蛋白激酶6和血色素的形成

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.003

Flore Nardella , Tiantian Jiang , Lushun Wang , Monica J. Bohmer , Subhoja Chakraborty , John Okombo , Jaeson Calla , Tatiane Macedo Silva , Samuel Pazicky , Jianwei Che , Jin Jeon , Evie Vincent , Nonlawat Boonyalai , Rachael Coyle , Mairi J. Buchanan , Samuel Schaefer , Daisy Chen , Amaan Khan , Emily Mayville , Mariana Laureano De Souza , Debopam Chakrabarti

{"title":"Plasmodium falciparum protein kinase 6 and hemozoin formation are inhibited by a type II human kinase inhibitor exhibiting antimalarial activity","authors":"Flore Nardella , Tiantian Jiang , Lushun Wang , Monica J. Bohmer , Subhoja Chakraborty , John Okombo , Jaeson Calla , Tatiane Macedo Silva , Samuel Pazicky , Jianwei Che , Jin Jeon , Evie Vincent , Nonlawat Boonyalai , Rachael Coyle , Mairi J. Buchanan , Samuel Schaefer , Daisy Chen , Amaan Khan , Emily Mayville , Mariana Laureano De Souza , Debopam Chakrabarti","doi":"10.1016/j.chembiol.2025.06.003","DOIUrl":"10.1016/j.chembiol.2025.06.003","url":null,"abstract":"<div><div>Kinase inhibitors are potent therapeutics, but most essential <em>Plasmodium</em> kinases remain unexploited as antimalarial targets. We identified compound <strong>12</strong>, a type II kinase inhibitor based on aminopyridine and 2,6-benzimidazole scaffolds, as a lead compound with nanomolar potency, fast action, and <em>in vivo</em> activity in the <em>Plasmodium berghei</em> rodent malaria model. Three-hybrid luciferase fragment complementation, enzymatic studies, and cellular thermal shift assays implicated <em>Plasmodium</em> protein kinase 6 (PfPK6) as the target. However, conditional knockdown of PfPK6 did not alter <strong>12</strong> potency, suggesting complex mechanisms of action. <em>In vitro</em> selection for compound <strong>12</strong> resistance revealed mutations in three transporters: multidrug-resistance protein 1, chloroquine resistance transporter and V-type ATPase, indicating a digestive vacuole site of action. Compound <strong>12</strong> inhibited β-hematin and hemozoin formation while increasing free heme levels, suggesting antimalarial activity via blockade of heme detoxification. Our studies repurpose a safe human kinase inhibitor as a potent, fast-acting antimalarial with established <em>in vivo</em> efficacy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 926-941.e23"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568957","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 inhibition of ACSL4 alleviates ferroptosis-induced acute liver injury ACSL4共价抑制可减轻铁中毒引起的急性肝损伤

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.004

Maoyuan Linghu , Xianyu Luo , Xinru Zhou , Didi Liu , Qian Huang , Yi Ru , Yingli Luo , Yinchu Ma , Yi Huang

引用次数: 0

Flush with insight: Decoding GPCR crosstalk in the spinal defecation center 顿悟：解码脊髓排便中心的GPCR串音

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.011

Nil Casajuana-Martin , Eli F. McDonald , M. Madan Babu

引用次数: 0

Electrochemical sensor toolkit for simultaneous glutamate detection at edge of cleft and peri-soma 用于裂口边缘和体周谷氨酸同时检测的电化学传感器工具箱

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.002

Jie Liu , Yuandong Liu , Dongmin Yin , Yang Tian

{"title":"Electrochemical sensor toolkit for simultaneous glutamate detection at edge of cleft and peri-soma","authors":"Jie Liu , Yuandong Liu , Dongmin Yin , Yang Tian","doi":"10.1016/j.chembiol.2025.05.002","DOIUrl":"10.1016/j.chembiol.2025.05.002","url":null,"abstract":"<div><div>Simultaneously monitoring glutamate (Glu) dynamic at edge of synaptic cleft and peri-soma is crucial for understanding Glu-related pathology. Here, we created an electrochemical Glu sensors toolkit with spatial resolution of ∼60 nm, combining biologically engineered Glu binding protein for specifically capturing Glu together with chemically designed ferrocene groups for signal labeling. Modulation conjugation approach between GluR and ferrocene significantly improved sensitivity up to 32-folds. More importantly, protein engineering of residue mutation and linker peptides flexibility expanded linear range from 10 μM to 6 mM, accelerated on/off times down to 35/40 ms. This toolkit realized real-time quantifying of Glu both at edge of cleft and peri-soma, we discovered that Glu was almost released through SLC7A11 channels in calyx of held synapse upon oxygen-glucose-deprivation, while Glu was mainly released through hemichannels upon β-amyloid<sub>42</sub> stimulation. Our work provided a methodology for investigating Glu release and reuptake and offered insights for Glu related pathology.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 6","pages":"Pages 885-898.e11"},"PeriodicalIF":6.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144202419","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