Cell Chemical Biology最新文献

Targeted O-GlcNAcylation enables functional rewiring of c-Myc 靶向o - glcn酰化使c-Myc的功能重新布线

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2026-09-02 DOI: 10.1016/j.chembiol.2026.08.008

Tongyang Xu,Zhihao Guo,Khadija S. Khan,Yunpeng Huang,Bowen Ma,Shuhui Ji,Jialin Liu,Dean W. Felsher,Billy Wai-Lung Ng

引用次数: 0

Oncogene activation mechanism determines the limits of targeted protein degradation. 癌基因的激活机制决定了靶蛋白降解的极限。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-09-01 DOI: 10.1016/j.chembiol.2026.08.006

Evelina Gudauskaitė, Brianda Hernández-Morán, Gillian C A Taylor, Andrew J Wood

{"title":"Oncogene activation mechanism determines the limits of targeted protein degradation.","authors":"Evelina Gudauskaitė, Brianda Hernández-Morán, Gillian C A Taylor, Andrew J Wood","doi":"10.1016/j.chembiol.2026.08.006","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.08.006","url":null,"abstract":"<p><p>Protein degrader drugs such as PROTACs are being advanced as therapeutics targeted against oncogenic proteins. During tumorigenesis, oncogenic proteins can become constitutively activated via mechanisms including gene amplification, which increases protein production, and point mutations, which can extend protein half-life. Few experimental studies have addressed how disease-associated changes in target protein homeostasis influence PROTAC activity. We developed orthogonal methods to increase production or enhance stability of β-catenin, an important oncoprotein and target for degrader therapeutics, and used the dTAG system to evaluate the consequences for PROTAC activity. Stabilizing oncogenic missense mutations increase protein expression up to 5-fold but do not alter the PROTAC-imposed minimal steady-state level. In contrast, transcriptional upregulation increases both pre- and post-treatment target levels, revealing a synthesis-dependent ceiling on achievable depletion. Our results highlight distinct constraints on PROTAC activity arising from different mechanisms of oncogene activation, with potential implications for preclinical modeling, drug resistance and personalized medicine.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872411","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 lysis-derived PMSF and orthovanadate oxidant defines a distinct cysteine-engagement profile 裂解衍生的PMSF和原钒酸盐氧化剂定义了独特的半胱氨酸接合剖面

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2026-08-31 DOI: 10.1016/j.chembiol.2026.08.005

Bethany E. Schaffer,Jung Seung Nam,Ceci A. Cohen,Clementina Mesaros,Robert W. Myers,Leigh Baxt,Kathryn E. Wellen,Lewis C. Cantley,Noah Dephoure,Nathaniel W. Snyder,Iok In Christine Chio,John Blenis

{"title":"A lysis-derived PMSF and orthovanadate oxidant defines a distinct cysteine-engagement profile","authors":"Bethany E. Schaffer,Jung Seung Nam,Ceci A. Cohen,Clementina Mesaros,Robert W. Myers,Leigh Baxt,Kathryn E. Wellen,Lewis C. Cantley,Noah Dephoure,Nathaniel W. Snyder,Iok In Christine Chio,John Blenis","doi":"10.1016/j.chembiol.2026.08.005","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.08.005","url":null,"abstract":"Reactive cysteines serve important functions in proteins, and characterizing their engagement by different electrophiles facilitates biological discovery and covalent drug development. Here, we show that the common lysis buffer components phenylmethylsulfonyl fluoride (PMSF) and orthovanadate generate a lysis-derived oxidant that engages cysteines during cell lysis. This oxidant sulfonylates N-acetyl-D-glucosamine kinase (NAGK) C217, producing a mobility shift on SDS-PAGE. C217 lies within the ATP-binding pocket, and a C217S mutant exhibits reduced ATP affinity and enzymatic activity. Competitive iodoacetamide-alkyne activity-based protein profiling (IAA-ABPP) chemoproteomics further showed that the PMSF/orthovanadate oxidant defines a cysteine-engagement profile that partially differs from that of pervanadate. These findings reveal an unrecognized source of chemical reactivity during protein extraction that expands the toolkit for cysteine-engagement profiling and underscores how sample preparation chemistry shapes chemoproteomic measurements.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"39 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148858169","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 STING inhibitor suppresses ferroptosis through radical-trapping antioxidant activity STING抑制剂通过自由基捕获抗氧化活性抑制铁下垂

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2026-08-27 DOI: 10.1016/j.chembiol.2026.08.004

Songlin Yin,Yan Li,Ting Mei,Jiayao Li,Xueting Wang,Xiaoxiao Li,Liguo Yang,Junhong Lin,Weijie Ye,Fujia Lu,Weimin Wang

引用次数: 0

Comparative protein engineering redirects the specificity of Clostridium botulinum proteases 比较蛋白工程重定向肉毒杆菌蛋白酶的特异性

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2026-08-26 DOI: 10.1016/j.chembiol.2026.08.003

Jason E. Garrido,Gabriela S. Salcedo,Max W. Strul,Shareen N. Ashby,Arjun S. Pamidi,Jaeho Cho,Katherine G. Waldvogel,Elizabeth L. Wiriadinata,Teodora Nedic,Natnicha Kaewtatip,Honoka Kato,Maya Chan,Rebekah P. Dyer,Gregory A. Weiss

{"title":"Comparative protein engineering redirects the specificity of Clostridium botulinum proteases","authors":"Jason E. Garrido,Gabriela S. Salcedo,Max W. Strul,Shareen N. Ashby,Arjun S. Pamidi,Jaeho Cho,Katherine G. Waldvogel,Elizabeth L. Wiriadinata,Teodora Nedic,Natnicha Kaewtatip,Honoka Kato,Maya Chan,Rebekah P. Dyer,Gregory A. Weiss","doi":"10.1016/j.chembiol.2026.08.003","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.08.003","url":null,"abstract":"Botulinum neurotoxin serotypes A and E (BoNT/A and BoNT/E) cleave SNAP25 and are widely used in therapeutic applications. Redirecting the substrate specificity of their protease domains, LC/A and LC/E, could expand their utility to new therapeutic targets. Here, we report a comparative protein engineering strategy that integrates prior mutagenesis, bioinformatics, and structural insights to reprogram LC protease specificity. Directed evolution yielded a 14-mutation LC/A variant with 273-fold greater specificity for SNAP23 than a previously reported engineered protease. Insights from LC/A engineering then guided six rounds of directed evolution to generate an 8-mutation LC/E variant with a 26,000-fold increase in SNAP29 cleavage and no detectable activity toward SNAP25. Importantly, both engineered proteases retain their altered substrate preferences under physiologically relevant substrate and salt concentrations. Together, these findings establish comparative protein engineering as an effective framework for retargeting botulinum neurotoxin proteases.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"26 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148821627","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

Localized covalent targeting of NMDA receptors reprograms behavior NMDA受体的局部共价靶向重编程行为

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2026-08-24 DOI: 10.1016/j.chembiol.2026.08.001

Daniel Bátora,Máté Varga,Sharad Kumar Suthar,András Málnási-Csizmadia

{"title":"Localized covalent targeting of NMDA receptors reprograms behavior","authors":"Daniel Bátora,Máté Varga,Sharad Kumar Suthar,András Málnási-Csizmadia","doi":"10.1016/j.chembiol.2026.08.001","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.08.001","url":null,"abstract":"Spatiotemporal control of neuronal activity has largely relied on genetically defined cell populations, limiting the ability to interrogate native biomolecules within intact circuits. Pharmacological approaches with high spatial precision are therefore needed to preserve physiological network architecture. Here, we demonstrate confined neuromodulation through two-photon molecular tattooing (sequential localized photocrosslinking). We introduce AL-701, an aryl azide derivatized photoreactive NMDA receptor antagonist that covalently binds receptors upon two-photon laser irradiation. In zebrafish larvae, molecular tattooing enabled spatially restricted inhibition of NMDA receptors in a hindbrain subregion regulating the acoustic startle reflex. This localized inhibition led to persistent suppression of NMDA receptor-dependent habituation, demonstrating that regionally restricted modulation of receptor function can alter behavior. Our results show the proof-of-concept for localized photocrosslinking within cell clusters in a vertebrate nervous system and thereby establish molecular tattooing as a robust chemical biology tool for circuit modulation and optically controlled reprogramming of behavior in vivo.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"14 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805870","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

The BAX/BAK apoptotic checkpoint polices entry to therapy-induced senescence BAX/BAK凋亡检查点调控治疗诱导的衰老

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 Epub Date: 2026-08-03 DOI: 10.1016/j.chembiol.2026.07.002

Aislinn Gallagher Aldave, Vaishnavi Venugopalan, Gokhan Gunay, Seren Hamsici, Ronaldo Rodrigues Ribeiro, Aoife Costigan, Anna Gabrielyan, Hande Efe-Cicek, Seamus J. Martin

{"title":"The BAX/BAK apoptotic checkpoint polices entry to therapy-induced senescence","authors":"Aislinn Gallagher Aldave, Vaishnavi Venugopalan, Gokhan Gunay, Seren Hamsici, Ronaldo Rodrigues Ribeiro, Aoife Costigan, Anna Gabrielyan, Hande Efe-Cicek, Seamus J. Martin","doi":"10.1016/j.chembiol.2026.07.002","DOIUrl":"10.1016/j.chembiol.2026.07.002","url":null,"abstract":"<div><div>Cytotoxic chemotherapy is intended to eliminate transformed cells but can also provoke therapy-induced senescence, a persistent and pro-inflammatory cell state that can promote tumor progression. The molecular mechanisms that govern the apoptosis-senescence fate decision remain incompletely understood. Here, we show that the mitochondrial pore-forming proteins BAX and BAK function as a critical checkpoint that restricts entry to therapy-induced senescence. Genetic ablation of BAX and BAK markedly enhanced entry to senescence in response to multiple DNA-damaging agents, whereas loss of the BAX/BAK antagonists Bcl-xL or Mcl-1 suppressed entry to senescence and promoted cell death. Mechanistically, genotoxic stress induced BH3-only proteins, including Noxa, Bid, and Puma, creating a dependence on Bcl-xL and Mcl-1 to restrain BAX/BAK activation and maintain survival. These findings identify the Bcl-2 family network as a central regulator of entry to therapy-induced senescence, a pro-inflammatory cell state that goes beyond the mere avoidance of apoptosis.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1117-1134.e6"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148666052","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 degrader gets degraded as cysteine fluctuates 随着半胱氨酸的波动，降解剂被降解

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 DOI: 10.1016/j.chembiol.2026.07.010

Junyi Chen, Haopeng Xiao

引用次数: 0

STINGing the brain: S-nitrosylation drives neuroinflammation in Alzheimer’s disease 刺痛大脑：s -亚硝基化引发阿尔茨海默病的神经炎症

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 DOI: 10.1016/j.chembiol.2026.07.003

Andrew A. Pieper, Emiko Miller, Oleh Khalimonchuk, Bindu D. Paul

引用次数: 0

Aptamer targeting HMGB1 attenuates inflammatory disease via domain-specific antagonism 靶向HMGB1的适体通过结构域特异性拮抗减轻炎性疾病。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-08-20 Epub Date: 2026-07-20 DOI: 10.1016/j.chembiol.2026.06.011

Hui Zhang, Lele Ma, Shaoju Gan, Mengyuan Jiang, Zheng Zhang, Weidi Sun, Wanlin Xie, Peiyu Xi, Fengli Qu, Weihong Tan

{"title":"Aptamer targeting HMGB1 attenuates inflammatory disease via domain-specific antagonism","authors":"Hui Zhang, Lele Ma, Shaoju Gan, Mengyuan Jiang, Zheng Zhang, Weidi Sun, Wanlin Xie, Peiyu Xi, Fengli Qu, Weihong Tan","doi":"10.1016/j.chembiol.2026.06.011","DOIUrl":"10.1016/j.chembiol.2026.06.011","url":null,"abstract":"<div><div>Damage-associated molecular patterns (DAMPs) are key mediators of inflammatory disease, among which HMGB1 is a prototypical extracellular alarmin and an attractive therapeutic target. Here, we report ZH-1a, a high-affinity DNA aptamer (Kd = 2.1 nM) identified through SELEX and sequence optimization, that preferentially recognizes the proinflammatory B-box region of HMGB1. ZH-1a functions as an extracellular HMGB1-neutralizing aptamer and suppresses HMGB1-induced inflammatory signaling, including cytokine secretion and NF-κB activation in macrophages. <em>In vivo</em>, ZH-1a reduced late-phase systemic inflammation and multiorgan injury in LPS-induced endotoxemia, improved survival in polymicrobial sepsis, and attenuated inflammatory responses and organ damage in an HMGB1-challenge model. In addition, ZH-1a alleviated joint inflammation and structural damage in collagen-induced arthritis, and further enhanced the therapeutic efficacy of methotrexate. Together, these findings establish ZH-1a as a promising anti-inflammatory aptamer targeting HMGB1 and support aptamer-based neutralization of pathogenic extracellular HMGB1 as a therapeutic strategy for inflammatory disease.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 8","pages":"Pages 1165-1178.e5"},"PeriodicalIF":9.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534781","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