Cell Chemical Biology最新文献_第2页

Redundancy of the OST catalytic subunit facilitates therapeutic targeting of N-glycosylation OST催化亚基的冗余有助于n -糖基化的治疗靶向

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.005

Marta Baro , Hojin Lee , Vanessa Kelley , Rongliang Lou , Chatchai Phoomak , Katerina Politi , Caroline J. Zeiss , Michael Van Zandt , Joseph N. Contessa

{"title":"Redundancy of the OST catalytic subunit facilitates therapeutic targeting of N-glycosylation","authors":"Marta Baro , Hojin Lee , Vanessa Kelley , Rongliang Lou , Chatchai Phoomak , Katerina Politi , Caroline J. Zeiss , Michael Van Zandt , Joseph N. Contessa","doi":"10.1016/j.chembiol.2025.05.005","DOIUrl":"10.1016/j.chembiol.2025.05.005","url":null,"abstract":"<div><div>Protein asparagine (N)-glycosylation, which promotes the folding and trafficking of cell surface receptors, has not traditionally been viewed as a viable target in oncology due to the essential and non-redundant enzymatic activities required for glycan synthesis and transfer. However, in mammals, an exception is the presence of the oligosaccharyltransferase (OST) catalytic subunit paralogs, STT3A and STT3B. In this study, we investigate the biological activity of OST inhibitors and develop a strategy for selectively inhibiting N-glycosylation that is optimized for its downstream effects on the EGFR glycoprotein. Small molecules with improved pharmacokinetic properties and selective preferences for STT3A or STT3B were synthesized, characterized <em>in vitro</em>, and advanced to <em>in vivo</em> testing. The lead compound from this series, NGI-189, induces tumor regression or growth delay in patient-derived and TKI-resistant EGFR-mutant lung cancer xenografts without causing toxicity. Collectively, these findings suggest that bioavailable OST inhibitors can be developed as therapeutic agents for oncology.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 6","pages":"Pages 839-853.e6"},"PeriodicalIF":6.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237922","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

EGR2 O-GlcNAcylation orchestrates the development of protumoral macrophages to limit CD8+ T cell antitumor responses EGR2 o - glcn酰化调节原肿瘤巨噬细胞的发育，以限制CD8+ T细胞的抗肿瘤反应

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.007

Yuchen Zhang (章雨辰) , Hongpeng Li (李鸿鹏) , Yi Hao (郝熠) , Jiaqi Chen (陈家祺) , Xing Chen (陈兴) , Hang Yin (尹航)

{"title":"EGR2 O-GlcNAcylation orchestrates the development of protumoral macrophages to limit CD8+ T cell antitumor responses","authors":"Yuchen Zhang (章雨辰) , Hongpeng Li (李鸿鹏) , Yi Hao (郝熠) , Jiaqi Chen (陈家祺) , Xing Chen (陈兴) , Hang Yin (尹航)","doi":"10.1016/j.chembiol.2025.05.007","DOIUrl":"10.1016/j.chembiol.2025.05.007","url":null,"abstract":"<div><div>Tumor associated macrophages (TAMs) exhibit a high capacity to take up glucose. However, how metabolic cues derived from glucose rewire TAMs remains unclear. Here, we report that glucose metabolism-driven protein O-GlcNAcylation increases in TAMs and shapes the differentiation and protumoral function of TAMs. Deficiency of O-GlcNAc transferase (OGT) in TAMs restricted tumor growth by reducing the proportion of C1QC<sup>+</sup> F4/80<sup>+</sup> TREM2<sup>+</sup> MerTK<sup>+</sup> TAMs as well as <em>Trem2 e</em>xpression, which in turn preserved the cytotoxic function of effector CD8<sup>+</sup> T cells while exhibiting reduced features of exhaustion. Mechanistically, O-GlcNAc targeted the macrophage-specific transcription factor EGR2 to promote its transcriptional activity. Transcriptional profiling revealed that OGT increased EGR2-related motifs accessibility in TAMs. O-GlcNAcylation of EGR2 at serine 299 enhanced its binding to myeloid cell differentiation-associated genes, including <em>Trem2</em>, thus facilitating the protumoral function of TAMs in GM-CSF-sufficient tumor. Overall, our work defines a tumor-specific reprogramming of protumoral TAMs via O-GlcNAc-modified EGR2 transcriptional regulation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 6","pages":"Pages 809-825.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252587","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

Mechanism by which the molecular glue-like verteporfin induces IRE1α dimerization and activation to synergize with AKT inhibition in breast cancer 分子胶样维替波芬诱导乳腺癌中IRE1α二聚化和活化协同抑制AKT的机制

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.004

Yongliang Liu , Hui Hua , Yalan Cao , Minjing Li , Hongying Zhang , Shan Du , Jieya Liu , Ting Luo , Yangfu Jiang

{"title":"Mechanism by which the molecular glue-like verteporfin induces IRE1α dimerization and activation to synergize with AKT inhibition in breast cancer","authors":"Yongliang Liu , Hui Hua , Yalan Cao , Minjing Li , Hongying Zhang , Shan Du , Jieya Liu , Ting Luo , Yangfu Jiang","doi":"10.1016/j.chembiol.2025.05.004","DOIUrl":"10.1016/j.chembiol.2025.05.004","url":null,"abstract":"<div><div>Inositol-requiring enzyme 1α (IRE1α) signaling is one of three arms of the unfolded protein response, playing a vital role in maintaining endoplasmic reticulum homeostasis. Pharmacological modulation of this pathway offers potential therapeutic strategies for various diseases. Molecular glues may regulate protein stability and activity by inducing protein-protein interaction. Here, we find that verteporfin functions as a molecular glue, promoting IRE1α dimerization and activation. Specifically, verteporfin binds to IRE1α, facilitating its dimerization, which relies on the His692 residue. This activation of IRE1α triggers XBP1 splicing and miR-153-mediated downregulation of PTEN, along with AKT phosphorylation. Additionally, we identify the pro-metastasis gene <em>BACH1</em> as a novel target of miR-153, which is downregulated by IRE1α and verteporfin. While verteporfin inhibits breast cancer cell viability and invasion, its combination with an AKT inhibitor synergistically suppresses breast cancer progression. Our findings establish a mechanistic link between IRE1α and PI3K/AKT signaling, highlighting a possibility for therapeutic intervention.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 6","pages":"Pages 854-871.e6"},"PeriodicalIF":6.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144211168","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

Two sides of a co(i)ndensate co(i)的两边紧密相连

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.010

Emre Pekbilir , Dorothee Dormann

引用次数: 0

Host-like conditions validate nutrient transport as an antimalarial drug target 类宿主条件验证了营养转运作为抗疟疾药物靶点的有效性

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.006

Rodion Gordzevich , Eric D. Brown

引用次数: 0

The critical role of PSAC channel in malaria parasite survival is driven home by phenotypic screening under relevant nutrient levels PSAC通道在疟疾寄生虫存活中的关键作用是通过相关营养水平下的表型筛选来实现的

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.001

Irene Molina , Ryan Mansell , Rui Liang , Benigno Crespo , Margarita Puente , Virginia Franco , Sara Viera , Isabel Camino , Anas Saadeddin , Peter Bellotti , Annie Leung , Sam Henning , Shan Sun , Mikayla Herring , Celia Lopez , Carmen Cuevas , Peter Pogány , Beatriz Urones , Leigh Baxt , Esther Fernández , Lydia Mata-Cantero

{"title":"The critical role of PSAC channel in malaria parasite survival is driven home by phenotypic screening under relevant nutrient levels","authors":"Irene Molina , Ryan Mansell , Rui Liang , Benigno Crespo , Margarita Puente , Virginia Franco , Sara Viera , Isabel Camino , Anas Saadeddin , Peter Bellotti , Annie Leung , Sam Henning , Shan Sun , Mikayla Herring , Celia Lopez , Carmen Cuevas , Peter Pogány , Beatriz Urones , Leigh Baxt , Esther Fernández , Lydia Mata-Cantero","doi":"10.1016/j.chembiol.2025.05.001","DOIUrl":"10.1016/j.chembiol.2025.05.001","url":null,"abstract":"<div><div>Spreading resistance to front-line treatments necessitate the search for new classes of antimalarials. Limitations of standard screening conditions lead us to develop an assay using culture media that more closely reflects nutrient levels in human serum to reveal new therapeutically relevant parasite pathways. Our approach was validated by testing 22k compounds followed by a full 750k compound screen and identified 29 chemotypes with higher activity in nutrient restricted media that were further characterized. Through a combination of chemo-genomics and innovative photocatalytic proximity labeling proteomics, we identified the target of two compounds as the CLAG3 component of the plasmodial surface anion channel (PSAC). Strikingly, every one of the other 29 chemotypes selected was also found to block PSAC activity, highlighting the importance of this nutrient channel for parasite survival under physiological conditions. The effect of PSAC inhibitors in the <em>in vivo</em> humanized mouse model was confirmed.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 6","pages":"Pages 826-838.e13"},"PeriodicalIF":6.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122572","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

Charting the development and engineering of CRISPR base editors: lessons and inspirations 绘制CRISPR碱基编辑器的发展和工程：教训和启示

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.003

Siyuan Zou , Yihong Sun , Weixin Tang

引用次数: 0

Integrator: A guardian against RNA-induced chaos 整合者：对抗rna引起的混乱的守护者

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.009

William Garland , Torben Heick Jensen

引用次数: 0

A cationic amphiphilic drug synergizes with strobilurin fungicides to control fungal-borne plant diseases 一种阳离子两亲性药物与异比脲类杀菌剂协同作用，控制真菌传播的植物病害

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.008

Bradley Laflamme , Christopher Blackman , Mackenzie Loranger , Richard Trilles , Kalina Doytchinova-Weil , Stephen S. Scully , J. Miles Blackburn , Anastasia L.G. Kanegesuku , Jennifer L. Roizen , Stephen Bengtson , Lauren E. Brown , John A. Porco , Keiko Yoshioka , Luke Whitesell , Rajagopal Subramaniam , Nicole Robbins , Leah E. Cowen

{"title":"A cationic amphiphilic drug synergizes with strobilurin fungicides to control fungal-borne plant diseases","authors":"Bradley Laflamme , Christopher Blackman , Mackenzie Loranger , Richard Trilles , Kalina Doytchinova-Weil , Stephen S. Scully , J. Miles Blackburn , Anastasia L.G. Kanegesuku , Jennifer L. Roizen , Stephen Bengtson , Lauren E. Brown , John A. Porco , Keiko Yoshioka , Luke Whitesell , Rajagopal Subramaniam , Nicole Robbins , Leah E. Cowen","doi":"10.1016/j.chembiol.2025.05.008","DOIUrl":"10.1016/j.chembiol.2025.05.008","url":null,"abstract":"<div><div>Fungal phytopathogens are responsible for major losses in agricultural yields annually. While the use of topical fungicides remains key to managing agricultural pathogens, the emergence of drug-resistant strains necessitates identifying additional treatment options. In this study, we performed an <em>in vitro</em> small molecule screen against the devastating cereal pathogen <em>Fusarium graminearum</em>, identifying <strong>CMLD009688</strong> as a priority growth inhibitor. Chemical-genetic profiling and subsequent experiments with <strong>CMLD009688</strong> revealed that this compound functions as a cationic amphiphilic drug (CAD) and perturbs vacuolar integrity in <em>F. graminearum</em>. <strong>CMLD009688</strong> displayed synergy with strobilurin fungicides in limiting <em>F. graminearum</em> growth—likely through both compounds independently affecting vacuolar stability—and a combination treatment of <strong>CMLD009688</strong> with the strobilurin pyraclostrobin strongly limited the virulence of both <em>F. graminearum</em> and <em>Botrytis cinerea</em> in distinct models of plant infection. Thus, our findings highlight that cationic amphiphilic molecules show immense promise in helping to protect crops from fungal diseases.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 6","pages":"Pages 872-884.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260593","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

Integrative proximal-ubiquitomics profiling for deubiquitinase substrate discovery applied to USP30 应用于USP30去泛素酶底物发现的综合近端泛素组学分析

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-05-15 DOI: 10.1016/j.chembiol.2025.04.004

Andreas Damianou , Hannah B.L. Jones , Athina Grigoriou , Mohammed A. Akbor , Edward Jenkins , Philip D. Charles , Iolanda Vendrell , Simon Davis , Benedikt M. Kessler

{"title":"Integrative proximal-ubiquitomics profiling for deubiquitinase substrate discovery applied to USP30","authors":"Andreas Damianou , Hannah B.L. Jones , Athina Grigoriou , Mohammed A. Akbor , Edward Jenkins , Philip D. Charles , Iolanda Vendrell , Simon Davis , Benedikt M. Kessler","doi":"10.1016/j.chembiol.2025.04.004","DOIUrl":"10.1016/j.chembiol.2025.04.004","url":null,"abstract":"<div><div>The growing interest in deubiquitinases (DUBs) as drug targets for modulating critical molecular pathways in disease is fueled by the discovery of their specific cellular roles. A crucial aspect of this fact is the identification of DUB substrates. While mass spectrometry-based proteomic methods can be used to study global changes in cellular ubiquitination following DUB activity perturbation, these datasets often include indirect and downstream ubiquitination events. To enrich for the direct substrates of DUB enzymes, we have developed a proximal-ubiquitome workflow that combines proximity labeling methodology (ascorbate peroxidase-2 [APEX2]) with subsequent ubiquitination enrichment based on the K-ε-GG motif. We applied this technology to identify altered ubiquitination events in the vicinity of the DUB ubiquitin-specific protease 30 (USP30) upon its inhibition. Our findings reveal ubiquitination events previously associated with USP30 on TOMM20 and FKBP8, as well as the candidate substrate LETM1, which is deubiquitinated in a USP30-dependent manner.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 5","pages":"Pages 736-751.e8"},"PeriodicalIF":6.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905662","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