Cell Chemical Biology最新文献_第4页

RNA infrastructure profiling illuminates transcriptome structure in crowded spaces RNA 基础结构剖析揭示拥挤空间中的转录组结构

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2024-10-23 DOI: 10.1016/j.chembiol.2024.09.009

Lu Xiao, Linglan Fang, Wenrui Zhong, Eric T. Kool

{"title":"RNA infrastructure profiling illuminates transcriptome structure in crowded spaces","authors":"Lu Xiao, Linglan Fang, Wenrui Zhong, Eric T. Kool","doi":"10.1016/j.chembiol.2024.09.009","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.09.009","url":null,"abstract":"RNAs fold into compact structures and undergo protein interactions in cells. These occluded environments can block reagents that probe the underlying RNAs. Probes that can analyze structure in crowded settings can shed light on RNA biology. Here, we employ 2′-OH-reactive probes that are small enough to access folded RNA structure underlying close molecular contacts within cells, providing considerably broader coverage for intracellular RNA structural analysis. The data are analyzed first with well-characterized human ribosomal RNAs and then applied transcriptome-wide to polyadenylated transcripts. The smallest probe acetylimidazole (AcIm) yields 80% greater structural coverage than larger conventional reagent NAIN3, providing enhanced structural information in hundreds of transcripts. The acetyl probe also provides superior signals for identifying m<sup>6</sup>A modification sites in transcripts, particularly in sites that are inaccessible to a standard probe. Our strategy enables profiling RNA infrastructure, enhancing analysis of transcriptome structure, modification, and intracellular interactions, especially in spatially crowded settings.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"21 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487423","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

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 8.6 1区生物学

Cell Chemical Biology Pub Date : 2024-10-22 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":"https://doi.org/10.1016/j.chembiol.2024.09.008","url":null,"abstract":"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.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"2 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-10-22","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quinoline-based compounds can inhibit diverse enzymes that act on DNA 喹啉类化合物可抑制作用于 DNA 的各种酶

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2024-10-21 DOI: 10.1016/j.chembiol.2024.09.007

Jujun Zhou, Qin Chen, Ren Ren, Jie Yang, Bigang Liu, John R. Horton, Caleb Chang, Chuxuan Li, Leora Maksoud, Yifei Yang, Dante Rotili, Abhinav K. Jain, Xing Zhang, Robert M. Blumenthal, Taiping Chen, Yang Gao, Sergio Valente, Antonello Mai, Xiaodong Cheng

{"title":"Quinoline-based compounds can inhibit diverse enzymes that act on DNA","authors":"Jujun Zhou, Qin Chen, Ren Ren, Jie Yang, Bigang Liu, John R. Horton, Caleb Chang, Chuxuan Li, Leora Maksoud, Yifei Yang, Dante Rotili, Abhinav K. Jain, Xing Zhang, Robert M. Blumenthal, Taiping Chen, Yang Gao, Sergio Valente, Antonello Mai, Xiaodong Cheng","doi":"10.1016/j.chembiol.2024.09.007","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.09.007","url":null,"abstract":"DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a key epigenetic process. Developing non-nucleoside inhibitors to cause DNA hypomethylation is crucial for treating various conditions without the toxicities associated with existing cytidine-based hypomethylating agents. This study characterized fifteen quinoline-based analogs, particularly compounds with additions like a methylamine (<strong>9</strong>) or methylpiperazine (<strong>11</strong>), which demonstrate similar low micromolar inhibitory potency against human DNMT1 and <em>Clostridioides difficile</em> CamA. These compounds (<strong>9</strong> and <strong>11</strong>) intercalate into CamA-bound DNA via the minor groove, causing a conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation. Additionally, some quinoline-based analogs inhibit other DNA-interacting enzymes, such as polymerases and base excision repair glycosylases. Finally, compound <strong>11</strong> elicits DNA damage response via p53 activation in cancer cells.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"75 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452302","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 tau dephosphorylation-targeting chimeraselectively recruits protein phosphatase-1 to ameliorate Alzheimer’s disease and tauopathies 牛头去磷酸化靶向嵌合酶选择性招募蛋白磷酸酶-1，改善阿尔茨海默病和牛头病的病情

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.09.003

Yue Xiao , Linyu Wei , Jingfen Su , Huiyang Lei , Fei Sun , Mengzhu Li , Shihong Li , Xiaochuan Wang , Jie Zheng , Jian-Zhi Wang

{"title":"A tau dephosphorylation-targeting chimeraselectively recruits protein phosphatase-1 to ameliorate Alzheimer’s disease and tauopathies","authors":"Yue Xiao , Linyu Wei , Jingfen Su , Huiyang Lei , Fei Sun , Mengzhu Li , Shihong Li , Xiaochuan Wang , Jie Zheng , Jian-Zhi Wang","doi":"10.1016/j.chembiol.2024.09.003","DOIUrl":"10.1016/j.chembiol.2024.09.003","url":null,"abstract":"<div><div>Abnormal accumulation of hyperphosphorylated tau (pTau) is a major cause of neurodegeneration in Alzheimer’s disease (AD) and related tauopathies. Therefore, reducing pTau holds therapeutic promise for these diseases. Here, we developed a chimeric peptide, named D20, for selective facilitation of tau dephosphorylation by recruiting protein phosphatase 1 (PP1) to tau. PP1 is one of the active phosphatases that dephosphorylates tau. In both cultured primary hippocampal neurons and mouse models for AD or related tauopathies, we demonstrated that single-dose D20 treatment significantly reduced pTau by dephosphorylation at multiple AD-related sites and total tau (tTau) levels were also decreased. Multiple-dose administration of D20 through tail vein injection in 3xTg AD mice effectively ameliorated tau-associated pathologies with improved cognitive functions. Importantly, at therapeutic doses, D20 did not cause detectable toxicity in cultured neurons, neural cells, or peripheral organs in mice. These results suggest that D20 is a promising drug candidate for AD and related tauopathies.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1787-1799.e6"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330242","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 acyclovir-induced RNA nanodevices for reversible and tunable control of aptamer function 设计阿昔洛韦诱导的 RNA 纳米器件，实现对适配体功能的可逆和可调控制。

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.07.017

Timo Hagen , Jacob L. Litke , Nahian Nasir , Qian Hou , Samie R. Jaffrey

{"title":"Engineering acyclovir-induced RNA nanodevices for reversible and tunable control of aptamer function","authors":"Timo Hagen , Jacob L. Litke , Nahian Nasir , Qian Hou , Samie R. Jaffrey","doi":"10.1016/j.chembiol.2024.07.017","DOIUrl":"10.1016/j.chembiol.2024.07.017","url":null,"abstract":"<div><div>Small molecule-regulated RNA devices have the potential to modulate diverse aspects of cellular function, but the small molecules used to date have potential toxicities limiting their use in cells. Here we describe a method for creating drug-regulated RNA nanodevices (RNs) using acyclovir, a biologically compatible small molecule with minimal toxicity. Our modular approach involves a scaffold comprising a central F30 three-way junction, an integrated acyclovir aptamer on the input arm, and a variable effector-binding aptamer on the output arm. This design allows for the rapid engineering of acyclovir-regulated RNs, facilitating temporal, tunable, and reversible control of intracellular aptamers. We demonstrate the control of the Broccoli aptamer and the iron-responsive element (IRE) by acyclovir. Regulating the IRE with acyclovir enables precise control over iron-regulatory protein (IRP) sequestration, consequently promoting the inhibition of ferroptosis. Overall, the method described here provides a platform for transforming aptamers into acyclovir-controllable antagonists against physiologic target proteins.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1827-1838.e7"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078687","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

Mitochondrial RelA empowers mtDNA G-quadruplex formation for hypoxia adaptation in cancer cells 线粒体 RelA 促进了 mtDNA G-四联体的形成，使癌细胞适应缺氧环境

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.05.003

引用次数: 0

Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation 以选择性 PCK1 和 PGC-1α 赖氨酸乙酰化为靶点的小分子通过增加乳酸氧化作用发挥抗糖尿病作用

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.09.001

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 , 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","doi":"10.1016/j.chembiol.2024.09.001","DOIUrl":"10.1016/j.chembiol.2024.09.001","url":null,"abstract":"<div><div>Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1772-1786.e5"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325634","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 anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113 以结核分枝杆菌特异性非必需膜蛋白 Rv2113 为靶标的抗结核药草素

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.06.002

{"title":"The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113","authors":"","doi":"10.1016/j.chembiol.2024.06.002","DOIUrl":"10.1016/j.chembiol.2024.06.002","url":null,"abstract":"<div><div>Spread of antimicrobial resistances urges a need for new drugs against <em>Mycobacterium tuberculosis</em> (Mtb) with mechanisms differing from current antibiotics. Previously, callyaerins were identified as promising anti-tubercular agents, representing a class of hydrophobic cyclopeptides with an unusual (<em>Z</em>)-2,3-di-aminoacrylamide unit. Here, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of structural determinants relevant for antibacterial activity. Callyaerins are bacteriostatics selectively active against Mtb, including extensively drug-resistant strains, with minimal cytotoxicity against human cells and promising intracellular activity. By combining mutant screens and various chemical proteomics approaches, we showed that callyaerins target the non-essential, Mtb-specific membrane protein Rv2113, triggering a complex dysregulation of the proteome, characterized by global downregulation of lipid biosynthesis, cell division, DNA repair, and replication. Our study thus identifies Rv2113 as a previously undescribed Mtb-specific drug target and demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1755-1771.e73"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561721","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

Dissecting the neuroprotective interaction between the BH4 domain of BCL-w and the IP3 receptor 剖析 BCL-w 的 BH4 结构域与 IP3 受体之间的神经保护相互作用

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.06.016

Sophia X. Tang , Christina M. Camara , Joy A. Franco , Maria F. Pazyra-Murphy , Yihang Li , Marina Godes , Benjamin M. Moyer , Gregory H. Bird , Rosalind A. Segal , Loren D. Walensky

{"title":"Dissecting the neuroprotective interaction between the BH4 domain of BCL-w and the IP3 receptor","authors":"Sophia X. Tang , Christina M. Camara , Joy A. Franco , Maria F. Pazyra-Murphy , Yihang Li , Marina Godes , Benjamin M. Moyer , Gregory H. Bird , Rosalind A. Segal , Loren D. Walensky","doi":"10.1016/j.chembiol.2024.06.016","DOIUrl":"10.1016/j.chembiol.2024.06.016","url":null,"abstract":"<div><div>BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining “staple” and alanine scanning approaches with molecular dynamics simulations. We generated and identified stapled BCL-w BH4 peptides with optimized IP3 receptor binding and neuroprotective activities. Point mutagenesis further revealed the sequence determinants for BCL-w BH4 specificity, providing a blueprint for therapeutic targeting of IP3 receptors to achieve neuroprotection.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 10","pages":"Pages 1815-1826.e5"},"PeriodicalIF":6.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141769251","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

Plant synthetic genomics: Big lessons from the little yeast 植物合成基因组学：从小酵母中汲取大教训

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.08.001

Hao Ye , Guangyu Luo , Zhenwu Zheng , Xiaofang Li , Jie Cao , Jia Liu , Junbiao Dai

引用次数: 0