Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.12.007
Aayushi Uberoi , Sofía M. Murga-Garrido , Preeti Bhanap , Amy E. Campbell , Simon A.B. Knight , Monica Wei , Anya Chan , Taylor Senay , Saba Tegegne , Ellen K. White , Carrie Hayes Sutter , Clementina Mesaros , Thomas R. Sutter , Elizabeth A. Grice
The epidermal barrier defends the body against dehydration and harmful substances. The commensal microbiota is essential for proper differentiation and repair of the epidermal barrier, an effect mediated by the aryl hydrocarbon receptor (AHR). However, the microbial mechanisms of AHR activation in skin are less understood. Tryptophan metabolites are AHR ligands that can be products of microbial metabolism. To identify microbially regulated tryptophan metabolites in vivo, we established a gnotobiotic model colonized with fifty human skin commensals and performed targeted mass spectrometry on murine skin. Indole-related metabolites were enriched in colonized skin compared to germ-free skin. In reconstructed human epidermis and in murine models of atopic-like barrier damage, these metabolites improved barrier repair and function individually and as a cocktail. These results provide a framework for the identification of microbial metabolites that mediate specific host functions, which can guide the development of microbe-based therapies for skin disorders.
{"title":"Commensal-derived tryptophan metabolites fortify the skin barrier: Insights from a 50-species gnotobiotic model of human skin microbiome","authors":"Aayushi Uberoi , Sofía M. Murga-Garrido , Preeti Bhanap , Amy E. Campbell , Simon A.B. Knight , Monica Wei , Anya Chan , Taylor Senay , Saba Tegegne , Ellen K. White , Carrie Hayes Sutter , Clementina Mesaros , Thomas R. Sutter , Elizabeth A. Grice","doi":"10.1016/j.chembiol.2024.12.007","DOIUrl":"10.1016/j.chembiol.2024.12.007","url":null,"abstract":"<div><div>The epidermal barrier defends the body against dehydration and harmful substances. The commensal microbiota is essential for proper differentiation and repair of the epidermal barrier, an effect mediated by the aryl hydrocarbon receptor (AHR). However, the microbial mechanisms of AHR activation in skin are less understood. Tryptophan metabolites are AHR ligands that can be products of microbial metabolism. To identify microbially regulated tryptophan metabolites <em>in vivo</em>, we established a gnotobiotic model colonized with fifty human skin commensals and performed targeted mass spectrometry on murine skin. Indole-related metabolites were enriched in colonized skin compared to germ-free skin. In reconstructed human epidermis and in murine models of atopic-like barrier damage, these metabolites improved barrier repair and function individually and as a cocktail. These results provide a framework for the identification of microbial metabolites that mediate specific host functions, which can guide the development of microbe-based therapies for skin disorders.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 111-125.e6"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986933","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}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.12.011
Dingjiacheng Jia , Shujie Chen
In this issue of Cell Chemical Biology, Rebeck et al.1 construct a system that enables Saccharomyces cerevisiae var. boulardii (Sb) to secrete immune checkpoint inhibitors, reducing intestinal tumor load. This safe and effective delivery platform using engineered yeast demonstrates potential for enhancing the efficacy of biologics.
在这一期的Cell Chemical Biology上，Rebeck et al.1构建了一个系统，使酿酒酵母（Saccharomyces cerevisiae var. boulardii, Sb）分泌免疫检查点抑制剂，减少肠道肿瘤负荷。这种安全有效的工程酵母传递平台显示了增强生物制剂功效的潜力。
{"title":"Yeast paves the way for cancer immunotherapy","authors":"Dingjiacheng Jia , Shujie Chen","doi":"10.1016/j.chembiol.2024.12.011","DOIUrl":"10.1016/j.chembiol.2024.12.011","url":null,"abstract":"<div><div>In this issue of <em>Cell Chemical Biology</em>, Rebeck et al.<span><span><sup>1</sup></span></span> construct a system that enables <em>Saccharomyces cerevisiae</em> var. <em>boulardii</em> (<em>Sb</em>) to secrete immune checkpoint inhibitors, reducing intestinal tumor load. This safe and effective delivery platform using engineered yeast demonstrates potential for enhancing the efficacy of biologics.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 9-11"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987081","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}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.12.003
Jianjun Yu (余建军) , Huijie Liu (刘慧洁) , Rui Gao (高瑞) , Tao V. Wang (王涛) , Chenggang Li (李成钢) , Yuxiang Liu (刘玉祥) , Lu Yang (杨璐) , Ying Xu (徐颖) , Yunfeng Cui (崔云凤) , Chenxi Jia (贾辰熙) , Juan Huang (黄娟) , Peng R. Chen (陈鹏) , Yi Rao (饶毅)
Research into mechanisms underlying sleep traditionally relies on electrophysiology and genetics. Because sleep can only be measured on whole animals by behavioral observations and physical means, no sleep research was initiated by biochemical and chemical biological approaches. We used phosphorylation sites of kinases important for sleep as targets for biochemical and chemical biological approaches. Sleep was increased in mice carrying a threonine-to-alanine substitution at residue T469 of salt-inducible kinase 3 (SIK3). Our biochemical purification and photo-crosslinking revealed calcineurin (CaN) dephosphorylation, both in vitro and in vivo, of SIK3 at T469 and S551, but not T221. Knocking down CaN regulatory subunit reduced daily sleep by more than 5 h, exceeding all known mouse mutants. Our work uncovered a critical physiological role for CaN in sleep and pioneered biochemical purification and chemical biology as effective approaches to study sleep.
{"title":"Calcineurin: An essential regulator of sleep revealed by biochemical, chemical biological, and genetic approaches","authors":"Jianjun Yu (余建军) , Huijie Liu (刘慧洁) , Rui Gao (高瑞) , Tao V. Wang (王涛) , Chenggang Li (李成钢) , Yuxiang Liu (刘玉祥) , Lu Yang (杨璐) , Ying Xu (徐颖) , Yunfeng Cui (崔云凤) , Chenxi Jia (贾辰熙) , Juan Huang (黄娟) , Peng R. Chen (陈鹏) , Yi Rao (饶毅)","doi":"10.1016/j.chembiol.2024.12.003","DOIUrl":"10.1016/j.chembiol.2024.12.003","url":null,"abstract":"<div><div>Research into mechanisms underlying sleep traditionally relies on electrophysiology and genetics. Because sleep can only be measured on whole animals by behavioral observations and physical means, no sleep research was initiated by biochemical and chemical biological approaches. We used phosphorylation sites of kinases important for sleep as targets for biochemical and chemical biological approaches. Sleep was increased in mice carrying a threonine-to-alanine substitution at residue T469 of salt-inducible kinase 3 (SIK3). Our biochemical purification and photo-crosslinking revealed calcineurin (CaN) dephosphorylation, both <em>in vitro</em> and <em>in vivo</em>, of SIK3 at T469 and S551, but not T221. Knocking down CaN regulatory subunit reduced daily sleep by more than 5 h, exceeding all known mouse mutants. Our work uncovered a critical physiological role for CaN in sleep and pioneered biochemical purification and chemical biology as effective approaches to study sleep.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 157-173.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902000","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}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.04.016
Samskrathi Aravinda Sharma , Sarah Olanrewaju Oladejo , Zheng Kuang
Circadian rhythms are intrinsic molecular mechanisms that synchronize biological functions with the day/night cycle. The mammalian gut is colonized by a myriad of microbes, collectively named the gut microbiota. The microbiota impacts host physiology via metabolites and structural components. A key mechanism is the modulation of host epigenetic pathways, especially histone modifications. An increasing number of studies indicate the role of the microbiota in regulating host circadian rhythms. However, the mechanisms remain largely unknown. Here, we summarize studies on microbial regulation of host circadian rhythms and epigenetic pathways, highlight recent findings on how the microbiota employs host epigenetic machinery to regulate circadian rhythms, and discuss its impacts on host physiology, particularly immune and metabolic functions. We further describe current challenges and resources that could facilitate research on microbiota-epigenetic-circadian rhythm interactions to advance our knowledge of circadian disorders and possible therapeutic avenues.
{"title":"Chemical interplay between gut microbiota and epigenetics: Implications in circadian biology","authors":"Samskrathi Aravinda Sharma , Sarah Olanrewaju Oladejo , Zheng Kuang","doi":"10.1016/j.chembiol.2024.04.016","DOIUrl":"10.1016/j.chembiol.2024.04.016","url":null,"abstract":"<div><div>Circadian rhythms are intrinsic molecular mechanisms that synchronize biological functions with the day/night cycle. The mammalian gut is colonized by a myriad of microbes, collectively named the gut microbiota. The microbiota impacts host physiology via metabolites and structural components. A key mechanism is the modulation of host epigenetic pathways, especially histone modifications. An increasing number of studies indicate the role of the microbiota in regulating host circadian rhythms. However, the mechanisms remain largely unknown. Here, we summarize studies on microbial regulation of host circadian rhythms and epigenetic pathways, highlight recent findings on how the microbiota employs host epigenetic machinery to regulate circadian rhythms, and discuss its impacts on host physiology, particularly immune and metabolic functions. We further describe current challenges and resources that could facilitate research on microbiota-epigenetic-circadian rhythm interactions to advance our knowledge of circadian disorders and possible therapeutic avenues.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 61-82"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079922","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}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.12.010
Aayushi Uberoi, Elizabeth A. Grice
In an interview with Samantha Nelson, a scientific editor of Cell Chemical Biology, the authors of the research article entitled “Commensal-derived tryptophan metabolites fortify the skin barrier: Insights from a 50-species gnotobiotic model of human skin microbiome” share insights about their paper, field, and lives as scientists.
{"title":"Meet the authors: Aayushi Uberoi and Elizabeth A. Grice","authors":"Aayushi Uberoi, Elizabeth A. Grice","doi":"10.1016/j.chembiol.2024.12.010","DOIUrl":"10.1016/j.chembiol.2024.12.010","url":null,"abstract":"<div><div>In an interview with Samantha Nelson, a scientific editor of <em>Cell Chemical Biology</em>, the authors of the research article entitled “Commensal-derived tryptophan metabolites fortify the skin barrier: Insights from a 50-species gnotobiotic model of human skin microbiome” share insights about their paper, field, and lives as scientists.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 1-2"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986930","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}
Pub Date : 2025-01-16DOI: 10.1016/j.chembiol.2024.11.001
Sidharth S. Madhavan , Stephanie Roa Diaz , Sawyer Peralta , Mitsunori Nomura , Christina D. King , Kaya E. Ceyhan , Anwen Lin , Dipa Bhaumik , Anna C. Foulger , Samah Shah , Thanh Blade , Wyatt Gray , Manish Chamoli , Brenda Eap , Oishika Panda , Diego Diaz , Thelma Y. Garcia , Brianna J. Stubbs , Scott M. Ulrich , Gordon J. Lithgow , John C. Newman
Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD.
{"title":"β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain","authors":"Sidharth S. Madhavan , Stephanie Roa Diaz , Sawyer Peralta , Mitsunori Nomura , Christina D. King , Kaya E. Ceyhan , Anwen Lin , Dipa Bhaumik , Anna C. Foulger , Samah Shah , Thanh Blade , Wyatt Gray , Manish Chamoli , Brenda Eap , Oishika Panda , Diego Diaz , Thelma Y. Garcia , Brianna J. Stubbs , Scott M. Ulrich , Gordon J. Lithgow , John C. Newman","doi":"10.1016/j.chembiol.2024.11.001","DOIUrl":"10.1016/j.chembiol.2024.11.001","url":null,"abstract":"<div><div>Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain <em>in vivo</em> after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 174-191.e8"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758618","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}
Pub Date : 2025-01-02DOI: 10.1016/j.chembiol.2024.12.002
Zher Yin Tan, Joel K.A. Adade, Xiebin Gu, Cody J.S. Hecht, Michael Salcius, Bingqi Tong, Shuang Liu, Seungmin Hwang, Frédéric J. Zécri, Daniel B. Graham, Stuart L. Schreiber, Ramnik J. Xavier
Chemical inducers of proximity (CIPs) are molecules that recruit one protein to another and introduce new functionalities toward modulating protein states and activities. While CIP-mediated recruitment of E3 ligases is widely exploited for the development of degraders, other therapeutic modalities remain underexplored. We describe a non-degrader CIP-DNA-encoded library (CIP-DEL) that recruits FKBP12 to target proteins using non-traditional acyclic structures, with an emphasis on introducing stereochemically diverse and rigid connectors to attach the combinatorial library. We deployed this strategy to modulate ATG16L1 T300A, which confers genetic susceptibility to Crohn’s disease (CD), and identified a compound that stabilizes the variant protein against caspase-3 (Casp3) cleavage in a FKBP12-independent manner. We demonstrate in cellular models that this compound potentiates autophagy, and reverses the xenophagy defects as well as increased cytokine secretion characteristic of ATG16L1 T300A. This study provides a platform to access unexplored chemical space for CIP design to develop therapeutic modalities guided by human genetics.
化学接近诱导剂（Chemical inductors of proximity, cip）是一种将一种蛋白质招募到另一种蛋白质并引入新功能来调节蛋白质状态和活性的分子。虽然cip介导的E3连接酶募集被广泛用于降解物的开发，但其他治疗方式仍未得到充分探索。我们描述了一个非降解的cip - dna编码文库（CIP-DEL），它使用非传统的无环结构招募FKBP12来靶向蛋白质，重点是引入立体化学多样性和刚性连接器来连接组合文库。我们采用这种策略来调节ATG16L1 T300A，它赋予克罗恩病（CD）的遗传易感性，并鉴定了一种化合物，该化合物以不依赖于fkbp12的方式稳定变异蛋白，防止Casp3切割。我们在细胞模型中证明，这种化合物增强了自噬，逆转了ATG16L1 T300A的异种吞噬缺陷以及增加的细胞因子分泌特征。这项研究为CIP设计提供了一个未经探索的化学空间，以开发由人类遗传学指导的治疗方式。
{"title":"Development of an FKBP12-recruiting chemical-induced proximity DNA-encoded library and its application to discover an autophagy potentiator","authors":"Zher Yin Tan, Joel K.A. Adade, Xiebin Gu, Cody J.S. Hecht, Michael Salcius, Bingqi Tong, Shuang Liu, Seungmin Hwang, Frédéric J. Zécri, Daniel B. Graham, Stuart L. Schreiber, Ramnik J. Xavier","doi":"10.1016/j.chembiol.2024.12.002","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.12.002","url":null,"abstract":"Chemical inducers of proximity (CIPs) are molecules that recruit one protein to another and introduce new functionalities toward modulating protein states and activities. While CIP-mediated recruitment of E3 ligases is widely exploited for the development of degraders, other therapeutic modalities remain underexplored. We describe a non-degrader CIP-DNA-encoded library (CIP-DEL) that recruits FKBP12 to target proteins using non-traditional acyclic structures, with an emphasis on introducing stereochemically diverse and rigid connectors to attach the combinatorial library. We deployed this strategy to modulate <em>ATG16L1</em> T300A, which confers genetic susceptibility to Crohn’s disease (CD), and identified a compound that stabilizes the variant protein against caspase-3 (Casp3) cleavage in a FKBP12-independent manner. We demonstrate in cellular models that this compound potentiates autophagy, and reverses the xenophagy defects as well as increased cytokine secretion characteristic of <em>ATG16L1</em> T300A. This study provides a platform to access unexplored chemical space for CIP design to develop therapeutic modalities guided by human genetics.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"16 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912189","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}
Pub Date : 2024-12-19DOI: 10.1016/j.chembiol.2024.11.008
Spenser H. Stone , Jeffrey C. Rathmell , Jackie E. Bader
Obesity is a leading risk factor and a negative prognostic indicator for many cancers. In a recent issue of Science Immunology, Bagchi et al. identified that tumor-associated macrophages upregulate GPR65 in response to obesity-driven intratumor acidity resulting in reduced effector function to promote tumor growth.1
{"title":"Macrophages make “sense” of obesity-driven acidity in the TME","authors":"Spenser H. Stone , Jeffrey C. Rathmell , Jackie E. Bader","doi":"10.1016/j.chembiol.2024.11.008","DOIUrl":"10.1016/j.chembiol.2024.11.008","url":null,"abstract":"<div><div>Obesity is a leading risk factor and a negative prognostic indicator for many cancers. In a recent issue of <em>Science Immunology</em>, Bagchi et al. identified that tumor-associated macrophages upregulate GPR65 in response to obesity-driven intratumor acidity resulting in reduced effector function to promote tumor growth.<span><span><sup>1</sup></span></span></div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2021-2023"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849689","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}
Pub Date : 2024-12-19DOI: 10.1016/j.chembiol.2024.09.009
Lu Xiao , Linglan Fang , Wenrui Zhong , Eric T. Kool
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 m6A 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.
{"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":"10.1016/j.chembiol.2024.09.009","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2156-2167.e5"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","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}
Pub Date : 2024-12-19DOI: 10.1016/j.chembiol.2024.10.009
Shuo Han , Xiaolei Ye , Jintong Yang , Xuefang Peng , Xiaming Jiang , Jin Li , Xiaojie Zheng , Xinchen Zhang , Yumin Zhang , Lingyu Zhang , Wei Wang , Jiaxin Li , Wenwen Xin , Xiaoai Zhang , Gengfu Xiao , Ke Peng , Leike Zhang , Xuguang Du , Lu Zhou , Wei Liu , Hao Li
Lipids and lipid metabolism play an important role in RNA virus replication, which typically occurs on host cell endomembrane structures in the cytoplasm through mechanisms that are not yet fully identified. We conducted genome-scale CRISPR screening and identified sphingomyelin synthase 1 (SMS1; encoded by SGMS1) as a critical host factor for infection by severe fever with thrombocytopenia syndrome virus (SFTSV). SGMS1 knockout reduced sphingomyelin (SM) (d18:1/16:1) levels, inhibiting SFTSV replication. A helix-turn-helix motif in SFTSV RNA-dependent RNA polymerase (RdRp) directly binds to SM(d18:1/16:1) in Golgi apparatus, which was also observed in SARS-CoV-2 and lymphocytic choriomeningitis virus (LCMV), both showing inhibited replication in SGMS1-KO cells. SM metabolic disturbance is associated with disease severity of viral infections. We designed a novel SMS1 inhibitor that protects mice against lethal SFTSV infection and reduce SARS-CoV-2 replication and pathogenesis. These findings highlight the critical role of SMS1 and SM(d18:1/16:1) in RNA virus replication, suggesting a broad-spectrum antiviral strategy.
{"title":"Host specific sphingomyelin is critical for replication of diverse RNA viruses","authors":"Shuo Han , Xiaolei Ye , Jintong Yang , Xuefang Peng , Xiaming Jiang , Jin Li , Xiaojie Zheng , Xinchen Zhang , Yumin Zhang , Lingyu Zhang , Wei Wang , Jiaxin Li , Wenwen Xin , Xiaoai Zhang , Gengfu Xiao , Ke Peng , Leike Zhang , Xuguang Du , Lu Zhou , Wei Liu , Hao Li","doi":"10.1016/j.chembiol.2024.10.009","DOIUrl":"10.1016/j.chembiol.2024.10.009","url":null,"abstract":"<div><div>Lipids and lipid metabolism play an important role in RNA virus replication, which typically occurs on host cell endomembrane structures in the cytoplasm through mechanisms that are not yet fully identified. We conducted genome-scale CRISPR screening and identified sphingomyelin synthase 1 (SMS1; encoded by SGMS1) as a critical host factor for infection by severe fever with thrombocytopenia syndrome virus (SFTSV). <em>SGMS1</em> knockout reduced sphingomyelin (SM) (d18:1/16:1) levels, inhibiting SFTSV replication. A helix-turn-helix motif in SFTSV RNA-dependent RNA polymerase (RdRp) directly binds to SM(d18:1/16:1) in Golgi apparatus, which was also observed in SARS-CoV-2 and lymphocytic choriomeningitis virus (LCMV), both showing inhibited replication in <em>SGMS1</em>-KO cells. SM metabolic disturbance is associated with disease severity of viral infections. We designed a novel SMS1 inhibitor that protects mice against lethal SFTSV infection and reduce SARS-CoV-2 replication and pathogenesis. These findings highlight the critical role of SMS1 and SM(d18:1/16:1) in RNA virus replication, suggesting a broad-spectrum antiviral strategy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 12","pages":"Pages 2052-2068.e11"},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142670993","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}
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