Pub Date : 2025-02-20DOI: 10.1016/j.chembiol.2024.11.002
Henry J. Bailey , Jonathan Eisert , Rubina Kazi , Jan Gerhartz , Dominika Ewa Pieńkowska , Ina Dressel , Joshua Vollrath , Ivan Kondratov , Tetiana Matviyuk , Nataliya Tolmachova , Varun Jayeshkumar Shah , Giulio Giuliani , Thorsten Mosler , Thomas M. Geiger , Ana M. Esteves , Sandra P. Santos , Raquel L. Sousa , Tiago M. Bandeiras , Eva-Maria Leibrock , Ulrike Bauer , Ivan Dikic
The majority of clinical degraders utilize an immunomodulatory imide drug (IMiD)-based derivative that directs their target to the E3 ligase receptor cereblon (CRBN); however, identification of IMiD molecular glue substrates has remained underexplored. To tackle this, we design human CRBN constructs, which retain all features for ternary complex formation, while allowing generation of homogenous and cost-efficient expression in E. coli. Extensive profiling of the construct shows it to be the “best of both worlds” in terms of binding activity and ease of production. We next designed the “Enamine focused IMiD library” and demonstrated applicability of the construct to high-throughput screening, identifying binders with high potency, ligand efficiency, and specificity. Finally, we adapt our construct for proof of principle glue screening approaches enabling IMiD cellular interactome determination. Coupled with our IMiD binding landscape the methods described here should serve as valuable tools to assist discovery of next generation CRBN glues.
{"title":"An engineered cereblon optimized for high-throughput screening and molecular glue discovery","authors":"Henry J. Bailey , Jonathan Eisert , Rubina Kazi , Jan Gerhartz , Dominika Ewa Pieńkowska , Ina Dressel , Joshua Vollrath , Ivan Kondratov , Tetiana Matviyuk , Nataliya Tolmachova , Varun Jayeshkumar Shah , Giulio Giuliani , Thorsten Mosler , Thomas M. Geiger , Ana M. Esteves , Sandra P. Santos , Raquel L. Sousa , Tiago M. Bandeiras , Eva-Maria Leibrock , Ulrike Bauer , Ivan Dikic","doi":"10.1016/j.chembiol.2024.11.002","DOIUrl":"10.1016/j.chembiol.2024.11.002","url":null,"abstract":"<div><div>The majority of clinical degraders utilize an immunomodulatory imide drug (IMiD)-based derivative that directs their target to the E3 ligase receptor cereblon (CRBN); however, identification of IMiD molecular glue substrates has remained underexplored. To tackle this, we design human CRBN constructs, which retain all features for ternary complex formation, while allowing generation of homogenous and cost-efficient expression in <em>E. coli</em>. Extensive profiling of the construct shows it to be the “best of both worlds” in terms of binding activity and ease of production. We next designed the “Enamine focused IMiD library” and demonstrated applicability of the construct to high-throughput screening, identifying binders with high potency, ligand efficiency, and specificity. Finally, we adapt our construct for proof of principle glue screening approaches enabling IMiD cellular interactome determination. Coupled with our IMiD binding landscape the methods described here should serve as valuable tools to assist discovery of next generation CRBN glues.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 363-376.e10"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718728","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}
Various types of post-transcriptional modifications contribute to physiological functions by regulating the abundance and function of RNAs. In particular, tRNAs have the widest variety and largest number of modifications, with crucial roles in protein synthesis. Queuosine (Q) is a characteristic tRNA modification with a 7-deazaguanosine core structure bearing a bulky side chain with a cyclopentene group. Q and its derivatives are found in the anticodon of specific tRNAs in both bacteria and eukaryotes. In metazoan tRNAs, Q is further glycosylated with galactose or mannose. The functions of these glycosylated Qs remained unknown for nearly half a century since their discovery. Recently, our group identified the glycosyltransferases responsible for these tRNA modifications and elucidated their biological roles. We, here, review the biochemical and physiological functions of Q and its glycosylated derivatives as well as their associations with human diseases, including cancer and inflammatory and neurological diseases.
{"title":"Biogenesis and roles of tRNA queuosine modification and its glycosylated derivatives in human health and diseases","authors":"Tsutomu Suzuki , Atsuya Ogizawa , Kensuke Ishiguro , Asuteka Nagao","doi":"10.1016/j.chembiol.2024.11.004","DOIUrl":"10.1016/j.chembiol.2024.11.004","url":null,"abstract":"<div><div>Various types of post-transcriptional modifications contribute to physiological functions by regulating the abundance and function of RNAs. In particular, tRNAs have the widest variety and largest number of modifications, with crucial roles in protein synthesis. Queuosine (Q) is a characteristic tRNA modification with a 7-deazaguanosine core structure bearing a bulky side chain with a cyclopentene group. Q and its derivatives are found in the anticodon of specific tRNAs in both bacteria and eukaryotes. In metazoan tRNAs, Q is further glycosylated with galactose or mannose. The functions of these glycosylated Qs remained unknown for nearly half a century since their discovery. Recently, our group identified the glycosyltransferases responsible for these tRNA modifications and elucidated their biological roles. We, here, review the biochemical and physiological functions of Q and its glycosylated derivatives as well as their associations with human diseases, including cancer and inflammatory and neurological diseases.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 227-238"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793567","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}
Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for targeting “undruggable” proteins, and several PROTACs have reached the stage of clinical candidates. However, the roles of cellular transmembrane transporters in PROTAC uptake and efflux remain underexplored. Here, we utilized transporter-focused genetic screens to identify the ATP-binding cassette transporter ABCC1/MRP1 as a key PROTAC resistance factor. Unlike the previously identified inducible PROTAC exporter ABCB1/MDR1, ABCC1 is highly expressed among cancers of various origins and constitutively restricts PROTAC bioavailability. Moreover, in a genome-wide PROTAC resistance screen, we identified candidates involved in processes such as ubiquitination, mTOR signaling, and apoptosis as genetic factors involved in PROTAC resistance. In summary, our findings reveal ABCC1 as a crucial constitutively active efflux pump limiting PROTAC efficacy in various cancer cells, offering insights for overcoming drug resistance.
{"title":"The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells","authors":"Gernot Wolf , Conner Craigon , Shao Thing Teoh , Patrick Essletzbichler , Svenja Onstein , Diane Cassidy , Esther C.H. Uijttewaal , Vojtech Dvorak , Yuting Cao , Ariel Bensimon , Ulrich Elling , Alessio Ciulli , Giulio Superti-Furga","doi":"10.1016/j.chembiol.2024.11.009","DOIUrl":"10.1016/j.chembiol.2024.11.009","url":null,"abstract":"<div><div>Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for targeting “undruggable” proteins, and several PROTACs have reached the stage of clinical candidates. However, the roles of cellular transmembrane transporters in PROTAC uptake and efflux remain underexplored. Here, we utilized transporter-focused genetic screens to identify the ATP-binding cassette transporter ABCC1/MRP1 as a key PROTAC resistance factor. Unlike the previously identified inducible PROTAC exporter ABCB1/MDR1, ABCC1 is highly expressed among cancers of various origins and constitutively restricts PROTAC bioavailability. Moreover, in a genome-wide PROTAC resistance screen, we identified candidates involved in processes such as ubiquitination, mTOR signaling, and apoptosis as genetic factors involved in PROTAC resistance. In summary, our findings reveal ABCC1 as a crucial constitutively active efflux pump limiting PROTAC efficacy in various cancer cells, offering insights for overcoming drug resistance.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 291-306.e6"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917462","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 : 2025-02-07DOI: 10.1016/j.chembiol.2025.01.006
Jason Z. Zhang, Nathan Greenwood, Jason Hernandez, Josh T. Cuperus, Buwei Huang, Bryan D. Ryder, Christine Queitsch, Jason E. Gestwicki, David Baker
Protein quality control (PQC) is carried out in part by the chaperone Hsp70 in concert with adapters of the J-domain protein (JDP) family. The JDPs, also called Hsp40s, are thought to recruit Hsp70 into complexes with specific client proteins. However, the molecular principles regulating this process are not well understood. We describe the de novo design of Hsp70 binding proteins that either inhibit or stimulate Hsp70 ATPase activity. An ATPase stimulating design promoted the refolding of denatured luciferase in vitro, similar to native JDPs. Targeting of this design to intracellular condensates resulted in their nearly complete dissolution and revealed roles as cell growth promoting signaling hubs. The designs inform our understanding of chaperone structure-function relationships and provide a general and modular way to target PQC systems to regulate condensates and other cellular targets.
{"title":"De novo designed Hsp70 activator dissolves intracellular condensates","authors":"Jason Z. Zhang, Nathan Greenwood, Jason Hernandez, Josh T. Cuperus, Buwei Huang, Bryan D. Ryder, Christine Queitsch, Jason E. Gestwicki, David Baker","doi":"10.1016/j.chembiol.2025.01.006","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.01.006","url":null,"abstract":"Protein quality control (PQC) is carried out in part by the chaperone Hsp70 in concert with adapters of the J-domain protein (JDP) family. The JDPs, also called Hsp40s, are thought to recruit Hsp70 into complexes with specific client proteins. However, the molecular principles regulating this process are not well understood. We describe the <em>de novo</em> design of Hsp70 binding proteins that either inhibit or stimulate Hsp70 ATPase activity. An ATPase stimulating design promoted the refolding of denatured luciferase <em>in vitro</em>, similar to native JDPs. Targeting of this design to intracellular condensates resulted in their nearly complete dissolution and revealed roles as cell growth promoting signaling hubs. The designs inform our understanding of chaperone structure-function relationships and provide a general and modular way to target PQC systems to regulate condensates and other cellular targets.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"141 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258446","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.2024.10.010
Kevin A. Scott , Hiroyuki Kojima , Nathalie Ropek , Charles D. Warren , Tiffany L. Zhang , Simon J. Hogg , Henry Sanford , Caroline Webster , Xiaoyu Zhang , Jahan Rahman , Bruno Melillo , Benjamin F. Cravatt , Jiankun Lyu , Omar Abdel-Wahab , Ekaterina V. Vinogradova
Despite significant interest in therapeutic targeting of splicing, few chemical probes are available for the proteins involved in splicing. Here, we show that elaborated stereoisomeric acrylamide EV96 and its analogues lead to a selective T cell state-dependent loss of interleukin 2-inducible T cell kinase (ITK) by targeting one of the core splicing factors SF3B1. Mechanistic investigations suggest that the state-dependency stems from a combination of differential protein turnover rates and extensive ITK mRNA alternative splicing. We further introduce the most comprehensive list to date of proteins involved in splicing and leverage cysteine- and protein-directed activity-based protein profiling with electrophilic scout fragments to demonstrate covalent ligandability for many classes of splicing factors and splicing regulators in T cells. Taken together, our findings show how chemical perturbation of splicing can lead to immune state-dependent changes in protein expression and provide evidence for the broad potential to target splicing factors with covalent chemistry.
尽管人们对剪接的靶向治疗非常感兴趣，但很少有化学探针可用于参与剪接的蛋白质。在这里，我们展示了精心制作的立体异构体丙烯酰胺 EV96 及其类似物通过靶向核心剪接因子之一 SF3B1，导致白细胞介素 2 诱导型 T 细胞激酶（ITK）的选择性 T 细胞状态依赖性缺失。 机制研究表明，状态依赖性源于不同的蛋白质周转率和广泛的 ITK mRNA 交替剪接。我们进一步介绍了迄今为止最全面的参与剪接的蛋白质列表，并利用半胱氨酸和蛋白质定向活性的蛋白质剖析以及亲电侦察片段证明了 T 细胞中许多种类的剪接因子和剪接调节因子的共价配体性。总之，我们的研究结果表明了剪接的化学扰动如何导致蛋白质表达的免疫状态依赖性变化，并为利用共价化学作用靶向剪接因子的广泛潜力提供了证据。
{"title":"Covalent targeting of splicing in T cells","authors":"Kevin A. Scott , Hiroyuki Kojima , Nathalie Ropek , Charles D. Warren , Tiffany L. Zhang , Simon J. Hogg , Henry Sanford , Caroline Webster , Xiaoyu Zhang , Jahan Rahman , Bruno Melillo , Benjamin F. Cravatt , Jiankun Lyu , Omar Abdel-Wahab , Ekaterina V. Vinogradova","doi":"10.1016/j.chembiol.2024.10.010","DOIUrl":"10.1016/j.chembiol.2024.10.010","url":null,"abstract":"<div><div>Despite significant interest in therapeutic targeting of splicing, few chemical probes are available for the proteins involved in splicing. Here, we show that elaborated stereoisomeric acrylamide EV96 and its analogues lead to a selective T cell state-dependent loss of interleukin 2-inducible T cell kinase (ITK) by targeting one of the core splicing factors SF3B1. Mechanistic investigations suggest that the state-dependency stems from a combination of differential protein turnover rates and extensive ITK mRNA alternative splicing. We further introduce the most comprehensive list to date of proteins involved in splicing and leverage cysteine- and protein-directed activity-based protein profiling with electrophilic scout fragments to demonstrate covalent ligandability for many classes of splicing factors and splicing regulators in T cells. Taken together, our findings show how chemical perturbation of splicing can lead to immune state-dependent changes in protein expression and provide evidence for the broad potential to target splicing factors with covalent chemistry.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 201-218.e17"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696958","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.2024.12.012
Judith Behnsen, Kerwyn Casey Huang, Matthew T. Sorbara, Meng C. Wang, Jun Yu, Melody Y. Zeng
The field of microbiome research has experienced remarkable growth, leading to unprecedented discoveries of the molecular mechanisms that dictate host-microbiota interactions and their crucial roles in human health. In this “chemical biology of the microbiome” focus issue from Cell Chemical Biology, this Voices piece asks researchers from a range of backgrounds to share their insights on the most exciting recent developments in the microbiome field.
{"title":"New opportunities in mechanistic and functional microbiome studies","authors":"Judith Behnsen, Kerwyn Casey Huang, Matthew T. Sorbara, Meng C. Wang, Jun Yu, Melody Y. Zeng","doi":"10.1016/j.chembiol.2024.12.012","DOIUrl":"10.1016/j.chembiol.2024.12.012","url":null,"abstract":"<div><div>The field of microbiome research has experienced remarkable growth, leading to unprecedented discoveries of the molecular mechanisms that dictate host-microbiota interactions and their crucial roles in human health. In this “chemical biology of the microbiome” focus issue from <em>Cell Chemical Biology</em>, this Voices piece asks researchers from a range of backgrounds to share their insights on the most exciting recent developments in the microbiome field.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 5-8"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986892","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.2024.12.009
Katerina Jones, Camila Bernardo de Brito, Mariana Xavier Byndloss
In an interview with Samantha Nelson, a scientific editor of Cell Chemical Biology, the authors of the review entitled “Metabolic tug-o-war: Microbial metabolism shapes colonization resistance against enteric pathogens” share their perspectives on the field and their lives as scientists.
在接受《细胞化学生物学》（Cell Chemical Biology）科学编辑萨曼莎-尼尔森（Samantha Nelson）的采访时，题为《新陈代谢拉锯战：微生物新陈代谢塑造了对肠道病原体的定植抗性》的综述作者分享了他们对这一领域的看法以及作为科学家的生活：微生物新陈代谢决定了对肠道病原体的定植抵抗力 "的评论文章的作者分享了他们对这一领域的看法以及他们作为科学家的生活。
{"title":"Meet the authors: Katerina Jones, Camila Bernardo de Brito, and Mariana Xavier Byndloss","authors":"Katerina Jones, Camila Bernardo de Brito, Mariana Xavier Byndloss","doi":"10.1016/j.chembiol.2024.12.009","DOIUrl":"10.1016/j.chembiol.2024.12.009","url":null,"abstract":"<div><div>In an interview with Samantha Nelson, a scientific editor of <em>Cell Chemical Biology</em>, the authors of the review entitled “<span><span>Metabolic tug-o-war: Microbial metabolism shapes colonization resistance against enteric pathogens</span><svg><path></path></svg></span>” share their perspectives on the field and their lives as scientists.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 3-4"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986931","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.2024.12.004
Christopher Whidbey
Microbiomes exist in ecological niches ranging from the ocean and soil to inside of larger organisms like plants and animals. Within these niches, microbes play key roles in biochemical processes that impact larger phenomena, such as biogeochemical cycling or health. By understanding of how these processes occur at the molecular level, it may be possible to develop new interventions to address global problems. The complexity of these systems poses challenges to more traditional techniques. Chemical biology can help overcome these challenges by providing tools that are broadly applicable and can obtain molecular-level information about complex systems. This primer is intended to serve as a brief introduction to chemical biology and microbiome science, to highlight some of the ways that these two disciplines complement each other, and to encourage dialog and collaboration between these fields.
{"title":"The right tool for the job: Chemical biology and microbiome science","authors":"Christopher Whidbey","doi":"10.1016/j.chembiol.2024.12.004","DOIUrl":"10.1016/j.chembiol.2024.12.004","url":null,"abstract":"<div><div>Microbiomes exist in ecological niches ranging from the ocean and soil to inside of larger organisms like plants and animals. Within these niches, microbes play key roles in biochemical processes that impact larger phenomena, such as biogeochemical cycling or health. By understanding of how these processes occur at the molecular level, it may be possible to develop new interventions to address global problems. The complexity of these systems poses challenges to more traditional techniques. Chemical biology can help overcome these challenges by providing tools that are broadly applicable and can obtain molecular-level information about complex systems. This primer is intended to serve as a brief introduction to chemical biology and microbiome science, to highlight some of the ways that these two disciplines complement each other, and to encourage dialog and collaboration between these fields.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 83-97"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929676","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.2024.07.011
Natavan Dudkina , Hyun Bong Park , Deguang Song , Abhishek Jain , Sajid A. Khan , Richard A. Flavell , Caroline H. Johnson , Noah W. Palm , Jason M. Crawford
Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product “sperminal” is reduced to “sperminol.” Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy in vitro. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.
{"title":"Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway","authors":"Natavan Dudkina , Hyun Bong Park , Deguang Song , Abhishek Jain , Sajid A. Khan , Richard A. Flavell , Caroline H. Johnson , Noah W. Palm , Jason M. Crawford","doi":"10.1016/j.chembiol.2024.07.011","DOIUrl":"10.1016/j.chembiol.2024.07.011","url":null,"abstract":"<div><div>Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product “sperminal” is reduced to “sperminol.” Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy <em>in vitro</em>. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones <em>in vitro</em>, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 126-144.e18"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007975","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.2024.07.012
Eric M. Brown , Phuong N.U. Nguyen , Ramnik J. Xavier
The strong association of the human leukocyte antigen B∗27 alleles (HLA-B∗27) with spondyloarthritis and related rheumatic conditions has long fascinated researchers, yet the precise mechanisms underlying its pathogenicity remain elusive. Here, we review how interplay between the microbiome, the immune system, and the enigmatic HLA-B∗27 could trigger spondyloarthritis, with a focus on whether HLA-B∗27 presents an arthritogenic peptide. We propose mechanisms by which the unique biochemical characteristics of the HLA-B∗27 protein structure, particularly its peptide binding groove, could dictate its propensity to induce pathological T cell responses. We further provide new insights into how TRBV9+ CD8+ T cells are implicated in the disease process, as well as how the immunometabolism of T cells modulates tissue-specific inflammatory responses in spondyloarthritis. Finally, we present testable models and suggest approaches to this problem in future studies given recent advances in computational biology, chemical biology, structural biology, and small-molecule therapeutics.
人类白细胞抗原B∗27等位基因（HLA-B∗27）与脊柱关节炎及相关风湿病的密切关系一直令研究人员着迷，但其致病的确切机制却仍然难以捉摸。在这里，我们回顾了微生物组、免疫系统和神秘的 HLA-B∗27 之间的相互作用是如何诱发脊柱关节炎的，重点是 HLA-B∗27 是否会产生致关节炎肽。我们提出了 HLA-B∗27 蛋白结构的独特生化特性（尤其是其肽结合槽）可能决定其诱导病理 T 细胞反应倾向的机制。我们进一步提供了关于 TRBV9+ CD8+ T 细胞如何参与疾病过程以及 T 细胞的免疫代谢如何调节脊柱关节炎组织特异性炎症反应的新见解。最后，鉴于计算生物学、化学生物学、结构生物学和小分子疗法的最新进展，我们提出了可检验的模型，并建议在未来研究中解决这一问题的方法。
{"title":"Emerging biochemical, microbial and immunological evidence in the search for why HLA-B∗27 confers risk for spondyloarthritis","authors":"Eric M. Brown , Phuong N.U. Nguyen , Ramnik J. Xavier","doi":"10.1016/j.chembiol.2024.07.012","DOIUrl":"10.1016/j.chembiol.2024.07.012","url":null,"abstract":"<div><div>The strong association of the human leukocyte antigen B<sup>∗</sup>27 alleles (<em>HLA-B<sup>∗</sup>27</em>) with spondyloarthritis and related rheumatic conditions has long fascinated researchers, yet the precise mechanisms underlying its pathogenicity remain elusive. Here, we review how interplay between the microbiome, the immune system, and the enigmatic HLA-B<sup>∗</sup>27 could trigger spondyloarthritis, with a focus on whether HLA-B<sup>∗</sup>27 presents an arthritogenic peptide. We propose mechanisms by which the unique biochemical characteristics of the HLA-B<sup>∗</sup>27 protein structure, particularly its peptide binding groove, could dictate its propensity to induce pathological T cell responses. We further provide new insights into how TRBV9<sup>+</sup> CD8<sup>+</sup> T cells are implicated in the disease process, as well as how the immunometabolism of T cells modulates tissue-specific inflammatory responses in spondyloarthritis. Finally, we present testable models and suggest approaches to this problem in future studies given recent advances in computational biology, chemical biology, structural biology, and small-molecule therapeutics.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 12-24"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015826","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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