Cell Chemical Biology最新文献

Visualization of calpain-1 activation during cell death and its role in GSDMD cleavage using chemical probes

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-28 DOI: 10.1016/j.chembiol.2025.03.002

Natalia Horbach, Małgorzata Kalinka, Natalia Ćwilichowska-Puślecka, Abdulla Al Mamun, Agata Mikołajczyk-Martinez, Boris Turk, Scott J. Snipas, Paulina Kasperkiewicz, Katarzyna M. Groborz, Marcin Poręba

{"title":"Visualization of calpain-1 activation during cell death and its role in GSDMD cleavage using chemical probes","authors":"Natalia Horbach, Małgorzata Kalinka, Natalia Ćwilichowska-Puślecka, Abdulla Al Mamun, Agata Mikołajczyk-Martinez, Boris Turk, Scott J. Snipas, Paulina Kasperkiewicz, Katarzyna M. Groborz, Marcin Poręba","doi":"10.1016/j.chembiol.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.03.002","url":null,"abstract":"Calpain-1, a calcium-dependent cysteine protease, plays a vital role in cellular processes such as cell death, cytoskeletal remodeling, signal transduction, and cell cycle progression. While its role in apoptosis, including substrate cleavage for orderly disassembly, is well established, its involvement in pyroptosis remains less understood. This study focused on developing chemical tools to detect calpain-1 activity. Using the hybrid combinatorial substrate library (HyCoSuL) approach with unnatural amino acids, we designed fluorescent substrates, inhibitors, and fluorescent activity-based probe (ABP) specific to calpain-1, enabling its visualization in living cells. We further investigated calpain-1’s expression alongside cell death proteins in immune cells using mass cytometry and observed strong colocalization with gasdermin D (GSDMD). Additionally, we demonstrated that calpain-1 can hydrolyze GSDMD <em>in vitro</em>. Through fluorescence-based substrate assays and mass spectrometry, we identified putative cleavage sites within the GSDMD sequence that may promote pyroptosis. These findings underscore calpain-1’s multifaceted role in cell death pathways, extending beyond apoptosis.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"18 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723550","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

Targeted degradation of CDK9 potently disrupts the MYC-regulated network

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-27 DOI: 10.1016/j.chembiol.2025.03.001

Mohammed A. Toure, Keisuke Motoyama, Yichen Xiang, Julie Urgiles, Florian Kabinger, Ann-Sophie Koglin, Ramya S. Iyer, Kaitlyn Gagnon, Amruth Kumar, Samuel Ojeda, Drew A. Harrison, Matthew G. Rees, Jennifer A. Roth, Christopher J. Ott, Richard Schiavoni, Charles A. Whittaker, Stuart S. Levine, Forest M. White, Eliezer Calo, Andre Richters, Angela N. Koehler

{"title":"Targeted degradation of CDK9 potently disrupts the MYC-regulated network","authors":"Mohammed A. Toure, Keisuke Motoyama, Yichen Xiang, Julie Urgiles, Florian Kabinger, Ann-Sophie Koglin, Ramya S. Iyer, Kaitlyn Gagnon, Amruth Kumar, Samuel Ojeda, Drew A. Harrison, Matthew G. Rees, Jennifer A. Roth, Christopher J. Ott, Richard Schiavoni, Charles A. Whittaker, Stuart S. Levine, Forest M. White, Eliezer Calo, Andre Richters, Angela N. Koehler","doi":"10.1016/j.chembiol.2025.03.001","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.03.001","url":null,"abstract":"CDK9 coordinates signaling events that regulate transcription and is implicated in oncogenic pathways, making it an actionable target for drug development. While numerous CDK9 inhibitors have been developed, success in the clinic has been limited. Targeted degradation offers a promising alternative. A comprehensive evaluation of degradation versus inhibition is needed to assess when degradation might offer superior therapeutic outcomes. We report a selective and potent CDK9 degrader with rapid kinetics, comparing its downstream effects to those of a conventional inhibitor. We validated that CDK9 inhibition triggers a compensatory feedback mechanism that dampens its anticipated effect on MYC expression and found that this was absent when degraded. Importantly, degradation is more effective at disrupting MYC transcriptional regulation and subsequently destabilizing nucleolar homeostasis, likely by abrogation of both enzymatic and scaffolding functions of CDK9. These findings suggest that CDK9 degradation offers a more robust strategy to overcome limitations associated with its inhibition.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"49 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713581","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

Antibiotic target discovery by integrated phenotypic and activity-based profiling of electrophilic fragments

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.001

Yizhen Jin , Sadhan Jana , Mikail E. Abbasov , Hening Lin

{"title":"Antibiotic target discovery by integrated phenotypic and activity-based profiling of electrophilic fragments","authors":"Yizhen Jin , Sadhan Jana , Mikail E. Abbasov , Hening Lin","doi":"10.1016/j.chembiol.2025.02.001","DOIUrl":"10.1016/j.chembiol.2025.02.001","url":null,"abstract":"<div><div>The emergence of antibiotic resistance necessitates the discovery of novel bacterial targets and antimicrobial agents. Here, we present a bacterial target discovery framework that integrates phenotypic screening of cysteine-reactive fragments with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits. Using this approach, we identify β-ketoacyl-acyl carrier protein synthase III (FabH) and MiaA tRNA prenyltransferase as primary targets of a hit fragment, 10-F05, that confer bacterial stress resistance and virulence in <em>Shigella flexneri</em>. Mechanistic investigations elucidate that covalent C112 modification in FabH, an enzyme involved in bacterial fatty acid synthesis, results in its inactivation and consequent growth inhibition. We further demonstrate that irreversible C273 modification at the MiaA RNA-protein interaction interface abrogates substrate tRNA binding, attenuating resistance and virulence through decreased translational accuracy. Our findings underscore the efficacy of integrating phenotypic and activity-based profiling of electrophilic fragments to accelerate the identification and pharmacologic validation of new therapeutic targets.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 434-448.e9"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507382","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

Development of an FKBP12-recruiting chemical-induced proximity DNA-encoded library and its application to discover an autophagy potentiator fkbp12募集化学诱导邻近dna编码文库的建立及其在发现自噬增强剂中的应用

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 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

{"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":"10.1016/j.chembiol.2024.12.002","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 498-510.e35"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","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}

引用次数: 0

NAPE-PLD is target of thiazide diuretics

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.01.008

Sara Chiarugi , Francesco Margheriti , Valentina De Lorenzi , Elisa Martino , Eleonora Germana Margheritis , Aldo Moscardini , Roberto Marotta , Antonio Chaves-Sanjuan , Cristina Del Seppia , Giuseppe Federighi , Dominga Lapi , Tiziano Bandiera , Simona Rapposelli , Rossana Scuri , Martino Bolognesi , Gianpiero Garau

{"title":"NAPE-PLD is target of thiazide diuretics","authors":"Sara Chiarugi , Francesco Margheriti , Valentina De Lorenzi , Elisa Martino , Eleonora Germana Margheritis , Aldo Moscardini , Roberto Marotta , Antonio Chaves-Sanjuan , Cristina Del Seppia , Giuseppe Federighi , Dominga Lapi , Tiziano Bandiera , Simona Rapposelli , Rossana Scuri , Martino Bolognesi , Gianpiero Garau","doi":"10.1016/j.chembiol.2025.01.008","DOIUrl":"10.1016/j.chembiol.2025.01.008","url":null,"abstract":"<div><div>Thiazide and thiazide-like diuretics are among the most efficacious and used drugs for the treatment of hypertension, edema, and major cardiovascular outcomes. Despite more then than six decades of clinical use, the molecular target and mechanism of action by which these drugs cure hypertension after long-term use have remained mysterious. Here we report the discovery and validation of a previously unknown renal and extrarenal target of these antihypertensives, the membrane-associated phospholipase N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) of the endocannabinoid system. Structural and functional insights, together with preclinical studies in hypertensive rats, disclose the molecular and physiological basis by which thiazides cause acute diuresis and, at the same time, the distinctive chronic reduction of vascular resistance. Our results shed light on the mechanism of treatment of hypertension and will be useful for developing more efficacious medications for the management of vascular risk factors, as well as associated leukoencephalopathies and myelin disorders.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 449-462.e5"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477580","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

Epigenetic fluidity meets phenotypic malleability in intestinal epithelial cells

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.007

Swarnabh Bhattacharya , Ramesh A. Shivdasani

引用次数: 0

De novo designed Hsp70 activator dissolves intracellular condensates

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 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

引用次数: 0

An affinity-based depletion strategy for evaluating the effects of ergothioneine on bacterial physiology

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.004

Anna B. Seminara , Stavroula K. Hatzios

{"title":"An affinity-based depletion strategy for evaluating the effects of ergothioneine on bacterial physiology","authors":"Anna B. Seminara , Stavroula K. Hatzios","doi":"10.1016/j.chembiol.2025.02.004","DOIUrl":"10.1016/j.chembiol.2025.02.004","url":null,"abstract":"<div><div>Ergothioneine (EGT) is a thiol-based antioxidant synthesized by certain fungal and bacterial species that is prevalent in the human diet. Recently, an EGT-specific transporter, EgtUV, was discovered in bacteria that are incapable of EGT biosynthesis, including the gastric pathogen <em>Helicobacter pylori</em>. However, EGT is naturally abundant in the complex media required to culture <em>H. pylori</em> and many other host-associated microbes, complicating efforts to understand how this molecule influences microbial physiology. Using the solute-binding domain of <em>H. pylori</em> EgtUV, we generated an EGT-chelating resin that depletes EGT from nutrient-rich media. We determined that wild-type <em>H. pylori</em> requires EGT to outcompete a transporter-deficient strain <em>in vitro</em>. Furthermore, EGT induces transcription of genes encoding outer-membrane transporters that may regulate intracellular EGT content upstream of the inner-membrane-localized EgtUV transporter. Our work establishes a method for tuning exposure to an abundant antioxidant <em>in vitro</em>, enabling future studies of EGT in diverse microbial strains and communities.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 486-497.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582511","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 it up: Freed fats drive ferroptosis

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.008

Madison S. Mortensen , Jennifer L. Watts

引用次数: 0

Ligand-induced assembly of antibody variable fragments for the chemical regulation of biological processes

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.01.007

Erik Rihtar , Tina Fink , Tina Lebar , Duško Lainšček , Živa Kolenc , Lucija Kadunc Polajnar , Roman Jerala

{"title":"Ligand-induced assembly of antibody variable fragments for the chemical regulation of biological processes","authors":"Erik Rihtar , Tina Fink , Tina Lebar , Duško Lainšček , Živa Kolenc , Lucija Kadunc Polajnar , Roman Jerala","doi":"10.1016/j.chembiol.2025.01.007","DOIUrl":"10.1016/j.chembiol.2025.01.007","url":null,"abstract":"<div><div>Precise control of biological processes by the application of small molecules can increase the safety and efficiency of therapies. Adverse side effects of small molecule signals and/or immunogenicity of regulatory domains hinder their biomedical utility. Here, we designed small molecule-responsive switches, based on the conditional reassembly of human antibody variable fragments, called Fv-CID switches. The principle was validated using high-affinity antibodies against nicotine and β-estradiol to construct chemically responsive transcription factors. Further, we developed an Fv-CID switch responsive to bio-inert, clinically approved compound fluorescein, which was used to control the activity of chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs) <em>in vivo</em>. This study provides a framework to regulate the expression of endogenous genes, combine multiple chemical signals, and regulate T cell-based immunotherapy in an animal cancer model using a clinically approved small molecule regulator that could be customized for regulating therapeutic proteins or cells.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 474-485.e5"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401350","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