Pub Date : 2026-03-16DOI: 10.1016/j.chembiol.2026.02.006
Fangmin Huang, Jianwei Li, Francis Ka-Ming Chan
Necroptosis is a critical host response against pathogenic challenge. As such, many pathogens have developed strategies to fend off host cell necroptosis. This tug-of-war between the host and pathogen has led to the widely held view that necroptosis evolves primarily as a host response to infection. Paradoxically, pathogens that encode caspase inhibitors and therefore render infected cells sensitive to necroptosis also develop strategies that block necroptosis. Hence, cell death alone may not be sufficient to account for the protective role of necroptosis signal adaptors in host defense. We propose an alternative model in which cell death signal adaptors function as sensors of pathogen-encoded activities. In this scenario, pathogen interference with necroptosis may not only affect host cell death but also tune the magnitude and quality of the ensuing immune response. The crosstalk between necroptosis and other inflammatory cell death programs during viral infection will also be discussed.
{"title":"Transcending cell death – The diverse roles of necroptosis signal adaptors in pathogen infection","authors":"Fangmin Huang, Jianwei Li, Francis Ka-Ming Chan","doi":"10.1016/j.chembiol.2026.02.006","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.02.006","url":null,"abstract":"Necroptosis is a critical host response against pathogenic challenge. As such, many pathogens have developed strategies to fend off host cell necroptosis. This tug-of-war between the host and pathogen has led to the widely held view that necroptosis evolves primarily as a host response to infection. Paradoxically, pathogens that encode caspase inhibitors and therefore render infected cells sensitive to necroptosis also develop strategies that block necroptosis. Hence, cell death alone may not be sufficient to account for the protective role of necroptosis signal adaptors in host defense. We propose an alternative model in which cell death signal adaptors function as sensors of pathogen-encoded activities. In this scenario, pathogen interference with necroptosis may not only affect host cell death but also tune the magnitude and quality of the ensuing immune response. The crosstalk between necroptosis and other inflammatory cell death programs during viral infection will also be discussed.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"96 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462117","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 : 2026-03-11DOI: 10.1016/j.chembiol.2026.02.008
Jason Z. Zhang, Xinting Li, Alexa Rane Batingana, Caixuan Liu, Hanlun Jiang, Kevin Shannon, Benjamin J. Huang, Kejia Wu, David Baker
The four major isoforms encoded by RAS proto-oncogenes are differentially associated with cancer, but there are few isoform-specific binding reagents becasue the sequence differences are confined to their disordered C termini. To overcome this limitation, we use deep learning-based methods to design Ras isoform-specific binders (RIBs) for all major Ras isoforms de novo by targeting the Ras C terminus. The RIBs bind to their target Ras isoforms both in vitro and in cells with remarkable specificity, disrupting their membrane localization and inhibiting Ras activity. The RIBs enable dissection of the distinct roles of Ras isoforms during RasG12C inhibitor resistance, demonstrating their utility in understanding Ras biology and disease and suggesting potential therapeutic applications.
{"title":"De novo design of Ras isoform selective binders","authors":"Jason Z. Zhang, Xinting Li, Alexa Rane Batingana, Caixuan Liu, Hanlun Jiang, Kevin Shannon, Benjamin J. Huang, Kejia Wu, David Baker","doi":"10.1016/j.chembiol.2026.02.008","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.02.008","url":null,"abstract":"The four major isoforms encoded by <em>RAS</em> proto-oncogenes are differentially associated with cancer, but there are few isoform-specific binding reagents becasue the sequence differences are confined to their disordered C termini. To overcome this limitation, we use deep learning-based methods to design Ras isoform-specific binders (RIBs) for all major Ras isoforms <em>de novo</em> by targeting the Ras C terminus. The RIBs bind to their target Ras isoforms both <em>in vitro</em> and in cells with remarkable specificity, disrupting their membrane localization and inhibiting Ras activity. The RIBs enable dissection of the distinct roles of Ras isoforms during Ras<sup>G12C</sup> inhibitor resistance, demonstrating their utility in understanding Ras biology and disease and suggesting potential therapeutic applications.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383946","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 : 2026-03-09DOI: 10.1016/j.chembiol.2026.02.005
Sipei Fu, Lushun Wang, Veronica L. Li, Xuchao Lyu, Wei Wei, Xu Shi, Shuliang Deng, Jacob L. Barber, Usman A. Tahir, Charleen Adams, April Carson, Bertha Hidalgo, Laura M. Raffield, James G. Wilson, Hlib Razumkov, Shuke Xiao, Jan Spaas, Daniel Fernandez, Tinghu Zhang, Robert E. Gerszten, Jonathan Z. Long
PTER (phosphotriesterase-related) is an amidohydrolase that mediates catabolism of the anorexigenic metabolite N-acetyltaurine. However, the structural basis of PTER ligand binding and catalysis remains unknown, limiting our ability to harness this pathway therapeutically. Here, we solve crystal structures of a eukaryotic PTER in apo and product-bound forms. These structures uncover an unexpected pocket homology between PTER and histone deacetylase (HDAC) enzymes. We exploit this similarity to engineer a substrate-competitive PTER inhibitor called PTERi with nanomolar potency and >100-fold selectivity for PTER over HDACs in vitro. The administration of PTERi to diet-induced obese mice reduces feeding, enhances glucagon-like peptide 1 receptor agonist (GLP1-RA)-induced weight loss, and prevents weight regain after GLP1-RA discontinuation. The structure of PTER connects histone and metabolite deacetylation into a parallel conceptual framework and enables proof-of-concept data for the pharmacological inhibition of PTER in obesity.
{"title":"A small molecule PTER-selective inhibitor reduces food intake and body weight","authors":"Sipei Fu, Lushun Wang, Veronica L. Li, Xuchao Lyu, Wei Wei, Xu Shi, Shuliang Deng, Jacob L. Barber, Usman A. Tahir, Charleen Adams, April Carson, Bertha Hidalgo, Laura M. Raffield, James G. Wilson, Hlib Razumkov, Shuke Xiao, Jan Spaas, Daniel Fernandez, Tinghu Zhang, Robert E. Gerszten, Jonathan Z. Long","doi":"10.1016/j.chembiol.2026.02.005","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.02.005","url":null,"abstract":"PTER (phosphotriesterase-related) is an amidohydrolase that mediates catabolism of the anorexigenic metabolite N-acetyltaurine. However, the structural basis of PTER ligand binding and catalysis remains unknown, limiting our ability to harness this pathway therapeutically. Here, we solve crystal structures of a eukaryotic PTER in apo and product-bound forms. These structures uncover an unexpected pocket homology between PTER and histone deacetylase (HDAC) enzymes. We exploit this similarity to engineer a substrate-competitive PTER inhibitor called PTERi with nanomolar potency and >100-fold selectivity for PTER over HDACs <em>in vitro</em>. The administration of PTERi to diet-induced obese mice reduces feeding, enhances glucagon-like peptide 1 receptor agonist (GLP1-RA)-induced weight loss, and prevents weight regain after GLP1-RA discontinuation. The structure of PTER connects histone and metabolite deacetylation into a parallel conceptual framework and enables proof-of-concept data for the pharmacological inhibition of PTER in obesity.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"74 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147384048","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 : 2026-03-06DOI: 10.1016/j.chembiol.2026.02.004
Krassimira A. Garbett, Chen Zheng, Julia Drube, Carsten Hoffmann, Vsevolod V. Gurevich, Richard C. Sando
The class B2 adhesion G protein-coupled receptors (aGPCRs) combines cell adhesion with GPCR signaling to control diverse biological processes. How aGPCRs interact with distinct groups of effectors including G proteins, arrestins, and G protein-coupled receptor kinases (GRKs) remains unclear. Here, we find that diversity in the aGPCR intracellular tail modulates G protein activation, arrestin-3 recruitment, and GRK selectivity in aGPCR ADGRL2. The C-terminal tail of ADGRL2 is required for G protein activation and arrestin-3 recruitment. ADGRL2 with an intact tail recruits arrestin-3 in the absence of G protein activation, suggesting arrestin-3-biased signaling. Alternative splicing of the ADGRL2 tail modulates G protein activation and arrestin-3 binding independently. GRKs are important but not essential for arrestin-3 recruitment to ADGRL2. Moreover, GRK2 increases arrestin-3 recruitment only in a subset of ADGRL2 variants. Collectively, these results show that the interactions of class B2 aGPCRs and arrestin are distinct from class A GPCRs and that ADGRL2 splicing determines effector bias.
{"title":"Cytoplasmic tail diversity determines the effector bias of the adhesion GPCR ADGRL2","authors":"Krassimira A. Garbett, Chen Zheng, Julia Drube, Carsten Hoffmann, Vsevolod V. Gurevich, Richard C. Sando","doi":"10.1016/j.chembiol.2026.02.004","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.02.004","url":null,"abstract":"The class B2 adhesion G protein-coupled receptors (aGPCRs) combines cell adhesion with GPCR signaling to control diverse biological processes. How aGPCRs interact with distinct groups of effectors including G proteins, arrestins, and G protein-coupled receptor kinases (GRKs) remains unclear. Here, we find that diversity in the aGPCR intracellular tail modulates G protein activation, arrestin-3 recruitment, and GRK selectivity in aGPCR ADGRL2. The C-terminal tail of ADGRL2 is required for G protein activation and arrestin-3 recruitment. ADGRL2 with an intact tail recruits arrestin-3 in the absence of G protein activation, suggesting arrestin-3-biased signaling. Alternative splicing of the ADGRL2 tail modulates G protein activation and arrestin-3 binding independently. GRKs are important but not essential for arrestin-3 recruitment to ADGRL2. Moreover, GRK2 increases arrestin-3 recruitment only in a subset of ADGRL2 variants. Collectively, these results show that the interactions of class B2 aGPCRs and arrestin are distinct from class A GPCRs and that ADGRL2 splicing determines effector bias.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"127 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368036","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 : 2026-03-05DOI: 10.1016/j.chembiol.2026.02.003
Amalie B. Rasmussen, Olivia C. Swann, Jonathan C. Brown, Ksenia Sukhova, Nancy Liu, Maryn D. Brown, Charles J.L. Levitt, Laura Martin-Sancho, Carol M. Sheppard, Wendy S. Barclay
The influenza A virus polymerase, consisting of a heterotrimer of three viral proteins, carries out both transcription and replication of the viral RNA genome. These distinct activities are regulated by viral proteins and various co-opted host cell proteins, which serve as targets for the development of novel antiviral interventions. However, little is known about which host proteins direct transcription versus replication. In this report, we performed a differential interactome screen to identify host proteins co-opted downstream or upstream of primary transcription, some of which may be transcription- or replication-specific factors. We found that distinct sets of host proteins interact with the influenza polymerase as it carries out the different activities. We functionally characterized HMGB2 and RUVBL2 as replication cofactors and RPAP2 as a transcription cofactor. Our data demonstrate that comparative proteomics can be used as a targeted approach to uncover virus-host interactions that regulate specific stages of the viral life cycle.
{"title":"Influenza A virus polymerase co-opts distinct sets of host proteins for RNA transcription or replication","authors":"Amalie B. Rasmussen, Olivia C. Swann, Jonathan C. Brown, Ksenia Sukhova, Nancy Liu, Maryn D. Brown, Charles J.L. Levitt, Laura Martin-Sancho, Carol M. Sheppard, Wendy S. Barclay","doi":"10.1016/j.chembiol.2026.02.003","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.02.003","url":null,"abstract":"The influenza A virus polymerase, consisting of a heterotrimer of three viral proteins, carries out both transcription and replication of the viral RNA genome. These distinct activities are regulated by viral proteins and various co-opted host cell proteins, which serve as targets for the development of novel antiviral interventions. However, little is known about which host proteins direct transcription versus replication. In this report, we performed a differential interactome screen to identify host proteins co-opted downstream or upstream of primary transcription, some of which may be transcription- or replication-specific factors. We found that distinct sets of host proteins interact with the influenza polymerase as it carries out the different activities. We functionally characterized HMGB2 and RUVBL2 as replication cofactors and RPAP2 as a transcription cofactor. Our data demonstrate that comparative proteomics can be used as a targeted approach to uncover virus-host interactions that regulate specific stages of the viral life cycle.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"1 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147360296","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 : 2026-03-03DOI: 10.1016/j.chembiol.2026.02.002
Andrew Brennan, Keith W. Vance, Jody M. Mason
Transcription factors remain essential yet intractable targets for drug discovery owing to their flat, dynamic interfaces. We present an intracellular cyclization strategy that enables in-cell generation of conformationally constrained peptide libraries. Bis-alkylating reagents traverse bacterial membranes and selectively bridge cysteine pairs, permitting post-translational peptide stapling during in vivo screening. Integrated with the transcription block survival (TBS) assay, this intracellular-cyclization TBS (icTBS) platform simultaneously selects both peptide sequence and optimal constraint site, eliminating iterative synthesis. Libraries directed against the oncogenic transcription factor CREB1 yielded three nanomolar-affinity antagonists, with cyclized variants selected by icTBS displaying enhanced functional activity in cellular assays. The lead peptide penetrated melanoma and colorectal cancer cells, suppressed CREB1-dependent transcription, reduced oncogenic protein expression, and triggered apoptosis. icTBS thus provides a general, genetically encoded route to discover constrained peptide therapeutics that disrupt protein-DNA interfaces previously considered “undruggable.”
{"title":"Intracellular cyclization-coupled peptide library screening yields potent transcription factor antagonists","authors":"Andrew Brennan, Keith W. Vance, Jody M. Mason","doi":"10.1016/j.chembiol.2026.02.002","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.02.002","url":null,"abstract":"Transcription factors remain essential yet intractable targets for drug discovery owing to their flat, dynamic interfaces. We present an intracellular cyclization strategy that enables <em>in-cell</em> generation of conformationally constrained peptide libraries. Bis-alkylating reagents traverse bacterial membranes and selectively bridge cysteine pairs, permitting post-translational peptide stapling during <em>in vivo</em> screening. Integrated with the transcription block survival (TBS) assay, this intracellular-cyclization TBS (icTBS) platform simultaneously selects both peptide sequence and optimal constraint site, eliminating iterative synthesis. Libraries directed against the oncogenic transcription factor CREB1 yielded three nanomolar-affinity antagonists, with cyclized variants selected by icTBS displaying enhanced functional activity in cellular assays. The lead peptide penetrated melanoma and colorectal cancer cells, suppressed CREB1-dependent transcription, reduced oncogenic protein expression, and triggered apoptosis. icTBS thus provides a general, genetically encoded route to discover constrained peptide therapeutics that disrupt protein-DNA interfaces previously considered “undruggable.”","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147330246","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}
Among the many proteins involved in cancer progression, an increasing number of RNA-binding proteins (RBPs) are central to the function of a cell and tightly associated to genetic diseases. In a recent study, small-molecule inhibitors have been identified as targeting NONO, an RBP known to be involved in mRNA splicing, DNA repair, and membraneless organelle stability. Here, we report the molecular basis of NONO targeting by the α-chloroacetamide molecule (R)-SKBG-1, its specific binding to NONO, and the enantiomer selectivity on the basis of mass spectrometry measurements and structure determination. We have determined the crystal structure of (R)-SKBG-1-bound to NONO homodimer. This study sheds light on the conformational plasticity of (R)-SKBG-1 when covalently bound to NONO. Altogether, these results give an experimental rationale for ligand modification and optimization in a future use as a drug against cancer.
{"title":"Structural basis for NONO-specific modification by the α-chloroacetamide compound (R)-SKBG-1","authors":"Alessia Vincenza Florio , Corinne Buré , Sébastien Fribourg","doi":"10.1016/j.chembiol.2025.12.013","DOIUrl":"10.1016/j.chembiol.2025.12.013","url":null,"abstract":"<div><div>Among the many proteins involved in cancer progression, an increasing number of RNA-binding proteins (RBPs) are central to the function of a cell and tightly associated to genetic diseases. In a recent study, small-molecule inhibitors have been identified as targeting NONO, an RBP known to be involved in mRNA splicing, DNA repair, and membraneless organelle stability. Here, we report the molecular basis of NONO targeting by the α-chloroacetamide molecule <em>(R)-</em>SKBG-1, its specific binding to NONO, and the enantiomer selectivity on the basis of mass spectrometry measurements and structure determination. We have determined the crystal structure of <em>(R</em>)-SKBG-1-bound to NONO homodimer. This study sheds light on the conformational plasticity of <em>(R)</em>-SKBG-1 when covalently bound to NONO. Altogether, these results give an experimental rationale for ligand modification and optimization in a future use as a drug against cancer.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 268-275.e3"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948244","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 : 2026-02-19Epub Date: 2026-02-11DOI: 10.1016/j.chembiol.2026.01.007
Laurens M. van Tienen , Shadwa Bayoumi , Khaja Muneeruddin , Nancy Leymarie , Alexandra Popa , Mrinal Shekhar , Madeline Mueller , Ruitong Li , Krzysztof M. Zak , Harsha Chilukuri , David J.P. Kornfilt , Thomas C. Atack , Devishi Kesar , Yuemin Bian , Katharin L. Shaw , Zuzana Jandova , Philipp Trollmann , Leonhard Geist , Peggy Stolt-Bergner , Klaus Rumpel , William R. Sellers
The discovery of druggable pockets within proteins that lack traditional active sites remains a significant challenge in the development of therapeutics. To address this, we developed Cysteine Mapping of Accessible Pockets (CysMAP), a method for identifying druggable pockets in proteins. CysMAP employs systematic pooled cysteine (Cys)-variant libraries screened against diverse covalent compound libraries by intact LC-MS. We applied CysMAP to 189 KRAS(G12D) variants, purifying KRAS Cys-variants and screening them against 47 covalent compounds, quantifying accessibility, and reactivity across KRAS(G12D). We discovered previously unidentified ligand-bound states of Cys-variants surrounding the KRAS switch-II pocket. Structural studies of the D92C variant in complex with the compound BI-1830 uncovered a distinct novel binding pocket, highlighting the inherent plasticity of the region between switch-II and α3, that can accommodate diverse chemical entities in various conformations. This method holds significant potential for advancing drug discovery efforts against elusive targets such as oncogenic RAS mutants.
{"title":"Systematic cysteine scanning identifies a druggable pocket in oncogenic KRAS","authors":"Laurens M. van Tienen , Shadwa Bayoumi , Khaja Muneeruddin , Nancy Leymarie , Alexandra Popa , Mrinal Shekhar , Madeline Mueller , Ruitong Li , Krzysztof M. Zak , Harsha Chilukuri , David J.P. Kornfilt , Thomas C. Atack , Devishi Kesar , Yuemin Bian , Katharin L. Shaw , Zuzana Jandova , Philipp Trollmann , Leonhard Geist , Peggy Stolt-Bergner , Klaus Rumpel , William R. Sellers","doi":"10.1016/j.chembiol.2026.01.007","DOIUrl":"10.1016/j.chembiol.2026.01.007","url":null,"abstract":"<div><div>The discovery of druggable pockets within proteins that lack traditional active sites remains a significant challenge in the development of therapeutics. To address this, we developed Cysteine Mapping of Accessible Pockets (CysMAP), a method for identifying druggable pockets in proteins. CysMAP employs systematic pooled cysteine (Cys)-variant libraries screened against diverse covalent compound libraries by intact LC-MS. We applied CysMAP to 189 KRAS(G12D) variants, purifying KRAS Cys-variants and screening them against 47 covalent compounds, quantifying accessibility, and reactivity across KRAS(G12D). We discovered previously unidentified ligand-bound states of Cys-variants surrounding the KRAS switch-II pocket. Structural studies of the D92C variant in complex with the compound BI-1830 uncovered a distinct novel binding pocket, highlighting the inherent plasticity of the region between switch-II and α3, that can accommodate diverse chemical entities in various conformations. This method holds significant potential for advancing drug discovery efforts against elusive targets such as oncogenic RAS mutants.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 241-255.e8"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146160841","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 : 2026-02-19Epub Date: 2026-02-04DOI: 10.1016/j.chembiol.2026.01.003
Wei Liu (刘薇) , Tianyi Zhang (张天一) , Bohong Wang (王博弘) , Hang Yin (尹航)
Bacteria-infected macrophages undergo pyroptosis to release inflammatory cytokines, which contributes to host defense. It has been known that activated macrophages involve metabolic reprogramming. However, the metabolic changes and the role of metabolites in pyroptotic macrophages are not fully understood. Here, we revealed that aerobic glycolysis product, lactate, could promote NLRP3 inflammasome activation induced pyroptosis. We found that endogenous lactate facilitates ASC recruitment to NLRP3 cores on the organelle membrane, thus inducing NLRP3 inflammasome complex formation. Mechanistically, we identified NLRP3 as a target protein modified by lactate, which is lactylated by AARS2. We confirmed lactylated sites on NLRP3 by LC-MS/MS analysis and verified that lactylation at K24 and K565 of NLRP3 facilitates inflammasome activation in macrophage. In vivo, inhibition of lactate production alleviates inflammatory responses in polymicrobial sepsis. Overall, our results indicate the role of lactate in regulating macrophage pyroptosis and the crosstalk between metabolism and innate immunity.
{"title":"Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation","authors":"Wei Liu (刘薇) , Tianyi Zhang (张天一) , Bohong Wang (王博弘) , Hang Yin (尹航)","doi":"10.1016/j.chembiol.2026.01.003","DOIUrl":"10.1016/j.chembiol.2026.01.003","url":null,"abstract":"<div><div>Bacteria-infected macrophages undergo pyroptosis to release inflammatory cytokines, which contributes to host defense. It has been known that activated macrophages involve metabolic reprogramming. However, the metabolic changes and the role of metabolites in pyroptotic macrophages are not fully understood. Here, we revealed that aerobic glycolysis product, lactate, could promote NLRP3 inflammasome activation induced pyroptosis. We found that endogenous lactate facilitates ASC recruitment to NLRP3 cores on the organelle membrane, thus inducing NLRP3 inflammasome complex formation. Mechanistically, we identified NLRP3 as a target protein modified by lactate, which is lactylated by AARS2. We confirmed lactylated sites on NLRP3 by LC-MS/MS analysis and verified that lactylation at K24 and K565 of NLRP3 facilitates inflammasome activation in macrophage. <em>In vivo</em>, inhibition of lactate production alleviates inflammatory responses in polymicrobial sepsis. Overall, our results indicate the role of lactate in regulating macrophage pyroptosis and the crosstalk between metabolism and innate immunity.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 213-226.e5"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115551","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 : 2026-02-19Epub Date: 2026-02-10DOI: 10.1016/j.chembiol.2026.01.006
Peter Geon Kim , Christopher B. Hergott , Aidan P. Miller , Amy Deik , Meaghan Boileau , Kevin Bullock , Kerry A. Pierce , Angelina H. Choy , Wesley Shin , Marie McConkey , Justin Loke , Birgitta A. Ryback , Michael N. Trinh , Justine C. Rutter , Hong Yue , Hojong Yoon , Paul Park , Shourya S. Roy Burman , Matthew G. Vander Heiden , Eric S. Fischer , Benjamin L. Ebert
Somatic mutations in TET2 drive hyper-inflammation in clonal hematopoiesis of indeterminate potential (CHIP), but the molecular link between TET2 inactivation and myeloid immune activation remains unclear. We used in vivo genome-wide genetic perturbations enabled by ultra-diverse barcoding in primary wild-type (WT) or Tet2 knockout (KO) Cas9+ hematopoietic stem-progenitor cells (HSPCs) to elucidate the basis of Tet2 KO inflammation. We uncover a metabolic circuit by which Tet2 restrains O-linked N-acetylglucosamine (O-GlcNAc) glycosyltransferase (Ogt), a Tet2 binding partner and metabolic sensor. Tet2 loss disrupts this inhibitory Tet2-Ogt interaction, and dysregulated Ogt facilitates widespread H3K4 trimethylation including lipid-related gene loci and inflammatory lipid droplet formation. We identified that ATP citrate lyase (Acly) is decorated with O-GlcNAc and is a critical node for lipid accumulation and inflammation in Tet2 KO. These findings reveal that Tet2 suppresses inflammation by gating nutrient-responsive chromatin remodeling and nominate metabolic interventions to restrain inflammatory disease in TET2-mutant clonal hematopoiesis.
TET2体细胞突变在克隆造血不确定电位（CHIP）中驱动高炎症，但TET2失活与髓系免疫激活之间的分子联系尚不清楚。我们在原生野生型（WT）或Tet2敲除（KO） Cas9+造血干细胞（HSPCs）中使用超多样化条形码实现体内全基因组遗传扰动来阐明Tet2 KO炎症的基础。我们发现了一个代谢回路，其中Tet2抑制O-linked n -乙酰氨基葡萄糖（O-GlcNAc）糖基转移酶（Ogt），这是Tet2的结合伙伴和代谢传感器。Tet2缺失破坏了这种抑制Tet2-Ogt相互作用，而失调的Ogt促进了广泛的H3K4三甲基化，包括脂质相关基因位点和炎症性脂滴的形成。我们发现ATP柠檬酸裂解酶（Acly）被O-GlcNAc修饰，是Tet2 KO中脂质积累和炎症的关键节点。这些研究结果表明，Tet2通过调控营养反应性染色质重塑来抑制炎症，并通过代谢干预来抑制Tet2突变克隆造血中的炎症疾病。
{"title":"Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis","authors":"Peter Geon Kim , Christopher B. Hergott , Aidan P. Miller , Amy Deik , Meaghan Boileau , Kevin Bullock , Kerry A. Pierce , Angelina H. Choy , Wesley Shin , Marie McConkey , Justin Loke , Birgitta A. Ryback , Michael N. Trinh , Justine C. Rutter , Hong Yue , Hojong Yoon , Paul Park , Shourya S. Roy Burman , Matthew G. Vander Heiden , Eric S. Fischer , Benjamin L. Ebert","doi":"10.1016/j.chembiol.2026.01.006","DOIUrl":"10.1016/j.chembiol.2026.01.006","url":null,"abstract":"<div><div>Somatic mutations in <em>TET2</em> drive hyper-inflammation in clonal hematopoiesis of indeterminate potential (CHIP), but the molecular link between <em>TET2</em> inactivation and myeloid immune activation remains unclear. We used <em>in vivo</em> genome-wide genetic perturbations enabled by ultra-diverse barcoding in primary wild-type (WT) or <em>Tet2</em> knockout (KO) Cas9<sup>+</sup> hematopoietic stem-progenitor cells (HSPCs) to elucidate the basis of <em>Tet2</em> KO inflammation. We uncover a metabolic circuit by which Tet2 restrains O-linked N-acetylglucosamine (O-GlcNAc) glycosyltransferase (Ogt), a Tet2 binding partner and metabolic sensor. Tet2 loss disrupts this inhibitory Tet2-Ogt interaction, and dysregulated Ogt facilitates widespread H3K4 trimethylation including lipid-related gene loci and inflammatory lipid droplet formation. We identified that ATP citrate lyase (Acly) is decorated with O-GlcNAc and is a critical node for lipid accumulation and inflammation in <em>Tet2</em> KO. These findings reveal that Tet2 suppresses inflammation by gating nutrient-responsive chromatin remodeling and nominate metabolic interventions to restrain inflammatory disease in <em>TET2</em>-mutant clonal hematopoiesis.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 2","pages":"Pages 183-197.e9"},"PeriodicalIF":7.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153223","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：