Pub Date : 2026-03-11DOI: 10.1038/s41589-026-02168-3
Kai Hao,Yunzheng Liu,Mykel Barrett,Zainalabedin Samadi,Amirhossein Zarezadeh,Yuka McGrath,Magdalena Zernicka-Goetz,Amjad Askary
Intensity and duration of biological signals encode a few pathways to direct diverse cellular behaviors, yet quantifying these features in single cells remains difficult. To address this challenge, we developed INSCRIBE, which uses a CRISPR base editor to mutate genomic targets at rates proportional to signaling activity. Edits are recovered at the endpoint through a new ratiometric readout strategy from images of two fluorescence channels. We engineered human cells to record WNT and BMP activity. Following defined exogenous stimulations, INSCRIBE accurately recovered signal intensity in dose-response experiments and exposure duration in time-course experiments. Applying INSCRIBE revealed a persistent memory in the BMP pathway, where progeny of high-responding cells remained more sensitive to subsequent BMP stimulation for up to 3 weeks. Together, our results establish a scalable platform for genetic recording and in situ readout of signaling activity in single cells, advancing quantitative analysis of cell-cell communication during development and disease.
{"title":"Genetic recording and in situ readout of single-cell signaling memory.","authors":"Kai Hao,Yunzheng Liu,Mykel Barrett,Zainalabedin Samadi,Amirhossein Zarezadeh,Yuka McGrath,Magdalena Zernicka-Goetz,Amjad Askary","doi":"10.1038/s41589-026-02168-3","DOIUrl":"https://doi.org/10.1038/s41589-026-02168-3","url":null,"abstract":"Intensity and duration of biological signals encode a few pathways to direct diverse cellular behaviors, yet quantifying these features in single cells remains difficult. To address this challenge, we developed INSCRIBE, which uses a CRISPR base editor to mutate genomic targets at rates proportional to signaling activity. Edits are recovered at the endpoint through a new ratiometric readout strategy from images of two fluorescence channels. We engineered human cells to record WNT and BMP activity. Following defined exogenous stimulations, INSCRIBE accurately recovered signal intensity in dose-response experiments and exposure duration in time-course experiments. Applying INSCRIBE revealed a persistent memory in the BMP pathway, where progeny of high-responding cells remained more sensitive to subsequent BMP stimulation for up to 3 weeks. Together, our results establish a scalable platform for genetic recording and in situ readout of signaling activity in single cells, advancing quantitative analysis of cell-cell communication during development and disease.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"232 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393901","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 : 2026-03-10DOI: 10.1038/s41589-026-02155-8
Hortense Mazon, Benjamin Selles, Sophie Rahuel-Clermont
Although long considered to be structured as oligomers comprising a single species, recent work highlights the ability of eukaryotic type 1 peroxiredoxin isoforms to assemble as heterodimers and heterodecamers in vivo. This key property redefines the current understanding of the biological scope of peroxiredoxins.
{"title":"Chimerization expands peroxiredoxin scope","authors":"Hortense Mazon, Benjamin Selles, Sophie Rahuel-Clermont","doi":"10.1038/s41589-026-02155-8","DOIUrl":"10.1038/s41589-026-02155-8","url":null,"abstract":"Although long considered to be structured as oligomers comprising a single species, recent work highlights the ability of eukaryotic type 1 peroxiredoxin isoforms to assemble as heterodimers and heterodecamers in vivo. This key property redefines the current understanding of the biological scope of peroxiredoxins.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 4","pages":"523-524"},"PeriodicalIF":13.7,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147434253","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 : 2026-03-10DOI: 10.1038/s41589-026-02164-7
J. Andrew N. Alexander, Shu-Yu Chen, Somnath Mukherjee, Mario de Capitani, Rossitza N. Irobalieva, Lorenzo Rossi, Parth Agrawal, Julia Kowal, Matheus A. Meirelles, Markus Aebi, Jean-Louis Reymond, Anthony A. Kossiakoff, Sereina Riniker, Kaspar P. Locher
Asparagine-linked glycans are essential for the maturation and function of most eukaryotic secretory proteins. The biosynthesis and transfer of dolichylpyrophosphate-anchored GlcNAc2Man9Glc3 glycan is a highly conserved process occurring in the endoplasmic reticulum (ER) membrane and involving over a dozen membrane proteins whose dysfunction is linked to congenital disorders of glycosylation (CDGs). Three membrane-integral mannosyltransferases, ALG3, ALG9 and ALG12, mediate four consecutive mannosylation reactions that convert GlcNAc2Man5 to GlcNAc2Man9. Here, using chemoenzymatically synthesized lipid-linked glycan donor and acceptor analogs, we recapitulated this biosynthetic pathway in vitro. High-resolution cryo-electron microscopy structures of pseudo-Michaelis complexes of each step revealed how the branched glycan is accurately synthesized and unwanted side products are averted. Molecular dynamics simulations and mutagenesis studies uncovered a subtle but precise mechanism selecting the dolichylphosphomannose donor substrate over dolichylphosphoglucose, which is also present in the ER membrane. Our results also provide mechanistic explanations for enzyme dysfunction in CDGs and offer opportunities for N-glycan engineering.
{"title":"Structures of ALG3/9/12 reveal the assembly logic of the N-glycan oligomannose core","authors":"J. Andrew N. Alexander, Shu-Yu Chen, Somnath Mukherjee, Mario de Capitani, Rossitza N. Irobalieva, Lorenzo Rossi, Parth Agrawal, Julia Kowal, Matheus A. Meirelles, Markus Aebi, Jean-Louis Reymond, Anthony A. Kossiakoff, Sereina Riniker, Kaspar P. Locher","doi":"10.1038/s41589-026-02164-7","DOIUrl":"https://doi.org/10.1038/s41589-026-02164-7","url":null,"abstract":"Asparagine-linked glycans are essential for the maturation and function of most eukaryotic secretory proteins. The biosynthesis and transfer of dolichylpyrophosphate-anchored GlcNAc2Man9Glc3 glycan is a highly conserved process occurring in the endoplasmic reticulum (ER) membrane and involving over a dozen membrane proteins whose dysfunction is linked to congenital disorders of glycosylation (CDGs). Three membrane-integral mannosyltransferases, ALG3, ALG9 and ALG12, mediate four consecutive mannosylation reactions that convert GlcNAc2Man5 to GlcNAc2Man9. Here, using chemoenzymatically synthesized lipid-linked glycan donor and acceptor analogs, we recapitulated this biosynthetic pathway in vitro. High-resolution cryo-electron microscopy structures of pseudo-Michaelis complexes of each step revealed how the branched glycan is accurately synthesized and unwanted side products are averted. Molecular dynamics simulations and mutagenesis studies uncovered a subtle but precise mechanism selecting the dolichylphosphomannose donor substrate over dolichylphosphoglucose, which is also present in the ER membrane. Our results also provide mechanistic explanations for enzyme dysfunction in CDGs and offer opportunities for N-glycan engineering.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"5 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381766","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 : 2026-03-10DOI: 10.1038/s41589-026-02157-6
Jannik Zimmermann, Lukas Lang, Julia Malo Pueyo, Mareike Riedel, Khadija Wahni, Dylan Stobbe, Laura Leiskau, Elham Aref, Christopher Lux, Steven Janvier, Didier Vertommen, Svenja Lenhard, Frank Hannemann, Sudharshini Thangamuragan, Helena Castro, Volkhard Helms, Ana Maria Tomas, Johannes M. Herrmann, Armindo Salvador, Timo Mühlhaus, Jan Riemer, Joris Messens, Marcel Deponte, Bruce Morgan
Peroxiredoxins are thiol peroxidases, which detoxify peroxides, relay redox signals and act as chaperones. In eukaryotes, multiple peroxiredoxin-1 (Prx1)/AhpC-type isoforms frequently co-exist in the same subcellular compartment, yet have been assumed to assemble only as homo-oligomeric complexes. Here we show that hetero-oligomerization is a conserved and functionally relevant property of Prx1/AhpC-type peroxiredoxins. Using biochemical reconstitution, native mass photometry, electron microscopy and live-cell assays, we demonstrate formation of heterodimers and heterodecamers, with diverse subunit stoichiometries, in peroxiredoxin pairs from different eukaryotic kingdoms. In Saccharomyces cerevisiae, oxidative challenge induces Tsa1–Tsa2 heterodecamerization with substoichiometric Tsa2 incorporation sufficing to stabilize the decameric state. Functional hetero-oligomers are also observed forming among human, plant and Leishmania peroxiredoxins. Our findings provide new insights into peroxiredoxin structural plasticity with broad implications for redox biology, stress responses and cellular adaptation, and also challenge the long-held paradigm of peroxiredoxin homo-oligomerization. Peroxiredoxins from diverse organisms were found to assemble into hybrid complexes, not just identical ones. These mixed assemblies reshape structure and stability, challenging a long-held view of peroxiredoxin assembly in cells.
{"title":"Hetero-oligomerization drives structural plasticity of eukaryotic peroxiredoxins","authors":"Jannik Zimmermann, Lukas Lang, Julia Malo Pueyo, Mareike Riedel, Khadija Wahni, Dylan Stobbe, Laura Leiskau, Elham Aref, Christopher Lux, Steven Janvier, Didier Vertommen, Svenja Lenhard, Frank Hannemann, Sudharshini Thangamuragan, Helena Castro, Volkhard Helms, Ana Maria Tomas, Johannes M. Herrmann, Armindo Salvador, Timo Mühlhaus, Jan Riemer, Joris Messens, Marcel Deponte, Bruce Morgan","doi":"10.1038/s41589-026-02157-6","DOIUrl":"10.1038/s41589-026-02157-6","url":null,"abstract":"Peroxiredoxins are thiol peroxidases, which detoxify peroxides, relay redox signals and act as chaperones. In eukaryotes, multiple peroxiredoxin-1 (Prx1)/AhpC-type isoforms frequently co-exist in the same subcellular compartment, yet have been assumed to assemble only as homo-oligomeric complexes. Here we show that hetero-oligomerization is a conserved and functionally relevant property of Prx1/AhpC-type peroxiredoxins. Using biochemical reconstitution, native mass photometry, electron microscopy and live-cell assays, we demonstrate formation of heterodimers and heterodecamers, with diverse subunit stoichiometries, in peroxiredoxin pairs from different eukaryotic kingdoms. In Saccharomyces cerevisiae, oxidative challenge induces Tsa1–Tsa2 heterodecamerization with substoichiometric Tsa2 incorporation sufficing to stabilize the decameric state. Functional hetero-oligomers are also observed forming among human, plant and Leishmania peroxiredoxins. Our findings provide new insights into peroxiredoxin structural plasticity with broad implications for redox biology, stress responses and cellular adaptation, and also challenge the long-held paradigm of peroxiredoxin homo-oligomerization. Peroxiredoxins from diverse organisms were found to assemble into hybrid complexes, not just identical ones. These mixed assemblies reshape structure and stability, challenging a long-held view of peroxiredoxin assembly in cells.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 4","pages":"580-592"},"PeriodicalIF":13.7,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41589-026-02157-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381765","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 : 2026-03-03DOI: 10.1038/s41589-026-02159-4
{"title":"Chemigenetic DNA nanotrap for the mapping of norepinephrine in subcellular organelles.","authors":"","doi":"10.1038/s41589-026-02159-4","DOIUrl":"https://doi.org/10.1038/s41589-026-02159-4","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"100 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346459","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 : 2026-03-02DOI: 10.1038/s41589-026-02166-5
Junfeng Ma,Chunyan Hou
{"title":"Cracking the code to O-GlcNAcylation networks.","authors":"Junfeng Ma,Chunyan Hou","doi":"10.1038/s41589-026-02166-5","DOIUrl":"https://doi.org/10.1038/s41589-026-02166-5","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"6 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147329354","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 : 2026-02-27DOI: 10.1038/s41589-026-02145-w
Kate S. Carroll, Jing Yang
Cysteine is one of the rarest amino acids yet exerts a profound influence on biology through the exceptional chemistry of its thiol group. Tunable acidity, high nucleophilicity and access to multiple oxidation states position cysteine as both a dominant cellular redox buffer and a privileged regulatory site. Chemoproteomics has revealed a vast, dynamic cysteine redoxome in which oxidative post-translational modifications act as sensors, switches and buffers across metabolism, signaling and stress responses, respectively. This study advances the following three frameworks: (1) separating intrinsic reactivity from redox sensitivity and regulatory function; (2) using probe chemistry to capture metastable intermediates with site-level precision; and (3) integrating ratiometric measurements with occupancy, exposure and flux to decode redox dynamics. Case studies show how ratiometric chemoproteomics resolves distinct oxoform kinetics, links enzymatic repair to function and exposes the cysteine redoxome as a dynamic regulatory layer and frontier for therapeutic targeting. This study provides a chemical framework of sulfur, defining the cysteine redoxome, linking thiol reactivity with oxoform kinetics/dynamics to proteome-wide mapping, occupancy and flux, and revealing cysteine oxidation as a programmable regulatory code.
{"title":"Defining and refining the cysteine redoxome through sulfur chemical biology","authors":"Kate S. Carroll, Jing Yang","doi":"10.1038/s41589-026-02145-w","DOIUrl":"10.1038/s41589-026-02145-w","url":null,"abstract":"Cysteine is one of the rarest amino acids yet exerts a profound influence on biology through the exceptional chemistry of its thiol group. Tunable acidity, high nucleophilicity and access to multiple oxidation states position cysteine as both a dominant cellular redox buffer and a privileged regulatory site. Chemoproteomics has revealed a vast, dynamic cysteine redoxome in which oxidative post-translational modifications act as sensors, switches and buffers across metabolism, signaling and stress responses, respectively. This study advances the following three frameworks: (1) separating intrinsic reactivity from redox sensitivity and regulatory function; (2) using probe chemistry to capture metastable intermediates with site-level precision; and (3) integrating ratiometric measurements with occupancy, exposure and flux to decode redox dynamics. Case studies show how ratiometric chemoproteomics resolves distinct oxoform kinetics, links enzymatic repair to function and exposes the cysteine redoxome as a dynamic regulatory layer and frontier for therapeutic targeting. This study provides a chemical framework of sulfur, defining the cysteine redoxome, linking thiol reactivity with oxoform kinetics/dynamics to proteome-wide mapping, occupancy and flux, and revealing cysteine oxidation as a programmable regulatory code.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 4","pages":"525-539"},"PeriodicalIF":13.7,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317802","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 : 2026-02-27DOI: 10.1038/s41589-026-02165-6
Yiwei Xiong, Dylan T Tomares, Jianjian Guo, Kazuki Sato, Longhui Zeng, Yuan Tian, Maohan Su, Ava Albis, Avnika Pant, Rohit V Pappu, Xiaolei Su
Biomolecular condensates are membraneless bodies that organize biochemical reactions typically within cells. However, the roles of condensates in extracellular space-where conditions differ substantially from intracellular space-remain poorly understood. Here we report that mast cell extracellular granules (MCEGs), a stable membraneless entity, are condensates assembled through electrostatic interactions between glycosaminoglycans and polyamines. Disrupting polyamine synthesis or trafficking blocks MCEG formation and compromises the storage of proteases and cytokines. Granules reconstituted with heparin and spermine are sufficient to enrich mediators such as carboxypeptidase A3 (CPA3) and tumor necrosis factor (TNF), maintaining an elevated pH and higher concentrations of calcium and zinc compared to the extracellular milieu. This unique environment enhances CPA3 enzymatic activity. Furthermore, the granules increase TNF binding and its bioactivity toward endothelial cells. Together, we reveal MCEGs as functionally active biomolecular condensates with distinct biochemical and immunological properties; MCEGs are formed through sugar-metabolite interactions, expanding the mechanisms of condensate assembly beyond classical protein-protein and protein-RNA interactions.
{"title":"Mast cell extracellular granules are bioactive condensates assembled by heparin and polyamine.","authors":"Yiwei Xiong, Dylan T Tomares, Jianjian Guo, Kazuki Sato, Longhui Zeng, Yuan Tian, Maohan Su, Ava Albis, Avnika Pant, Rohit V Pappu, Xiaolei Su","doi":"10.1038/s41589-026-02165-6","DOIUrl":"10.1038/s41589-026-02165-6","url":null,"abstract":"<p><p>Biomolecular condensates are membraneless bodies that organize biochemical reactions typically within cells. However, the roles of condensates in extracellular space-where conditions differ substantially from intracellular space-remain poorly understood. Here we report that mast cell extracellular granules (MCEGs), a stable membraneless entity, are condensates assembled through electrostatic interactions between glycosaminoglycans and polyamines. Disrupting polyamine synthesis or trafficking blocks MCEG formation and compromises the storage of proteases and cytokines. Granules reconstituted with heparin and spermine are sufficient to enrich mediators such as carboxypeptidase A3 (CPA3) and tumor necrosis factor (TNF), maintaining an elevated pH and higher concentrations of calcium and zinc compared to the extracellular milieu. This unique environment enhances CPA3 enzymatic activity. Furthermore, the granules increase TNF binding and its bioactivity toward endothelial cells. Together, we reveal MCEGs as functionally active biomolecular condensates with distinct biochemical and immunological properties; MCEGs are formed through sugar-metabolite interactions, expanding the mechanisms of condensate assembly beyond classical protein-protein and protein-RNA interactions.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13010460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317812","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 : 2026-02-26DOI: 10.1038/s41589-026-02162-9
Thomas A Laskarzewski, Thomas J Maresca
{"title":"Grip it and rip it.","authors":"Thomas A Laskarzewski, Thomas J Maresca","doi":"10.1038/s41589-026-02162-9","DOIUrl":"https://doi.org/10.1038/s41589-026-02162-9","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147308436","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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