Pub Date : 2026-01-27DOI: 10.1038/s41589-025-02122-9
Valerie Siahaan, Romana Weissova, Adela Karhanova, Eva Lanska, María J. Ruiz-Estrada, Barbora Pukajová, Vojtěch Dostál, Veronique Henriot, Carsten Janke, Lenka Libusová, Marcus Braun, Martin Balastik, Zdenek Lansky
Tau is an axonal microtubule-associated protein. Tau interaction with microtubules is regulated by phosphorylation. Hyperphosphorylation of tau is implicated in microtubule destabilization related to neurodegenerative disorders. However, how tau phosphorylation leads to microtubule destabilization is unknown. Recently, it was shown that tau molecules on microtubules cooperatively assemble into cohesive layers termed envelopes. Tau envelopes protect microtubules against degradation by microtubule-severing enzymes, suggesting a functional link between envelopes and microtubule stability. Here we show that tau phosphorylation has deleterious effects on the microtubule-protective function of tau envelopes. Using reconstitution and live-cell experiments, we found that tau phosphorylation destabilizes tau envelopes and decreases their integrity, leading to reduced microtubule protection against microtubule-severing enzymes. Our data suggest that a perturbation of microtubule homeostasis linked to tau hyperphosphorylation in neurodegeneration can be explained by the disassembly and impaired functionality of the tau envelopes.
{"title":"Tau phosphorylation impedes functionality of protective tau envelopes","authors":"Valerie Siahaan, Romana Weissova, Adela Karhanova, Eva Lanska, María J. Ruiz-Estrada, Barbora Pukajová, Vojtěch Dostál, Veronique Henriot, Carsten Janke, Lenka Libusová, Marcus Braun, Martin Balastik, Zdenek Lansky","doi":"10.1038/s41589-025-02122-9","DOIUrl":"https://doi.org/10.1038/s41589-025-02122-9","url":null,"abstract":"Tau is an axonal microtubule-associated protein. Tau interaction with microtubules is regulated by phosphorylation. Hyperphosphorylation of tau is implicated in microtubule destabilization related to neurodegenerative disorders. However, how tau phosphorylation leads to microtubule destabilization is unknown. Recently, it was shown that tau molecules on microtubules cooperatively assemble into cohesive layers termed envelopes. Tau envelopes protect microtubules against degradation by microtubule-severing enzymes, suggesting a functional link between envelopes and microtubule stability. Here we show that tau phosphorylation has deleterious effects on the microtubule-protective function of tau envelopes. Using reconstitution and live-cell experiments, we found that tau phosphorylation destabilizes tau envelopes and decreases their integrity, leading to reduced microtubule protection against microtubule-severing enzymes. Our data suggest that a perturbation of microtubule homeostasis linked to tau hyperphosphorylation in neurodegeneration can be explained by the disassembly and impaired functionality of the tau envelopes.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"42 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057259","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 : 2026-01-27DOI: 10.1038/s41589-026-02144-x
Katherine K Moran, Wilton T Snead
{"title":"Phases align at the membrane.","authors":"Katherine K Moran, Wilton T Snead","doi":"10.1038/s41589-026-02144-x","DOIUrl":"https://doi.org/10.1038/s41589-026-02144-x","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146065199","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 : 2026-01-26DOI: 10.1038/s41589-025-02136-3
Cyntia Taveneau, Her Xiang Chai, Jovita D’Silva, Rebecca S. Bamert, Honglin Chen, Brooke K. Hayes, Roland W. Calvert, Jacob Purcell, Daniel J. Curwen, Fabian Munder, Lisandra L. Martin, Jeremy J. Barr, Joseph Rosenbluh, Mohamed Fareh, Rhys Grinter, Gavin J. Knott
CRISPR–Cas systems are transformative tools for gene editing that can be tuned or controlled by anti-CRISPRs (Acrs)—phage-derived inhibitors that regulate CRISPR–Cas activity. However, Acrs that can inhibit biotechnologically relevant CRISPR systems are relatively rare and challenging to discover. To overcome this limitation, we describe a highly successful and rapid approach that leverages de novo protein design to develop new-to-nature proteins for controlling CRISPR–Cas activity. Here, using Leptotrichiabuccalis CRISPR–Cas13a as a representative example, we demonstrate that Acrs designed using artificial intelligence (AIcrs) are capable of highly potent and specific inhibition of CRISPR–Cas13a nuclease activity. We present a comprehensive workflow for design validation and demonstrate AIcr functionality in controlling CRISPR–Cas13 activity in bacterial and human cells. The ability to design bespoke inhibitors of Cas effectors will contribute to the ongoing development of CRISPR–Cas tools in diverse applications across research, medicine, agriculture and microbiology.
{"title":"De novo design of potent CRISPR–Cas13 inhibitors","authors":"Cyntia Taveneau, Her Xiang Chai, Jovita D’Silva, Rebecca S. Bamert, Honglin Chen, Brooke K. Hayes, Roland W. Calvert, Jacob Purcell, Daniel J. Curwen, Fabian Munder, Lisandra L. Martin, Jeremy J. Barr, Joseph Rosenbluh, Mohamed Fareh, Rhys Grinter, Gavin J. Knott","doi":"10.1038/s41589-025-02136-3","DOIUrl":"https://doi.org/10.1038/s41589-025-02136-3","url":null,"abstract":"CRISPR–Cas systems are transformative tools for gene editing that can be tuned or controlled by anti-CRISPRs (Acrs)—phage-derived inhibitors that regulate CRISPR–Cas activity. However, Acrs that can inhibit biotechnologically relevant CRISPR systems are relatively rare and challenging to discover. To overcome this limitation, we describe a highly successful and rapid approach that leverages de novo protein design to develop new-to-nature proteins for controlling CRISPR–Cas activity. Here, using <jats:italic>Leptotrichia</jats:italic> <jats:italic>buccalis</jats:italic> CRISPR–Cas13a as a representative example, we demonstrate that Acrs designed using artificial intelligence (AIcrs) are capable of highly potent and specific inhibition of CRISPR–Cas13a nuclease activity. We present a comprehensive workflow for design validation and demonstrate AIcr functionality in controlling CRISPR–Cas13 activity in bacterial and human cells. The ability to design bespoke inhibitors of Cas effectors will contribute to the ongoing development of CRISPR–Cas tools in diverse applications across research, medicine, agriculture and microbiology.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"274 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048303","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 : 2026-01-22DOI: 10.1038/s41589-025-02096-8
Indigo C Geohring, Pengxin Chai, Bharat R Iyer, William D Ton, Jun Yang, Amy H Ide, Sydney C George, Jaiveer S Bagri, Samuel V Baird, Kai Zhang, Steven M Markus
Dynein-1 is a microtubule motor that transports numerous cytoplasmic cargoes. Activation of motility requires it first overcome an autoinhibited state before its assembly with dynactin and a cargo adaptor. Studies suggest that Lis1 may relieve dynein's autoinhibited state, although evidence for this is lacking. We first determined the rules governing dynein-Lis1 binding, revealing that their binding affinity is regulated by the nucleotide-bound states of each of three nucleotide-binding pockets within dynein. We also found that distinct nucleotide 'codes' coordinate their binding stoichiometry by impacting binding affinity at two different sites within the dynein motor domain. Electron microscopy revealed that a 1 dynein:1 Lis1 complex directly promotes an uninhibited conformational state of dynein, whereas a 1:2 complex resembles the autoinhibited state. Cryo-electron microscopy revealed that the structural basis for Lis1 opening dynein relies on interactions with the linker domain. Our work reveals the biochemical basis by which Lis1 relieves dynein autoinhibition.
{"title":"A nucleotide code governs Lis1's ability to relieve dynein autoinhibition.","authors":"Indigo C Geohring, Pengxin Chai, Bharat R Iyer, William D Ton, Jun Yang, Amy H Ide, Sydney C George, Jaiveer S Bagri, Samuel V Baird, Kai Zhang, Steven M Markus","doi":"10.1038/s41589-025-02096-8","DOIUrl":"10.1038/s41589-025-02096-8","url":null,"abstract":"<p><p>Dynein-1 is a microtubule motor that transports numerous cytoplasmic cargoes. Activation of motility requires it first overcome an autoinhibited state before its assembly with dynactin and a cargo adaptor. Studies suggest that Lis1 may relieve dynein's autoinhibited state, although evidence for this is lacking. We first determined the rules governing dynein-Lis1 binding, revealing that their binding affinity is regulated by the nucleotide-bound states of each of three nucleotide-binding pockets within dynein. We also found that distinct nucleotide 'codes' coordinate their binding stoichiometry by impacting binding affinity at two different sites within the dynein motor domain. Electron microscopy revealed that a 1 dynein:1 Lis1 complex directly promotes an uninhibited conformational state of dynein, whereas a 1:2 complex resembles the autoinhibited state. Cryo-electron microscopy revealed that the structural basis for Lis1 opening dynein relies on interactions with the linker domain. Our work reveals the biochemical basis by which Lis1 relieves dynein autoinhibition.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030312","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}
Thymine DNA glycosylase (TDG) is a multifaceted protein involved in base-excision repair, DNA demethylation and transcriptional regulation, with key roles in embryonic development and tumorigenesis. However, the mechanisms underlying its role in cancer progression and the therapeutic applications targeting TDG remain largely unknown. Here we demonstrate that targeting TDG induces synthetic lethality in p53-deficient cancers. We developed C-271, a first-in-class, small-molecule inhibitor that covalently binds to TDG, disrupting its DNA-binding capability. C-271 exhibits potent therapeutic efficacy in suppressing p53-deficient tumors. Mechanistically, TDG and p53 redundantly promote the transcription of DHX9, an RNA helicase that resolves double-stranded RNA (dsRNA). TDG inhibition in p53-deficient cancer cells leads to DHX9 downregulation and, thus, aberrant dsRNA accumulation, which activates the RIG-I/MDA5-MAVS sensing pathway, resulting in tumor suppression and enhanced antitumor immunity. These findings highlight the synthetic lethality between TDG and p53, positioning TDG inhibition as a promising therapeutic strategy for p53-deficient cancers.
{"title":"Targeting thymine DNA glycosylase induces synthetic lethality in p53-deficient cancers.","authors":"Jia-Xin Zhou,Zhen-Yu Shao,Lin Zhang,Jian-Nan Guo,Meng Wang,Qin Xu,Yi-Qin Wang,Qing Xu,Dan Zhou,Sheng-Xiang Ren,Yan-Hao Yu,Zhi-Hao Lu,Guo-Zheng Pang,Yao Cao,Yi-Lin Liu,Bin Zhou,Hong-Bin Ji,Yi-Han Chen,Hai-Ping Wu,Guo-Liang Xu,Liang Zhang,Ya-Rui Du","doi":"10.1038/s41589-025-02100-1","DOIUrl":"https://doi.org/10.1038/s41589-025-02100-1","url":null,"abstract":"Thymine DNA glycosylase (TDG) is a multifaceted protein involved in base-excision repair, DNA demethylation and transcriptional regulation, with key roles in embryonic development and tumorigenesis. However, the mechanisms underlying its role in cancer progression and the therapeutic applications targeting TDG remain largely unknown. Here we demonstrate that targeting TDG induces synthetic lethality in p53-deficient cancers. We developed C-271, a first-in-class, small-molecule inhibitor that covalently binds to TDG, disrupting its DNA-binding capability. C-271 exhibits potent therapeutic efficacy in suppressing p53-deficient tumors. Mechanistically, TDG and p53 redundantly promote the transcription of DHX9, an RNA helicase that resolves double-stranded RNA (dsRNA). TDG inhibition in p53-deficient cancer cells leads to DHX9 downregulation and, thus, aberrant dsRNA accumulation, which activates the RIG-I/MDA5-MAVS sensing pathway, resulting in tumor suppression and enhanced antitumor immunity. These findings highlight the synthetic lethality between TDG and p53, positioning TDG inhibition as a promising therapeutic strategy for p53-deficient cancers.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"67 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021696","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 : 2026-01-22DOI: 10.1038/s41589-025-02101-0
Simon D Schwarz
{"title":"Targeting transcriptional plasticity in cancer.","authors":"Simon D Schwarz","doi":"10.1038/s41589-025-02101-0","DOIUrl":"https://doi.org/10.1038/s41589-025-02101-0","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030294","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 : 2026-01-20DOI: 10.1038/s41589-025-02113-w
Zhen Li,Himanshi Chawla,Lucia Di Vagno,Aisling Ní Cheallaigh,Meg Critcher,Douglas Sammon,Edgar Gonzalez-Rodriguez,David C Briggs,Nara Chung,Vincent Chang,Keira E Mahoney,Anna Cioce,Ganka Bineva-Todd,Pei-Ying Wang,Yi-Chang Liu,Lloyd D Murphy,Yen-Hsi Chen,Yoshiki Narimatsu,Rebecca L Miller,Lianne I Willems,Stacy A Malaker,Mia L Huang,Gavin J Miller,Erhard Hohenester,Benjamin Schumann
Mammalian cells receive signaling instructions through interactions on their surfaces. Proteoglycans are critical to these interactions, carrying long glycosaminoglycans that recruit signaling molecules. Biosynthetic redundancy in the first glycosylation step by two xylosyltransferases XT1/2 complicates annotation of proteoglycans. Here we develop a chemical genetic strategy that manipulates the glycan attachment site of cellular proteoglycans. Through a bump-and-hole tactic, we engineer the two isoenzymes XT1 and XT2 to specifically transfer the chemically tagged xylose analog 6AzGlc to target proteins. The tag contains a bioorthogonal functionality, allowing to visualize and profile target proteins in mammalian cells. Unlike xylose analogs, 6AzGlc is amenable to cellular nucleotide-sugar biosynthesis, establishing the XT1/2 bump-and-hole tactic in cells. The approach allows pinpointing glycosylation sites by mass spectrometry and exploiting the chemical handle to manufacture proteoglycans with defined glycosaminoglycan chains for cellular applications. Engineered XT enzymes permit an orthogonal view into proteoglycan biology through conventional techniques in biochemistry.
{"title":"Xylosyltransferase engineering to manipulate proteoglycans in mammalian cells.","authors":"Zhen Li,Himanshi Chawla,Lucia Di Vagno,Aisling Ní Cheallaigh,Meg Critcher,Douglas Sammon,Edgar Gonzalez-Rodriguez,David C Briggs,Nara Chung,Vincent Chang,Keira E Mahoney,Anna Cioce,Ganka Bineva-Todd,Pei-Ying Wang,Yi-Chang Liu,Lloyd D Murphy,Yen-Hsi Chen,Yoshiki Narimatsu,Rebecca L Miller,Lianne I Willems,Stacy A Malaker,Mia L Huang,Gavin J Miller,Erhard Hohenester,Benjamin Schumann","doi":"10.1038/s41589-025-02113-w","DOIUrl":"https://doi.org/10.1038/s41589-025-02113-w","url":null,"abstract":"Mammalian cells receive signaling instructions through interactions on their surfaces. Proteoglycans are critical to these interactions, carrying long glycosaminoglycans that recruit signaling molecules. Biosynthetic redundancy in the first glycosylation step by two xylosyltransferases XT1/2 complicates annotation of proteoglycans. Here we develop a chemical genetic strategy that manipulates the glycan attachment site of cellular proteoglycans. Through a bump-and-hole tactic, we engineer the two isoenzymes XT1 and XT2 to specifically transfer the chemically tagged xylose analog 6AzGlc to target proteins. The tag contains a bioorthogonal functionality, allowing to visualize and profile target proteins in mammalian cells. Unlike xylose analogs, 6AzGlc is amenable to cellular nucleotide-sugar biosynthesis, establishing the XT1/2 bump-and-hole tactic in cells. The approach allows pinpointing glycosylation sites by mass spectrometry and exploiting the chemical handle to manufacture proteoglycans with defined glycosaminoglycan chains for cellular applications. Engineered XT enzymes permit an orthogonal view into proteoglycan biology through conventional techniques in biochemistry.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"59 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005477","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 : 2026-01-19DOI: 10.1038/s41589-025-02129-2
Kiroo Shin, Da Bean Han, Hyun Woo Kim, Jungwook Kim
Modifications at the wobble position of transfer RNA (tRNA) are critical for accurate codon recognition and efficient translation. 5-Hydroxyuridine serves as a key intermediate for more complex wobble uridine derivatives commonly found in bacterial tRNAs and is synthesized by either prephenate-dependent TrhP or dioxygen-dependent TrhO. Despite its biological importance, structural and mechanistic insights into these enzymes have remained elusive. Here, we report the cryo-electron microscopy structure of Bacillus subtilis TrhO-tRNAAla complex. Combined with biochemical analyses, our results reveal that TrhO functions without any metal or organic cofactor, unlike most other oxygenases. We propose that the conserved C179 reacts with dioxygen to form a thiohydroperoxy intermediate, which is cleaved to produce 5-hydroxyuridine and a sulfenic acid at C179. The oxidized cysteine subsequently forms a disulfide bond with the adjacent C185, protecting the catalytic cysteine from irreversible overoxidation. These findings broaden our understanding of cofactor-independent dioxygen use in aromatic ring hydroxylation.
{"title":"Unconventional monooxygenation by the O<sub>2</sub>-dependent tRNA wobble uridine hydroxylase TrhO.","authors":"Kiroo Shin, Da Bean Han, Hyun Woo Kim, Jungwook Kim","doi":"10.1038/s41589-025-02129-2","DOIUrl":"https://doi.org/10.1038/s41589-025-02129-2","url":null,"abstract":"<p><p>Modifications at the wobble position of transfer RNA (tRNA) are critical for accurate codon recognition and efficient translation. 5-Hydroxyuridine serves as a key intermediate for more complex wobble uridine derivatives commonly found in bacterial tRNAs and is synthesized by either prephenate-dependent TrhP or dioxygen-dependent TrhO. Despite its biological importance, structural and mechanistic insights into these enzymes have remained elusive. Here, we report the cryo-electron microscopy structure of Bacillus subtilis TrhO-tRNA<sup>Ala</sup> complex. Combined with biochemical analyses, our results reveal that TrhO functions without any metal or organic cofactor, unlike most other oxygenases. We propose that the conserved C179 reacts with dioxygen to form a thiohydroperoxy intermediate, which is cleaved to produce 5-hydroxyuridine and a sulfenic acid at C179. The oxidized cysteine subsequently forms a disulfide bond with the adjacent C185, protecting the catalytic cysteine from irreversible overoxidation. These findings broaden our understanding of cofactor-independent dioxygen use in aromatic ring hydroxylation.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003794","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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