Pub Date : 2026-02-11DOI: 10.1038/s41467-026-69543-5
Josep Bonsoms, Sergi González-Herrero, Xavier Fettweis, Marc Lemus-Cánovas, Marc Oliva, Juan I. López-Moreno
The Greenland Ice Sheet (GrIS) has experienced a strong intensification of summer surface melting, with extreme events becoming more frequent, extensive, and severe. Despite its importance for global sea-level rise, the mechanisms driving these extremes remain incompletely understood. We analyze extreme melting events over 1950–2023 using an analog-based framework combined with a regional climate model to disentangle thermodynamic and dynamic contributions. Thermodynamic processes intensify meltwater production by 25% relative to 1950–1975 when circulation analog events are included, increasing to 63% when circulation-analog events are included, with the strongest increases in northern Greenland. Seven of the ten most extreme events occurred after 2000, with meltwater anomalies reaching up to three times their synoptic average. Record-breaking events such as August 2012, July 2019, and July 2021 show no dynamic precedents. Future projections under high-emission scenarios suggest that extreme meltwater anomalies could increase by up to +372% by 2100 (SSP5-8.5, CMIP6), highlighting the profound impact of climate change on GrIS melt extremes.
{"title":"Record-breaking Greenland ice sheet melt events under recent and future climate","authors":"Josep Bonsoms, Sergi González-Herrero, Xavier Fettweis, Marc Lemus-Cánovas, Marc Oliva, Juan I. López-Moreno","doi":"10.1038/s41467-026-69543-5","DOIUrl":"https://doi.org/10.1038/s41467-026-69543-5","url":null,"abstract":"The Greenland Ice Sheet (GrIS) has experienced a strong intensification of summer surface melting, with extreme events becoming more frequent, extensive, and severe. Despite its importance for global sea-level rise, the mechanisms driving these extremes remain incompletely understood. We analyze extreme melting events over 1950–2023 using an analog-based framework combined with a regional climate model to disentangle thermodynamic and dynamic contributions. Thermodynamic processes intensify meltwater production by 25% relative to 1950–1975 when circulation analog events are included, increasing to 63% when circulation-analog events are included, with the strongest increases in northern Greenland. Seven of the ten most extreme events occurred after 2000, with meltwater anomalies reaching up to three times their synoptic average. Record-breaking events such as August 2012, July 2019, and July 2021 show no dynamic precedents. Future projections under high-emission scenarios suggest that extreme meltwater anomalies could increase by up to +372% by 2100 (SSP5-8.5, CMIP6), highlighting the profound impact of climate change on GrIS melt extremes.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"88 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-11DOI: 10.1038/s41467-026-69422-z
Sujit Suklabaidya, Suchitra Mohanty, Irene E. Reider, Jesse White, Dominic Colter, Sarah M. McCormick, Noula Shembade, Young Bong Choi, Christopher C. Norbury, Edward W. Harhaj
The cGAS-STING pathway is a critical regulator of type I Interferon (IFN) and inflammation upon cytosolic DNA-sensing. cGAS-STING signaling termination is regulated by lysosomal-mediated degradation of STING; however, the mechanisms controlling the inhibitory targeting of STING are incompletely understood. Here, we identify the selective autophagy receptor TAX1BP1 as a negative regulator of the cGAS-STING pathway. TAX1BP1-deficient macrophages activated by cGAS or STING agonists accumulate higher-order STING aggregates, exhibit heightened STING signaling, and increased production of type I IFN and proinflammatory cytokines. Mechanistically, TAX1BP1 promotes STING degradation through microautophagy by facilitating the interaction of STING with the ESCRT-0 protein HGS. Furthermore, STING activation is associated with the swelling and fragmentation of the Golgi apparatus, and TAX1BP1 and p62/SQSTM1 are essential for the autophagic degradation of fragmented Golgi (Golgiphagy). Our findings suggest that STING activation at the Golgi is coupled to its downregulation by Golgiphagy to restrict innate immune responses.
{"title":"Negative feedback regulation of STING signaling by TAX1BP1-directed Golgiphagy","authors":"Sujit Suklabaidya, Suchitra Mohanty, Irene E. Reider, Jesse White, Dominic Colter, Sarah M. McCormick, Noula Shembade, Young Bong Choi, Christopher C. Norbury, Edward W. Harhaj","doi":"10.1038/s41467-026-69422-z","DOIUrl":"https://doi.org/10.1038/s41467-026-69422-z","url":null,"abstract":"The cGAS-STING pathway is a critical regulator of type I Interferon (IFN) and inflammation upon cytosolic DNA-sensing. cGAS-STING signaling termination is regulated by lysosomal-mediated degradation of STING; however, the mechanisms controlling the inhibitory targeting of STING are incompletely understood. Here, we identify the selective autophagy receptor TAX1BP1 as a negative regulator of the cGAS-STING pathway. TAX1BP1-deficient macrophages activated by cGAS or STING agonists accumulate higher-order STING aggregates, exhibit heightened STING signaling, and increased production of type I IFN and proinflammatory cytokines. Mechanistically, TAX1BP1 promotes STING degradation through microautophagy by facilitating the interaction of STING with the ESCRT-0 protein HGS. Furthermore, STING activation is associated with the swelling and fragmentation of the Golgi apparatus, and TAX1BP1 and p62/SQSTM1 are essential for the autophagic degradation of fragmented Golgi (Golgiphagy). Our findings suggest that STING activation at the Golgi is coupled to its downregulation by Golgiphagy to restrict innate immune responses.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"3 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-11DOI: 10.1038/s41467-026-69418-9
Linling He, Yi-Zong Lee, Yi-Nan Zhang, Maddy L. Newby, Benjamin M. Janus, Fabrizio G. Gonzalez, Garrett Ward, Connor DesRoberts, Shr-Hau Hung, Erick Giang, Joel D. Allen, Liudmila Kulakova, Eric A. Toth, Thomas R. Fuerst, Mansun Law, Gilad Ofek, Max Crispin, Jiang Zhu
Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. Development of an E1E2-based HCV vaccine has been hindered by the difficulty of producing a soluble E1E2 (sE1E2) antigen that faithfully recapitulates the native virion-associated heterodimer. Guided by cryo-electron microscopy (cryo-EM) structures, we engineer genotype 1a H77 sE1E2 by truncating the E1 and E2 stems (Cut1), deleting a putative fusion peptide–containing region in E1 (Cut2), and stabilizing the heterodimer using diverse scaffolds. All H77 sE1E2.Cut1+2 scaffolds exhibit native-like E1–E2 association and strong binding to the broadly neutralizing antibody (bNAb) AR4A. A genotype 1a HCV-1 sE1E2.Cut1+2 variant scaffolded by a modified SpyTag/SpyCatcher (SPYΔN) is selected for in vitro and in vivo characterization, as well as further construct refinement. The structure of this HCV-1 sE1E2 construct in complex with bNAbs is determined by cryo-EM and negative-stain EM (nsEM), with an nsEM-based strategy established for antibody epitope mapping. HCV-1 sE1E2.Cut1+2.SPYΔN is displayed on self-assembling protein nanoparticles (SApNPs) to enhance immunogenicity. The HCV-1 sE1E2.Cut1+2.SPYΔN heterodimer and SApNPs bearing wildtype or modified glycans are evaluated in mice, alongside E2 core-based immunogens for comparison. Together, these results establish a framework for advancing E1E2-based HCV vaccines toward clinical development.
{"title":"Native-like soluble E1E2 glycoprotein heterodimers on self-assembling protein nanoparticles for hepatitis C virus vaccine design","authors":"Linling He, Yi-Zong Lee, Yi-Nan Zhang, Maddy L. Newby, Benjamin M. Janus, Fabrizio G. Gonzalez, Garrett Ward, Connor DesRoberts, Shr-Hau Hung, Erick Giang, Joel D. Allen, Liudmila Kulakova, Eric A. Toth, Thomas R. Fuerst, Mansun Law, Gilad Ofek, Max Crispin, Jiang Zhu","doi":"10.1038/s41467-026-69418-9","DOIUrl":"https://doi.org/10.1038/s41467-026-69418-9","url":null,"abstract":"Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. Development of an E1E2-based HCV vaccine has been hindered by the difficulty of producing a soluble E1E2 (sE1E2) antigen that faithfully recapitulates the native virion-associated heterodimer. Guided by cryo-electron microscopy (cryo-EM) structures, we engineer genotype 1a H77 sE1E2 by truncating the E1 and E2 stems (Cut1), deleting a putative fusion peptide–containing region in E1 (Cut2), and stabilizing the heterodimer using diverse scaffolds. All H77 sE1E2.Cut1+2 scaffolds exhibit native-like E1–E2 association and strong binding to the broadly neutralizing antibody (bNAb) AR4A. A genotype 1a HCV-1 sE1E2.Cut1+2 variant scaffolded by a modified SpyTag/SpyCatcher (SPYΔN) is selected for in vitro and in vivo characterization, as well as further construct refinement. The structure of this HCV-1 sE1E2 construct in complex with bNAbs is determined by cryo-EM and negative-stain EM (nsEM), with an nsEM-based strategy established for antibody epitope mapping. HCV-1 sE1E2.Cut1+2.SPYΔN is displayed on self-assembling protein nanoparticles (SApNPs) to enhance immunogenicity. The HCV-1 sE1E2.Cut1+2.SPYΔN heterodimer and SApNPs bearing wildtype or modified glycans are evaluated in mice, alongside E2 core-based immunogens for comparison. Together, these results establish a framework for advancing E1E2-based HCV vaccines toward clinical development.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"51 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Optically active defects in hexagonal boron nitride (hBN) have become amongst the most attractive single-photon emitters in the solid state, owing to their high-quality photophysical properties, combined with the unlimited possibilities of integration offered by the host van der Waals material. In particular, the B centres, with their narrow linewidth, low wavelength spread and controllable positioning, have raised a particular interest for integrated quantum photonics. However, to date, either their excitation or their detection has been performed non-resonantly due to the difficulty of rejecting the backreflected laser light at the same wavelength, thereby preventing to take full benefit from their high coherence in quantum protocols. Here, we make use of narrow-linewidth emitters integrated in a hybrid metal-dielectric structure to implement cross-polarisation laser rejection. This allows us to observe resonantly scattered photons, with associated experimental signatures of optical coherence in both continuous-wave (cw) and pulsed regimes, respectively the Mollow triplet and Hong-Ou-Mandel interference from zero-phonon-line emission. The two-photon interference visibilities of (0.9{3}_{-0.21}^{+0.07}) and (0.9{2}_{-0.26}^{+0.08}) we measured for two emitters demonstrate the potential of B centres in hBN for applications to integrated quantum information.
{"title":"Resonance fluorescence and indistinguishable photons from a coherently driven B centre in hBN","authors":"Domitille Gérard, Stéphanie Buil, Kenji Watanabe, Takashi Taniguchi, Jean-Pierre Hermier, Aymeric Delteil","doi":"10.1038/s41467-026-68555-5","DOIUrl":"https://doi.org/10.1038/s41467-026-68555-5","url":null,"abstract":"Optically active defects in hexagonal boron nitride (hBN) have become amongst the most attractive single-photon emitters in the solid state, owing to their high-quality photophysical properties, combined with the unlimited possibilities of integration offered by the host van der Waals material. In particular, the B centres, with their narrow linewidth, low wavelength spread and controllable positioning, have raised a particular interest for integrated quantum photonics. However, to date, either their excitation or their detection has been performed non-resonantly due to the difficulty of rejecting the backreflected laser light at the same wavelength, thereby preventing to take full benefit from their high coherence in quantum protocols. Here, we make use of narrow-linewidth emitters integrated in a hybrid metal-dielectric structure to implement cross-polarisation laser rejection. This allows us to observe resonantly scattered photons, with associated experimental signatures of optical coherence in both continuous-wave (cw) and pulsed regimes, respectively the Mollow triplet and Hong-Ou-Mandel interference from zero-phonon-line emission. The two-photon interference visibilities of (0.9{3}_{-0.21}^{+0.07}) and (0.9{2}_{-0.26}^{+0.08}) we measured for two emitters demonstrate the potential of B centres in hBN for applications to integrated quantum information.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"11 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-11DOI: 10.1038/s41467-026-69431-y
Wen-Ting Wu, Chun-Yun Deng, Zhi-Yuan Zhang, Yue-Yi Zhang, Kun Liu, Yanli Zhao, Chunju Li
Realizing reliable medicine anticounterfeiting with safe and robust materials remains a challenge. We address this issue by preparing a class of edible phosphorescent supramolecules (VB10@α/β-CDs) based on easily available α/β-cyclodextrins (α/β-CDs) and vitamin B10 (VB10). Concisely grinding them with water or co-crystallization from aqueous solution, the resulting host−guest complexes VB10@α/β-CDs exhibit a long phosphorescence lifetime of up to 1.16 s and a high photoluminescent quantum yield of up to 86.5%, The encapsulation of α/β-CDs reverses the energy ordering of VB10’s excited singlet states, promotes the formation of the minimum energy crossing point (MECP) between singlet state and triplet state, and therefore boosts phosphorescence. VB10@α/β-CDs are attractive as phosphorescent inks for in-medicine anticounterfeiting because of the advantages of an edible nature, good moisture robustness, room-temperature phosphorescence and circularly polarized luminescence. Therefore, the present phosphorescent supramolecules as well as the elucidated MECP-involved mechanism would promote in-depth understanding of phosphorescence enhancement strategy.
{"title":"Phosphorescent supramolecular systems for medicine anticounterfeiting","authors":"Wen-Ting Wu, Chun-Yun Deng, Zhi-Yuan Zhang, Yue-Yi Zhang, Kun Liu, Yanli Zhao, Chunju Li","doi":"10.1038/s41467-026-69431-y","DOIUrl":"https://doi.org/10.1038/s41467-026-69431-y","url":null,"abstract":"Realizing reliable medicine anticounterfeiting with safe and robust materials remains a challenge. We address this issue by preparing a class of edible phosphorescent supramolecules (VB10@α/β-CDs) based on easily available α/β-cyclodextrins (α/β-CDs) and vitamin B10 (VB10). Concisely grinding them with water or co-crystallization from aqueous solution, the resulting host−guest complexes VB10@α/β-CDs exhibit a long phosphorescence lifetime of up to 1.16 s and a high photoluminescent quantum yield of up to 86.5%, The encapsulation of α/β-CDs reverses the energy ordering of VB10’s excited singlet states, promotes the formation of the minimum energy crossing point (MECP) between singlet state and triplet state, and therefore boosts phosphorescence. VB10@α/β-CDs are attractive as phosphorescent inks for in-medicine anticounterfeiting because of the advantages of an edible nature, good moisture robustness, room-temperature phosphorescence and circularly polarized luminescence. Therefore, the present phosphorescent supramolecules as well as the elucidated MECP-involved mechanism would promote in-depth understanding of phosphorescence enhancement strategy.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"43 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Circularly polarized luminescence is crucial for optoelectronics, bioimaging, and three-dimensional display, yet most of current materials suffer from complex synthesis and limited tunability. Herein, we show the regulation of chiroptical properties in metal halides through mechanochemical engineering. Specifically, phosphorescent indium-based chiral metal halides exhibit blue circularly polarized luminescence, along with antimony-doped indium-based metal halides emit orange circularly polarized luminescence. A grinding strategy using bromide salts like potassium bromide induces bright yellow fluorescence and enables versatile circularly polarized luminescence modulation. When antimony-doped indium-based metal halides are ground with five different bromide salts, it exhibits intriguing and tunable properties: (i) enhanced circularly polarized luminescence, with a luminescence dissymmetry factor value up to 10⁻²; (ii) inversion of the circularly polarized luminescence signal; (iii) generation of near-infrared circularly polarized luminescence with a substantial Stokes shift of 370 nm; and most notably, (iv) a 29.71-fold improvement in second-harmonic generation efficiency. This approach also realizes applications in circularly polarized light-emitting diodes.
{"title":"Mechanochemical engineering of chiroptical properties in indium-based chiral metal halides by grinding","authors":"Junhong Wu, Hao Li, Jialu Wang, Xiaorui Yang, Tianyong Zhang, Bin Li, Shuang Jiang","doi":"10.1038/s41467-026-69353-9","DOIUrl":"https://doi.org/10.1038/s41467-026-69353-9","url":null,"abstract":"Circularly polarized luminescence is crucial for optoelectronics, bioimaging, and three-dimensional display, yet most of current materials suffer from complex synthesis and limited tunability. Herein, we show the regulation of chiroptical properties in metal halides through mechanochemical engineering. Specifically, phosphorescent indium-based chiral metal halides exhibit blue circularly polarized luminescence, along with antimony-doped indium-based metal halides emit orange circularly polarized luminescence. A grinding strategy using bromide salts like potassium bromide induces bright yellow fluorescence and enables versatile circularly polarized luminescence modulation. When antimony-doped indium-based metal halides are ground with five different bromide salts, it exhibits intriguing and tunable properties: (i) enhanced circularly polarized luminescence, with a luminescence dissymmetry factor value up to 10⁻²; (ii) inversion of the circularly polarized luminescence signal; (iii) generation of near-infrared circularly polarized luminescence with a substantial Stokes shift of 370 nm; and most notably, (iv) a 29.71-fold improvement in second-harmonic generation efficiency. This approach also realizes applications in circularly polarized light-emitting diodes.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"82 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-11DOI: 10.1038/s41467-026-69464-3
Ricardo I. Rodríguez, Julien Paut, Giona Armellin, Stefano Visentini, Gabriel Cormier, Federico Droghetti, Mirco Natali, Marco Bortolus, Giorgio Pelosi, Luca Dell’ Amico
The activation of amines into thiocarbamoyl fluorides (TCarbFs) provides access to valuable nitrogen-based functionalities. However, their broader use has been hindered by the reliance on harsh reagents and conditions. Here we report a photochemical method for in situ generation of thiocarbonyl difluoride (TCF) from N-trifluoromethylthiophthalimide (Phth–SCF₃) using visible light and organic reductants. This strategy allows the synthesis of structurally complex azetidines from strained azabicyclo[1.1.0]butanes (ABBs). TCF-mediated ring opening followed by semipinacol rearrangement or nucleophilic additions enables direct access to spiro- and fluorinated TCarbF-azetidines in a single step. Mechanistic studies support a single-electron reduction pathway and rationalize the impact of the photocatalyst on the observed selectivity. The discovery offers a general platform for amine activation and addresses a long-standing gap in azetidine functionalization.
{"title":"Photochemical thiocarbonyl difluoride generation enables azetidine synthesis","authors":"Ricardo I. Rodríguez, Julien Paut, Giona Armellin, Stefano Visentini, Gabriel Cormier, Federico Droghetti, Mirco Natali, Marco Bortolus, Giorgio Pelosi, Luca Dell’ Amico","doi":"10.1038/s41467-026-69464-3","DOIUrl":"https://doi.org/10.1038/s41467-026-69464-3","url":null,"abstract":"The activation of amines into thiocarbamoyl fluorides (TCarbFs) provides access to valuable nitrogen-based functionalities. However, their broader use has been hindered by the reliance on harsh reagents and conditions. Here we report a photochemical method for in situ generation of thiocarbonyl difluoride (TCF) from N-trifluoromethylthiophthalimide (Phth–SCF₃) using visible light and organic reductants. This strategy allows the synthesis of structurally complex azetidines from strained azabicyclo[1.1.0]butanes (ABBs). TCF-mediated ring opening followed by semipinacol rearrangement or nucleophilic additions enables direct access to spiro- and fluorinated TCarbF-azetidines in a single step. Mechanistic studies support a single-electron reduction pathway and rationalize the impact of the photocatalyst on the observed selectivity. The discovery offers a general platform for amine activation and addresses a long-standing gap in azetidine functionalization.","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"47 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-11DOI: 10.1038/s41586-026-10129-y
Huigang Shi, Xiaorong Wang, Clinton Yu, Haibin Mao, Fenglong Jiao, Merav Braitbard, Ben Shor, Zhongsheng Zhang, Thomas R. Hinds, Shiyun Cao, Erkang Fan, Dina Schneidman-Duhovny, Lan Huang, Ning Zheng
Orthosteric inhibitors block enzyme active sites and prevent substrates from binding1. Enhancing their specificity through substrate dependence seems inherently unlikely, as their mechanism hinges on direct competition rather than selective recognition. Here we show that a molecular glue mechanism unexpectedly imparts substrate-dependent potency to CSN5i-3, an orthosteric inhibitor of the COP9 signalosome (CSN). We first confirm that CSN5i-3 inhibits CSN, which catalyses NEDD8 (N8) deconjugation from the cullin-RING ubiquitin ligases, by occupying the active site of its catalytic subunit, CSN5, and directly competing with the iso-peptide bond substrate. Notably, the orthosteric inhibitor binds free CSN with only micromolar affinity, yet achieves nanomolar potency in blocking its deneddylase activity. Cryogenic electron microscopy structures of the enzyme–substrate–inhibitor complex reveal that active site-engaged CSN5i-3 occludes the substrate iso-peptide linkage while simultaneously extending an N8-binding exosite of CSN5, acting as a molecular glue to cement the N8–CSN5 interaction. The cooperativity of this trimolecular CSN5i-3–N8–CSN5 assembly, in turn, sequesters CSN5i-3 at its binding site, conferring high potency to the orthosteric inhibitor despite its low affinity for the free enzyme. Together, our findings highlight the modest affinity requirements of molecule glues for individual target proteins and establish orthosteric molecular glue inhibitors as a new class of substrate-dependent enzyme antagonists.
{"title":"CSN5i-3 is an orthosteric molecular glue inhibitor of COP9 signalosome","authors":"Huigang Shi, Xiaorong Wang, Clinton Yu, Haibin Mao, Fenglong Jiao, Merav Braitbard, Ben Shor, Zhongsheng Zhang, Thomas R. Hinds, Shiyun Cao, Erkang Fan, Dina Schneidman-Duhovny, Lan Huang, Ning Zheng","doi":"10.1038/s41586-026-10129-y","DOIUrl":"https://doi.org/10.1038/s41586-026-10129-y","url":null,"abstract":"Orthosteric inhibitors block enzyme active sites and prevent substrates from binding1. Enhancing their specificity through substrate dependence seems inherently unlikely, as their mechanism hinges on direct competition rather than selective recognition. Here we show that a molecular glue mechanism unexpectedly imparts substrate-dependent potency to CSN5i-3, an orthosteric inhibitor of the COP9 signalosome (CSN). We first confirm that CSN5i-3 inhibits CSN, which catalyses NEDD8 (N8) deconjugation from the cullin-RING ubiquitin ligases, by occupying the active site of its catalytic subunit, CSN5, and directly competing with the iso-peptide bond substrate. Notably, the orthosteric inhibitor binds free CSN with only micromolar affinity, yet achieves nanomolar potency in blocking its deneddylase activity. Cryogenic electron microscopy structures of the enzyme–substrate–inhibitor complex reveal that active site-engaged CSN5i-3 occludes the substrate iso-peptide linkage while simultaneously extending an N8-binding exosite of CSN5, acting as a molecular glue to cement the N8–CSN5 interaction. The cooperativity of this trimolecular CSN5i-3–N8–CSN5 assembly, in turn, sequesters CSN5i-3 at its binding site, conferring high potency to the orthosteric inhibitor despite its low affinity for the free enzyme. Together, our findings highlight the modest affinity requirements of molecule glues for individual target proteins and establish orthosteric molecular glue inhibitors as a new class of substrate-dependent enzyme antagonists.","PeriodicalId":18787,"journal":{"name":"Nature","volume":"35 1","pages":""},"PeriodicalIF":64.8,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-11DOI: 10.1038/s41586-025-10068-0
Olena Bukalo, Ruairi O’Sullivan, Yuta Tanisumi, Adriana Mendez, Chase Weinholtz, Sydney Zimmerman, Victoria Offenberg, Olivia Carpenter, Hrishikesh Bhagwat, Sophie Mosley, John J. O’Malley, Kerri Lyons, Yulan Fang, Jess Goldschlager, Linnaea E. Ostroff, Mario A. Penzo, Hiroaki Wake, Lindsay R. Halladay, Andrew Holmes
Brain systems mediating responses to previously encountered threats provide critical survival functions. Fear memory and extinction are underpinned by neural representations in the basolateral amygdala (BLA)1,2,3,4,5,6,7, but the contribution of non-neuronal cells, including astrocytes, to these processes remains unresolved. Here, using in vivo calcium (Ca2+) imaging and causal astrocyte manipulations, we find that BLA astrocytes dynamically track fear state and support fear memory retrieval and extinction. By combining astrocyte manipulations with in vivo BLA neuronal Ca2+ imaging and electrophysiological recordings, we show that astrocyte Ca2+ signalling enables neuronal encoding of fear memory retrieval and extinction, and readout through a BLA–prefrontal circuit. Our findings reveal a key role for astrocytes in the generation and adaptation of fear-state-related neural representations, revising neurocentric models of critical amygdala-mediated adaptive functions.
{"title":"Astrocytes enable amygdala neural representations supporting memory","authors":"Olena Bukalo, Ruairi O’Sullivan, Yuta Tanisumi, Adriana Mendez, Chase Weinholtz, Sydney Zimmerman, Victoria Offenberg, Olivia Carpenter, Hrishikesh Bhagwat, Sophie Mosley, John J. O’Malley, Kerri Lyons, Yulan Fang, Jess Goldschlager, Linnaea E. Ostroff, Mario A. Penzo, Hiroaki Wake, Lindsay R. Halladay, Andrew Holmes","doi":"10.1038/s41586-025-10068-0","DOIUrl":"https://doi.org/10.1038/s41586-025-10068-0","url":null,"abstract":"Brain systems mediating responses to previously encountered threats provide critical survival functions. Fear memory and extinction are underpinned by neural representations in the basolateral amygdala (BLA)1,2,3,4,5,6,7, but the contribution of non-neuronal cells, including astrocytes, to these processes remains unresolved. Here, using in vivo calcium (Ca2+) imaging and causal astrocyte manipulations, we find that BLA astrocytes dynamically track fear state and support fear memory retrieval and extinction. By combining astrocyte manipulations with in vivo BLA neuronal Ca2+ imaging and electrophysiological recordings, we show that astrocyte Ca2+ signalling enables neuronal encoding of fear memory retrieval and extinction, and readout through a BLA–prefrontal circuit. Our findings reveal a key role for astrocytes in the generation and adaptation of fear-state-related neural representations, revising neurocentric models of critical amygdala-mediated adaptive functions.","PeriodicalId":18787,"journal":{"name":"Nature","volume":"156 1","pages":""},"PeriodicalIF":64.8,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Endocytosis enables neurons to internalize molecules, maintaining homeostasis and responsiveness. The neuronal membrane–associated periodic skeleton (MPS), an actin spectrin–based cytoskeletal lattice, is known to restrict clathrin-mediated endocytosis (CME) in axons, but its broader role in other neuronal compartments and endocytic pathways remains unclear. Here, we show that all four major endocytic pathways—CME, caveolin-, flotillin-, and fast endophilin–mediated endocytosis—are spatially gated by the MPS and occur exclusively within MPS-free “clearing” zones throughout all neuronal compartments. Disrupting the MPS broadly enhances both basal and ligand-induced endocytosis. We also identify a previously unknown feedback loop in which ligand-triggered endocytosis activates extracellular signal–regulated kinase signaling, promoting protease-mediated spectrin cleavage and MPS disruption, which in turn facilitates further endocytosis. Furthermore, the MPS limits amyloid precursor protein endocytosis, thereby suppressing Aβ42 production and linking MPS integrity to neurodegeneration. Our findings establish the MPS as a dynamic, signal-responsive modulator coupling membrane trafficking with cortical cytoskeletal organization and neuronal health.
{"title":"Membrane-associated periodic skeleton regulates major forms of endocytosis in neurons through a signaling-driven positive feedback loop","authors":"Jinyu Fei, Yuanmin Zheng, Caden LaLonde, Yuan Tao, Ruobo Zhou","doi":"10.1126/sciadv.aeb0803","DOIUrl":"10.1126/sciadv.aeb0803","url":null,"abstract":"<div >Endocytosis enables neurons to internalize molecules, maintaining homeostasis and responsiveness. The neuronal membrane–associated periodic skeleton (MPS), an actin spectrin–based cytoskeletal lattice, is known to restrict clathrin-mediated endocytosis (CME) in axons, but its broader role in other neuronal compartments and endocytic pathways remains unclear. Here, we show that all four major endocytic pathways—CME, caveolin-, flotillin-, and fast endophilin–mediated endocytosis—are spatially gated by the MPS and occur exclusively within MPS-free “clearing” zones throughout all neuronal compartments. Disrupting the MPS broadly enhances both basal and ligand-induced endocytosis. We also identify a previously unknown feedback loop in which ligand-triggered endocytosis activates extracellular signal–regulated kinase signaling, promoting protease-mediated spectrin cleavage and MPS disruption, which in turn facilitates further endocytosis. Furthermore, the MPS limits amyloid precursor protein endocytosis, thereby suppressing Aβ42 production and linking MPS integrity to neurodegeneration. Our findings establish the MPS as a dynamic, signal-responsive modulator coupling membrane trafficking with cortical cytoskeletal organization and neuronal health.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 7","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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