Pub Date : 2025-03-25Epub Date: 2025-03-17DOI: 10.1073/pnas.2425993122
Gang Chen, Guangxin Lv, James H Zhang, Yaodong Tu
{"title":"Reply to Ahmed and Lu: Cluster signals depend on how samples are made and measured.","authors":"Gang Chen, Guangxin Lv, James H Zhang, Yaodong Tu","doi":"10.1073/pnas.2425993122","DOIUrl":"https://doi.org/10.1073/pnas.2425993122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 12","pages":"e2425993122"},"PeriodicalIF":9.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650022","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 : 2025-03-25Epub Date: 2025-03-17DOI: 10.1073/pnas.2502286122
Hannes Ruwe, Thomas Spallek
{"title":"Systemic signals control infection plasticity in parasitic plants.","authors":"Hannes Ruwe, Thomas Spallek","doi":"10.1073/pnas.2502286122","DOIUrl":"https://doi.org/10.1073/pnas.2502286122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 12","pages":"e2502286122"},"PeriodicalIF":9.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650131","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 : 2025-03-25Epub Date: 2025-03-06DOI: 10.1073/pnas.2503547122
{"title":"Correction for Yao et al., An organic electrochemical neuron for a neuromorphic perception system.","authors":"","doi":"10.1073/pnas.2503547122","DOIUrl":"https://doi.org/10.1073/pnas.2503547122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 12","pages":"e2503547122"},"PeriodicalIF":9.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573694","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 : 2025-03-25Epub Date: 2025-03-13DOI: 10.1073/pnas.2500631122
Kevin Fiscella
{"title":"Research needed on tipping points and reversal of erosions in democracy.","authors":"Kevin Fiscella","doi":"10.1073/pnas.2500631122","DOIUrl":"https://doi.org/10.1073/pnas.2500631122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 12","pages":"e2500631122"},"PeriodicalIF":9.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625646","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}
Jiawen Zhang, Zhenqi Hua, Chengwei Wang, Michael Smidman, David Graf, Sean Thomas, Priscila F. S. Rosa, Steffen Wirth, Xi Dai, Peng Xiong, Huiqiu Yuan, Xiaoyu Wang, Lin Jiao
Introducing the concept of topology into material science has sparked a revolution from classic electronic and optoelectronic devices to topological quantum devices. The latter has potential for transferring energy and information with unprecedented efficiency. Here, we demonstrate a topological diode effect on the surface of a three-dimensional material, SmB 6 , a candidate topological Kondo insulator. The diode effect is evidenced by pronounced rectification and photogalvanic effects under electromagnetic modulation and radiation at radio frequency. Our experimental results and modeling suggest that these prominent effects are intimately tied to the spatially inhomogeneous formation of topological surface states (TSS) at the intermediate temperature. This work provides a manner of breaking the mirror symmetry (in addition to the inversion symmetry), resulting in the formation of pn -junctions between puddles of metallic TSS. This effect paves the way for efficient current rectifiers or energy-harvesting devices working down to radio frequency range at low temperature, which could be extended to high temperatures using other topological insulators with large bulk gap.
{"title":"Realizing a topological diode effect on the surface of a topological Kondo insulator","authors":"Jiawen Zhang, Zhenqi Hua, Chengwei Wang, Michael Smidman, David Graf, Sean Thomas, Priscila F. S. Rosa, Steffen Wirth, Xi Dai, Peng Xiong, Huiqiu Yuan, Xiaoyu Wang, Lin Jiao","doi":"10.1073/pnas.2417709122","DOIUrl":"https://doi.org/10.1073/pnas.2417709122","url":null,"abstract":"Introducing the concept of topology into material science has sparked a revolution from classic electronic and optoelectronic devices to topological quantum devices. The latter has potential for transferring energy and information with unprecedented efficiency. Here, we demonstrate a topological diode effect on the surface of a three-dimensional material, SmB <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:msub> <mml:mrow/> <mml:mn>6</mml:mn> </mml:msub> </mml:math> </jats:inline-formula> , a candidate topological Kondo insulator. The diode effect is evidenced by pronounced rectification and photogalvanic effects under electromagnetic modulation and radiation at radio frequency. Our experimental results and modeling suggest that these prominent effects are intimately tied to the spatially inhomogeneous formation of topological surface states (TSS) at the intermediate temperature. This work provides a manner of breaking the mirror symmetry (in addition to the inversion symmetry), resulting in the formation of <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:mi mathvariant=\"italic\">pn</mml:mi> </mml:mrow> </mml:math> </jats:inline-formula> -junctions between puddles of metallic TSS. This effect paves the way for efficient current rectifiers or energy-harvesting devices working down to radio frequency range at low temperature, which could be extended to high temperatures using other topological insulators with large bulk gap.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"27 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666496","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}
Leiming Lin, Zheng Li, Jun Ren, Ying Meng, Fubo Luan
The co-occurrence of arsenic and uranium in groundwater has been found in many countries, posing a significant challenge to human health. Here, we have demonstrated the efficient simultaneous removal of arsenic and uranyl-carbonate complexes from groundwater using {001}-TiO 2 . Surprisingly, the presence of U(VI) greatly enhanced the adsorption of As(V) on {001}-TiO 2 , while As(V) had a negligible impact on U(VI) adsorption. Through in situ ATR-FTIR spectroscopy, we uncovered a mechanism involving the formation of a ternary surface complex [Ti–U(VI)–As(V)] on the surface of {001}-TiO 2 . This ternary surface complex formed through the substitution of CO 32- from uranyl coordination sites. Furthermore, the adsorbed As(V) and U(VI) can be easily recovered using a sodium hydroxide solution, and {001}-TiO 2 can be used repeatedly. Our findings offer a promising solution for the simultaneous removal of As(V) and U(VI) from groundwater and provide valuable insights into the mechanisms involved in their removal.
{"title":"Ternary surface complexation promotes simultaneous removal of arsenic and uranium by TiO 2","authors":"Leiming Lin, Zheng Li, Jun Ren, Ying Meng, Fubo Luan","doi":"10.1073/pnas.2501354122","DOIUrl":"https://doi.org/10.1073/pnas.2501354122","url":null,"abstract":"The co-occurrence of arsenic and uranium in groundwater has been found in many countries, posing a significant challenge to human health. Here, we have demonstrated the efficient simultaneous removal of arsenic and uranyl-carbonate complexes from groundwater using {001}-TiO <jats:sub>2</jats:sub> . Surprisingly, the presence of U(VI) greatly enhanced the adsorption of As(V) on {001}-TiO <jats:sub>2</jats:sub> , while As(V) had a negligible impact on U(VI) adsorption. Through in situ ATR-FTIR spectroscopy, we uncovered a mechanism involving the formation of a ternary surface complex [Ti–U(VI)–As(V)] on the surface of {001}-TiO <jats:sub>2</jats:sub> . This ternary surface complex formed through the substitution of CO <jats:sub>3</jats:sub> <jats:sup>2-</jats:sup> from uranyl coordination sites. Furthermore, the adsorbed As(V) and U(VI) can be easily recovered using a sodium hydroxide solution, and {001}-TiO <jats:sub>2</jats:sub> can be used repeatedly. Our findings offer a promising solution for the simultaneous removal of As(V) and U(VI) from groundwater and provide valuable insights into the mechanisms involved in their removal.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"92 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666575","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}
Diapause, a developmental arrest mechanism, helps animals to survive seasonal changes via endocrine regulation. While obligate diapause is genetically programmed, facultative diapause is typically triggered by environmental cues such as photoperiod. In insects, this often leads to reproductive diapause characterized by reduced juvenile hormone (JH) signaling, resulting in ovarian arrest and lipid accumulation. However, the molecular link between photoperiod and hormonal control remains poorly understood. In this study, we investigated the cabbage beetle Colaphellus bowringi as our model system. This species exhibits a photoperiodic response, where short-day (SD) conditions promote reproduction, whereas long-day (LD) conditions induce diapause. Our research identified the PBAP chromatin remodeling complex as a key regulator of LD-induced summer diapause entry. Through RNAi screening of 56 transcriptional regulators that were differentially expressed between SD and LD females, we identified BAP170, a PBAP-specific component, as a key mediator of diapause. Knockdown of bap170 in SD females induced reproductive diapause traits, which were reversed by treatment with methoprene, a JH analog, suggesting that the PBAP complex regulates diapause by influencing JH production. We further demonstrated that the PBAP complex modulates JH biosynthesis via SET1/COMPASS-mediated trimethylation of H3K4. Transcriptome analysis and a second RNAi screen identified calmodulin , a calcium-binding messenger protein gene, as a direct target of PBAP-SET1/COMPASS-H3K4me3 signaling in the corpora allata (CA), the primary source of JH. These findings reveal how the chromatin remodeling machinery translates photoperiod signals into endocrine responses governing seasonal adaptation.
{"title":"The PBAP chromatin remodeling complex mediates summer diapause via H3K4me3-driven juvenile hormone regulation in Colaphellus bowringi","authors":"Zhong Tian, Kou Wang, Shuang Guo, Jia-Xu Li, Kirst King-Jones, Fen Zhu, Wen Liu, Xiao-Ping Wang","doi":"10.1073/pnas.2422328122","DOIUrl":"https://doi.org/10.1073/pnas.2422328122","url":null,"abstract":"Diapause, a developmental arrest mechanism, helps animals to survive seasonal changes via endocrine regulation. While obligate diapause is genetically programmed, facultative diapause is typically triggered by environmental cues such as photoperiod. In insects, this often leads to reproductive diapause characterized by reduced juvenile hormone (JH) signaling, resulting in ovarian arrest and lipid accumulation. However, the molecular link between photoperiod and hormonal control remains poorly understood. In this study, we investigated the cabbage beetle <jats:italic>Colaphellus bowringi</jats:italic> as our model system. This species exhibits a photoperiodic response, where short-day (SD) conditions promote reproduction, whereas long-day (LD) conditions induce diapause. Our research identified the PBAP chromatin remodeling complex as a key regulator of LD-induced summer diapause entry. Through RNAi screening of 56 transcriptional regulators that were differentially expressed between SD and LD females, we identified BAP170, a PBAP-specific component, as a key mediator of diapause. Knockdown of <jats:italic>bap170</jats:italic> in SD females induced reproductive diapause traits, which were reversed by treatment with methoprene, a JH analog, suggesting that the PBAP complex regulates diapause by influencing JH production. We further demonstrated that the PBAP complex modulates JH biosynthesis via SET1/COMPASS-mediated trimethylation of H3K4. Transcriptome analysis and a second RNAi screen identified <jats:italic>calmodulin</jats:italic> , a calcium-binding messenger protein gene, as a direct target of PBAP-SET1/COMPASS-H3K4me3 signaling in the corpora allata (CA), the primary source of JH. These findings reveal how the chromatin remodeling machinery translates photoperiod signals into endocrine responses governing seasonal adaptation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"13 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666411","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}
Jared J. Stewart, Brendan S. Allen, Stephanie K. Polutchko, Troy W. Ocheltree, Sean M. Gleason
Plant hydraulic dysfunction by embolism formation can impair photosynthesis, growth, and reproduction and, in severe cases, lead to death. Embolism reversal, or “refilling,” is a hypothesized adaptive process in which xylem functionality is rapidly and sustainably restored. This study investigated xylem embolism refilling during recovery from severe drought stress using entirely noninvasive measurements of the same plants. These results were considered in relation to functional traits to address long-standing gaps in understanding the consequences of severe drought stress. Leaf and stem xylem embolism as well as transpiration, photosynthesis, and stem water potential were characterized nondestructively on intact barnyard grass plants during an acute drought event. Plants were rewatered and returned to growth conditions for 10 d, during which time recovery of stem xylem embolism and transpiration were monitored. Leaf xylem embolism and declines in leaf gas exchange occurred mostly between −1.0 MPa and −2.0 MPa, whereas stem xylem embolism occurred mostly between −3.0 MPa and −4.0 MPa. In all measured plants, which included embolism levels up to 88%, stem xylem embolism reversed completely within 24 h after rewatering, and this refilling supported recovery of transpiration and growth after plants were returned to growth conditions. This study provides direct evidence of complete and functional stem xylem refilling. These results present a clear need to elucidate underlying mechanisms and the adaptive significance of this phenomenon as well as its prevalence in nature.
{"title":"Xylem embolism refilling revealed in stems of a weedy grass","authors":"Jared J. Stewart, Brendan S. Allen, Stephanie K. Polutchko, Troy W. Ocheltree, Sean M. Gleason","doi":"10.1073/pnas.2420618122","DOIUrl":"https://doi.org/10.1073/pnas.2420618122","url":null,"abstract":"Plant hydraulic dysfunction by embolism formation can impair photosynthesis, growth, and reproduction and, in severe cases, lead to death. Embolism reversal, or “refilling,” is a hypothesized adaptive process in which xylem functionality is rapidly and sustainably restored. This study investigated xylem embolism refilling during recovery from severe drought stress using entirely noninvasive measurements of the same plants. These results were considered in relation to functional traits to address long-standing gaps in understanding the consequences of severe drought stress. Leaf and stem xylem embolism as well as transpiration, photosynthesis, and stem water potential were characterized nondestructively on intact barnyard grass plants during an acute drought event. Plants were rewatered and returned to growth conditions for 10 d, during which time recovery of stem xylem embolism and transpiration were monitored. Leaf xylem embolism and declines in leaf gas exchange occurred mostly between −1.0 MPa and −2.0 MPa, whereas stem xylem embolism occurred mostly between −3.0 MPa and −4.0 MPa. In all measured plants, which included embolism levels up to 88%, stem xylem embolism reversed completely within 24 h after rewatering, and this refilling supported recovery of transpiration and growth after plants were returned to growth conditions. This study provides direct evidence of complete and functional stem xylem refilling. These results present a clear need to elucidate underlying mechanisms and the adaptive significance of this phenomenon as well as its prevalence in nature.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"10 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666500","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}
Desiccation-tolerant cyanobacteria are able to survive frequent cycles of hydration and dehydration, which are closely linked to diurnal light oscillations. Previous studies have shown that light serves as a crucial anticipatory cue, activating desert cyanobacteria to prepare for desiccation. However, the mechanisms underlying their light-coupled desiccation tolerance remain largely unknown. Here, we demonstrate that red-light-induced photosynthetic genes are positively regulated by a LuxR family transcription factor NfSrr1. We further identified the cyanobacteriochrome NfPixJ as interacting with NfSrr1 and functioning as a red light sensor. Phenotypic analysis revealed that the red-light signaling module NfPixJ-NfSrr1 plays a key role in preparing cyanobacteria for desiccation tolerance. This module also regulates the synthesis of protective compatible solutes, suggesting that red light functions as a global regulatory signal for the broader stress response. Phylogenetic analysis indicates that the presence of this red-light signaling pathway, mediated by NfPixJ-NfSrr1 module, correlates with the ability of cyanobacteria to thrive in water-deficit habitats. Overall, our findings uncover a red-light signaling pathway that enhances desiccation tolerance as desert cyanobacteria encounter red light at dawn, before water limitation. These results provide insights into the mechanisms behind light-induced anticipatory stress tolerance in photosynthetic organisms.
{"title":"Red-light signaling pathway activates desert cyanobacteria to prepare for desiccation tolerance","authors":"Hai-Feng Xu, Guo-Zheng Dai, Ren-Han Li, Yang Bai, Ai-Wei Zuo, Lei Zhao, Shu-Ren Cui, Jin-Long Shang, Chao Cheng, Yu-Jie Wang, Gui-Fang Feng, Deqiang Duanmu, Aaron Kaplan, Bao-Sheng Qiu","doi":"10.1073/pnas.2502034122","DOIUrl":"https://doi.org/10.1073/pnas.2502034122","url":null,"abstract":"Desiccation-tolerant cyanobacteria are able to survive frequent cycles of hydration and dehydration, which are closely linked to diurnal light oscillations. Previous studies have shown that light serves as a crucial anticipatory cue, activating desert cyanobacteria to prepare for desiccation. However, the mechanisms underlying their light-coupled desiccation tolerance remain largely unknown. Here, we demonstrate that red-light-induced photosynthetic genes are positively regulated by a LuxR family transcription factor NfSrr1. We further identified the cyanobacteriochrome NfPixJ as interacting with NfSrr1 and functioning as a red light sensor. Phenotypic analysis revealed that the red-light signaling module NfPixJ-NfSrr1 plays a key role in preparing cyanobacteria for desiccation tolerance. This module also regulates the synthesis of protective compatible solutes, suggesting that red light functions as a global regulatory signal for the broader stress response. Phylogenetic analysis indicates that the presence of this red-light signaling pathway, mediated by NfPixJ-NfSrr1 module, correlates with the ability of cyanobacteria to thrive in water-deficit habitats. Overall, our findings uncover a red-light signaling pathway that enhances desiccation tolerance as desert cyanobacteria encounter red light at dawn, before water limitation. These results provide insights into the mechanisms behind light-induced anticipatory stress tolerance in photosynthetic organisms.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"12 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666499","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}
Anni Kumari, Sanne W. R. Larsen, Signe Bondesen, Yuewei Qian, Hao D. Tian, Sydney G. Walker, Brandon S. J. Davies, Alan T. Remaley, Stephen G. Young, Robert J. Konrad, Thomas J. D. Jørgensen, Michael Ploug
Lipoprotein lipase (LPL) carries out the lipolytic processing of triglyceride-rich lipoproteins (TRL) along the luminal surface of capillaries. LPL activity is regulated by the angiopoietin-like proteins (ANGPTL3, ANGPTL4, ANGPTL8), which control the delivery of TRL-derived lipid nutrients to tissues in a temporal and spatial fashion. This regulation of LPL mediates the partitioning of lipid delivery to adipose tissue and striated muscle according to nutritional status. A complex between ANGPTL3 and ANGPTL8 (ANGPTL3/8) inhibits LPL activity in oxidative tissues, but its mode of action has remained unknown. Here, we used biophysical techniques to define how ANGPTL3/8 and ANGPTL3 interact with LPL and how they drive LPL inactivation. We demonstrate, by mass photometry, that ANGPTL3/8 is a heterotrimer with a 2:1 ANGPTL3:ANGPTL8 stoichiometry and that ANGPTL3 is a homotrimer. Hydrogen–deuterium exchange mass spectrometry (HDX-MS) studies revealed that ANGPTL3/8 and ANGPTL3 use the proximal portion of their N-terminal α-helices to interact with sequences surrounding the catalytic pocket in LPL. That binding event triggers unfolding of LPL’s α/β -hydrolase domain and irreversible loss of LPL catalytic activity. The binding of LPL to its endothelial transporter protein (GPIHBP1) or to heparan-sulfate proteoglycans protects LPL from unfolding and inactivation, particularly against the unfolding triggered by ANGPTL3. Pulse-labeling HDX-MS studies revealed that ANGPTL3/8 and ANGPTL3 catalyze LPL unfolding in an ATP-independent fashion, which categorizes these LPL inhibitors as atypical unfoldases. The catalytic nature of LPL unfolding by ANGPTL3/8 explains why low plasma concentrations of ANGPTL3/8 are effective in inhibiting a molar excess of LPL in capillaries.
{"title":"ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase","authors":"Anni Kumari, Sanne W. R. Larsen, Signe Bondesen, Yuewei Qian, Hao D. Tian, Sydney G. Walker, Brandon S. J. Davies, Alan T. Remaley, Stephen G. Young, Robert J. Konrad, Thomas J. D. Jørgensen, Michael Ploug","doi":"10.1073/pnas.2420721122","DOIUrl":"https://doi.org/10.1073/pnas.2420721122","url":null,"abstract":"Lipoprotein lipase (LPL) carries out the lipolytic processing of triglyceride-rich lipoproteins (TRL) along the luminal surface of capillaries. LPL activity is regulated by the angiopoietin-like proteins (ANGPTL3, ANGPTL4, ANGPTL8), which control the delivery of TRL-derived lipid nutrients to tissues in a temporal and spatial fashion. This regulation of LPL mediates the partitioning of lipid delivery to adipose tissue and striated muscle according to nutritional status. A complex between ANGPTL3 and ANGPTL8 (ANGPTL3/8) inhibits LPL activity in oxidative tissues, but its mode of action has remained unknown. Here, we used biophysical techniques to define how ANGPTL3/8 and ANGPTL3 interact with LPL and how they drive LPL inactivation. We demonstrate, by mass photometry, that ANGPTL3/8 is a heterotrimer with a 2:1 ANGPTL3:ANGPTL8 stoichiometry and that ANGPTL3 is a homotrimer. Hydrogen–deuterium exchange mass spectrometry (HDX-MS) studies revealed that ANGPTL3/8 and ANGPTL3 use the proximal portion of their N-terminal α-helices to interact with sequences surrounding the catalytic pocket in LPL. That binding event triggers unfolding of LPL’s <jats:italic>α/β</jats:italic> -hydrolase domain and irreversible loss of LPL catalytic activity. The binding of LPL to its endothelial transporter protein (GPIHBP1) or to heparan-sulfate proteoglycans protects LPL from unfolding and inactivation, particularly against the unfolding triggered by ANGPTL3. Pulse-labeling HDX-MS studies revealed that ANGPTL3/8 and ANGPTL3 <jats:italic>catalyze</jats:italic> LPL unfolding in an ATP-independent fashion, which categorizes these LPL inhibitors as atypical unfoldases. The catalytic nature of LPL unfolding by ANGPTL3/8 explains why low plasma concentrations of ANGPTL3/8 are effective in inhibiting a molar excess of LPL in capillaries.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"43 4 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666501","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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