Pub Date : 2024-11-14DOI: 10.1038/s42003-024-07217-y
Julien Damoczi, Adrien Knoops, Marie-Sophie Martou, Félix Jaumaux, Philippe Gabant, Jacques Mahillon, Jan-Willem Veening, Johann Mignolet, Pascal Hols
Facing the antibiotic resistance crisis, bacteriocins are considered as a promising alternative to treat bacterial infections. In the human commensal Streptococcus salivarius, the production of unmodified bacteriocins (or salivaricins) is directly controlled at the transcriptional level by quorum-sensing. To discover hidden bacteriocins, we harnessed here the unique molecular signatures of salivaricins not yet used in available computational pipelines and performed genome mining followed by orthogonal reconstitution and expression. From 100 genomes of S. salivarius, we identified more than 50 bacteriocin candidates clustered into 21 groups. Strain-based analysis of bacteriocin combinations revealed significant diversity, reflecting the plasticity of seven independent loci. Activity tests showed both narrow and broad-spectrum bacteriocins with overlapping activities against a wide panel of Gram-positive bacteria, including notorious multidrug-resistant pathogens. Overall, this work provides a search-to-test generic pipeline for bacteriocin discovery with high impact for bacterial ecology and broad applications in the food and biomedical fields. Class II bacteriocins in the Streptococcus salivarius pan-genome were bioinformatically identified based on conserved sequence properties. These diverse “salivaricins” show antibacterial activity against Gram-positive pathogens.
{"title":"Uncovering the arsenal of class II bacteriocins in salivarius streptococci","authors":"Julien Damoczi, Adrien Knoops, Marie-Sophie Martou, Félix Jaumaux, Philippe Gabant, Jacques Mahillon, Jan-Willem Veening, Johann Mignolet, Pascal Hols","doi":"10.1038/s42003-024-07217-y","DOIUrl":"10.1038/s42003-024-07217-y","url":null,"abstract":"Facing the antibiotic resistance crisis, bacteriocins are considered as a promising alternative to treat bacterial infections. In the human commensal Streptococcus salivarius, the production of unmodified bacteriocins (or salivaricins) is directly controlled at the transcriptional level by quorum-sensing. To discover hidden bacteriocins, we harnessed here the unique molecular signatures of salivaricins not yet used in available computational pipelines and performed genome mining followed by orthogonal reconstitution and expression. From 100 genomes of S. salivarius, we identified more than 50 bacteriocin candidates clustered into 21 groups. Strain-based analysis of bacteriocin combinations revealed significant diversity, reflecting the plasticity of seven independent loci. Activity tests showed both narrow and broad-spectrum bacteriocins with overlapping activities against a wide panel of Gram-positive bacteria, including notorious multidrug-resistant pathogens. Overall, this work provides a search-to-test generic pipeline for bacteriocin discovery with high impact for bacterial ecology and broad applications in the food and biomedical fields. Class II bacteriocins in the Streptococcus salivarius pan-genome were bioinformatically identified based on conserved sequence properties. These diverse “salivaricins” show antibacterial activity against Gram-positive pathogens.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":" ","pages":"1-15"},"PeriodicalIF":5.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07217-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616316","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 : 2024-11-14DOI: 10.1038/s42003-024-07236-9
Siru Wang, Oyesola O. Ojewunmi, Abram Kamiza, Michele Ramsay, Andrew P. Morris, Tinashe Chikowore, Segun Fatumo, Jennifer L. Asimit
Meta-analysis of genome-wide association studies (GWAS) across diverse populations offers power gains to identify loci associated with complex traits and diseases. Often heterogeneity in effect sizes across populations will be correlated with genetic ancestry and environmental exposures (e.g. lifestyle factors). We present an environment-adjusted meta-regression model (env-MR-MEGA) to detect genetic associations by adjusting for and quantifying environmental and ancestral heterogeneity between populations. In simulations, env-MR-MEGA has similar or greater association power than MR-MEGA, with notable gains when the environmental factor has a greater correlation with the trait than ancestry. In our analysis of low-density lipoprotein cholesterol in ~19,000 individuals across twelve sex-stratified GWAS from Africa, adjusting for sex, BMI, and urban status, we identify additional heterogeneity beyond ancestral effects for seven variants. Env-MR-MEGA provides an approach to account for environmental effects using summary-level data, making it a useful tool for meta-analyses without the need to share individual-level data. Adjusting for and quantifying environmental heterogeneity in the meta-analysis of genomewide association studies of diverse populations identifies additional heterogeneity beyond ancestral effects.
{"title":"Accounting for heterogeneity due to environmental sources in meta-analysis of genome-wide association studies","authors":"Siru Wang, Oyesola O. Ojewunmi, Abram Kamiza, Michele Ramsay, Andrew P. Morris, Tinashe Chikowore, Segun Fatumo, Jennifer L. Asimit","doi":"10.1038/s42003-024-07236-9","DOIUrl":"10.1038/s42003-024-07236-9","url":null,"abstract":"Meta-analysis of genome-wide association studies (GWAS) across diverse populations offers power gains to identify loci associated with complex traits and diseases. Often heterogeneity in effect sizes across populations will be correlated with genetic ancestry and environmental exposures (e.g. lifestyle factors). We present an environment-adjusted meta-regression model (env-MR-MEGA) to detect genetic associations by adjusting for and quantifying environmental and ancestral heterogeneity between populations. In simulations, env-MR-MEGA has similar or greater association power than MR-MEGA, with notable gains when the environmental factor has a greater correlation with the trait than ancestry. In our analysis of low-density lipoprotein cholesterol in ~19,000 individuals across twelve sex-stratified GWAS from Africa, adjusting for sex, BMI, and urban status, we identify additional heterogeneity beyond ancestral effects for seven variants. Env-MR-MEGA provides an approach to account for environmental effects using summary-level data, making it a useful tool for meta-analyses without the need to share individual-level data. Adjusting for and quantifying environmental heterogeneity in the meta-analysis of genomewide association studies of diverse populations identifies additional heterogeneity beyond ancestral effects.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":" ","pages":"1-12"},"PeriodicalIF":5.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07236-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616138","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 : 2024-11-14DOI: 10.1038/s42003-024-07168-4
Julia Vergalli, Matthieu Réfrégiers, Paolo Ruggerone, Mathias Winterhalter, Jean-Marie Pagès
The sophisticated envelope of Gram-negative bacteria modulates the uptake of small molecules in a side-chain-sensitive manner. Despite intensive theoretical and experimental investigations, a general set of pathways underpinning antibiotic uptake has not been identified. This manuscript discusses the passive influx versus active efflux of antibiotics, considering the responsible membrane proteins and the transported molecules. Recent methods have analyzed drug transport across the bacterial membrane in order to understand their activity. The combination of in vitro, in cellulo and in silico methods shed light on the key, mainly electrostatic, interactions between the molecule surface, porins and transporters during permeation. A key factor is the relationship between the dose of an active compound near its target and its antibacterial activity during the critical early window. Today, methodology breakthroughs provide fruitful tools to precisely dissect drug transport, identify key steps in drug resistance associated with membrane impermeability and efflux, and highlight key parameters to generate more effective drugs. Gram-negative bacteria envelope controls drug accumulation via passive influx and active efflux mechanisms. This article discusses recent in cellulo, in vitro, and in silico methods highlighting key “drug-transporters” dialogues and proposes new perspectives to overcome drug resistance.
{"title":"Advances in methods and concepts provide new insight into antibiotic fluxes across the bacterial membrane","authors":"Julia Vergalli, Matthieu Réfrégiers, Paolo Ruggerone, Mathias Winterhalter, Jean-Marie Pagès","doi":"10.1038/s42003-024-07168-4","DOIUrl":"10.1038/s42003-024-07168-4","url":null,"abstract":"The sophisticated envelope of Gram-negative bacteria modulates the uptake of small molecules in a side-chain-sensitive manner. Despite intensive theoretical and experimental investigations, a general set of pathways underpinning antibiotic uptake has not been identified. This manuscript discusses the passive influx versus active efflux of antibiotics, considering the responsible membrane proteins and the transported molecules. Recent methods have analyzed drug transport across the bacterial membrane in order to understand their activity. The combination of in vitro, in cellulo and in silico methods shed light on the key, mainly electrostatic, interactions between the molecule surface, porins and transporters during permeation. A key factor is the relationship between the dose of an active compound near its target and its antibacterial activity during the critical early window. Today, methodology breakthroughs provide fruitful tools to precisely dissect drug transport, identify key steps in drug resistance associated with membrane impermeability and efflux, and highlight key parameters to generate more effective drugs. Gram-negative bacteria envelope controls drug accumulation via passive influx and active efflux mechanisms. This article discusses recent in cellulo, in vitro, and in silico methods highlighting key “drug-transporters” dialogues and proposes new perspectives to overcome drug resistance.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":" ","pages":"1-14"},"PeriodicalIF":5.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07168-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616139","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 : 2024-11-14DOI: 10.1038/s42003-024-07211-4
Xiaojuan Zhou, Niubing Zhang, Jie Gong, Kaixiang Zhang, Ping Chen, Xiang Cheng, Bang-Ce Ye, Guoping Zhao, Xinyun Jing, Xuan Li
As a fundamental unit for packaging genomic DNA into chromatin, the eukaryotic nucleosome core comprises a canonical octamer with two copies for each histone, H2A, H2B, H3, and H4, wrapped around with 147 base pairs of DNA. While H3 and H4 share structure-fold with archaeal histone-like proteins, the eukaryotic nucleosome core and the complete nucleosome (the core plus H1 histone) are unique to eukaryotes. To explore whether the eukaryotic nucleosome can assemble in prokaryotes and to reconstruct the possible route for its emergence in eukaryogenesis, we developed an in vivo system for assembly of nucleosomes in the model bacterium, Escherichia coli, and successfully reconstituted the core nucleosome, the complete nucleosome, and unexpectedly the non-canonical (H3-H4)4 octasome. The core and complete nucleosomes assembled in E. coli exhibited footprints typical of eukaryotic hosts after in situ micrococcal nuclease digestion. Additionally, they caused condensation of E. coli nucleoid. We also demonstrated the stable formation of non-canonical (H3-H4)2 tetrasome and (H3-H4)4 octasomes in vivo, which are suggested to be ‘fossil complex’ that marks the intermediate in the progressive development of eukaryotic nucleosome. The study presents a unique platform in a bacterium for in vivo assembly and studying the properties of non-canonical variants of nucleosome. Development of an in vivo system for assembly of eukaryotic nucleosomes in Escherichia coli, including the non-canonical (H3-H4)4 octasome, suggests the H3-H4 tetrasome and octasomes are likely intermediate complexes in the evolution of the eukaryotic nucleosome.
{"title":"In vivo assembly of complete eukaryotic nucleosomes and (H3-H4)-only non-canonical nucleosomal particles in the model bacterium Escherichia coli","authors":"Xiaojuan Zhou, Niubing Zhang, Jie Gong, Kaixiang Zhang, Ping Chen, Xiang Cheng, Bang-Ce Ye, Guoping Zhao, Xinyun Jing, Xuan Li","doi":"10.1038/s42003-024-07211-4","DOIUrl":"10.1038/s42003-024-07211-4","url":null,"abstract":"As a fundamental unit for packaging genomic DNA into chromatin, the eukaryotic nucleosome core comprises a canonical octamer with two copies for each histone, H2A, H2B, H3, and H4, wrapped around with 147 base pairs of DNA. While H3 and H4 share structure-fold with archaeal histone-like proteins, the eukaryotic nucleosome core and the complete nucleosome (the core plus H1 histone) are unique to eukaryotes. To explore whether the eukaryotic nucleosome can assemble in prokaryotes and to reconstruct the possible route for its emergence in eukaryogenesis, we developed an in vivo system for assembly of nucleosomes in the model bacterium, Escherichia coli, and successfully reconstituted the core nucleosome, the complete nucleosome, and unexpectedly the non-canonical (H3-H4)4 octasome. The core and complete nucleosomes assembled in E. coli exhibited footprints typical of eukaryotic hosts after in situ micrococcal nuclease digestion. Additionally, they caused condensation of E. coli nucleoid. We also demonstrated the stable formation of non-canonical (H3-H4)2 tetrasome and (H3-H4)4 octasomes in vivo, which are suggested to be ‘fossil complex’ that marks the intermediate in the progressive development of eukaryotic nucleosome. The study presents a unique platform in a bacterium for in vivo assembly and studying the properties of non-canonical variants of nucleosome. Development of an in vivo system for assembly of eukaryotic nucleosomes in Escherichia coli, including the non-canonical (H3-H4)4 octasome, suggests the H3-H4 tetrasome and octasomes are likely intermediate complexes in the evolution of the eukaryotic nucleosome.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":" ","pages":"1-12"},"PeriodicalIF":5.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07211-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616232","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 : 2024-11-14DOI: 10.1038/s42003-024-07015-6
Hao Wu, Douglas V. Guzior, Christian Martin, Kerri A. Neugebauer, Madison M. Rzepka, Julie C. Lumeng, Robert A. Quinn, Gustavo de los Campos
Population studies have shown that the infant’s microbiome and metabolome undergo significant changes in early childhood. However, no previous study has investigated how diverse these changes are across subjects and whether the subject-specific dynamics of some microbes correlate with the over-time dynamics of specific metabolites. Using mixed-effects models, and data from the ABC study, we investigated the early childhood dynamics of fecal microbiome and metabolome and identified 83 amplicon sequence variants (ASVs) and 753 metabolites with seemingly coordinated trajectories. Enrichment analysis of these microbes and molecules revealed eight ASV families and 23 metabolite groups involving 1032 ASV-metabolite pairs with their presence-absence changing in a coordinated fashion. Members of the Lachnospiraceae (464/1032) and metabolites related to cholestane steroids (309/1032) dominated proportional shifts within the fecal microbiome and metabolome as infants aged. Longitudinal analyses of subject-specific dynamics in infants’ microbiome and metabolome identified microbes and metabolites with seemingly coordinated dynamics.
{"title":"Longitudinal analyses of infants’ microbiome and metabolome reveal microbes and metabolites with seemingly coordinated dynamics","authors":"Hao Wu, Douglas V. Guzior, Christian Martin, Kerri A. Neugebauer, Madison M. Rzepka, Julie C. Lumeng, Robert A. Quinn, Gustavo de los Campos","doi":"10.1038/s42003-024-07015-6","DOIUrl":"10.1038/s42003-024-07015-6","url":null,"abstract":"Population studies have shown that the infant’s microbiome and metabolome undergo significant changes in early childhood. However, no previous study has investigated how diverse these changes are across subjects and whether the subject-specific dynamics of some microbes correlate with the over-time dynamics of specific metabolites. Using mixed-effects models, and data from the ABC study, we investigated the early childhood dynamics of fecal microbiome and metabolome and identified 83 amplicon sequence variants (ASVs) and 753 metabolites with seemingly coordinated trajectories. Enrichment analysis of these microbes and molecules revealed eight ASV families and 23 metabolite groups involving 1032 ASV-metabolite pairs with their presence-absence changing in a coordinated fashion. Members of the Lachnospiraceae (464/1032) and metabolites related to cholestane steroids (309/1032) dominated proportional shifts within the fecal microbiome and metabolome as infants aged. Longitudinal analyses of subject-specific dynamics in infants’ microbiome and metabolome identified microbes and metabolites with seemingly coordinated dynamics.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":" ","pages":"1-10"},"PeriodicalIF":5.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07015-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616153","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 : 2024-11-14DOI: 10.1038/s42003-024-07230-1
Rong Zhang, Jun Sun, Shuting Liu, Junjun Ding, Mengqing Xiang
The genome is intricately folded into chromatin compartments, topologically associating domains (TADs) and loops unique to each cell type. How this higher-order genome organization regulates cell fate transition remains elusive. Here we show how a single non-neural progenitor transcription factor, PTF1A, reorchestrates the 3D genome during fibroblast transdifferentiation into neural stem cells (NSCs). Multiomics analyses integrating Hi-C data, PTF1A and CTCF DNA-binding profiles, H3K27ac modification, and gene expression, demonstrate that PTF1A binds to subTAD boundaries subsequently associated with elevated CTCF binding and enhanced boundary insulation, and reorganizes chromatin loops, leading to gene expression changes that drive transdifferentiation into NSCs. Moreover, PTF1A activates enhancers and super-enhancers near low-insulation boundaries and modulates H3K27ac deposition, promoting cell fate transitions. Together, our data implicate an involvement of 3D genome in transcriptional and cell fate alterations, and highlight an essential role for PTF1A in gene expression control and multiscale 3D genome remodeling during cell reprogramming. This study explores the role of the transcription factor PTF1A in remodeling 3D genome architecture during the transdifferentiation of fibroblasts to neural stem cells, highlighting changes in gene expression and TAD organization.
{"title":"Multiscale 3D genome rewiring during PTF1A-mediated somatic cell reprogramming into neural stem cells","authors":"Rong Zhang, Jun Sun, Shuting Liu, Junjun Ding, Mengqing Xiang","doi":"10.1038/s42003-024-07230-1","DOIUrl":"10.1038/s42003-024-07230-1","url":null,"abstract":"The genome is intricately folded into chromatin compartments, topologically associating domains (TADs) and loops unique to each cell type. How this higher-order genome organization regulates cell fate transition remains elusive. Here we show how a single non-neural progenitor transcription factor, PTF1A, reorchestrates the 3D genome during fibroblast transdifferentiation into neural stem cells (NSCs). Multiomics analyses integrating Hi-C data, PTF1A and CTCF DNA-binding profiles, H3K27ac modification, and gene expression, demonstrate that PTF1A binds to subTAD boundaries subsequently associated with elevated CTCF binding and enhanced boundary insulation, and reorganizes chromatin loops, leading to gene expression changes that drive transdifferentiation into NSCs. Moreover, PTF1A activates enhancers and super-enhancers near low-insulation boundaries and modulates H3K27ac deposition, promoting cell fate transitions. Together, our data implicate an involvement of 3D genome in transcriptional and cell fate alterations, and highlight an essential role for PTF1A in gene expression control and multiscale 3D genome remodeling during cell reprogramming. This study explores the role of the transcription factor PTF1A in remodeling 3D genome architecture during the transdifferentiation of fibroblasts to neural stem cells, highlighting changes in gene expression and TAD organization.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":" ","pages":"1-18"},"PeriodicalIF":5.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07230-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616258","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}
The potency of frontline antimalarial drug artemisinin (ART) derivatives is triggered by heme-induced cleavage of the endoperoxide bond to form reactive heme-ART alkoxy radicals and covalent heme-ART adducts, which are highly toxic to the parasite. ART-resistant (ART-R) parasites with mutations in the Plasmodium falciparum Kelch-containing protein Kelch13 (PfKekch13) exhibit impaired hemoglobin uptake, reduced yield of hemoglobin-derived heme, and thus decreased ART activation. However, any direct involvement of PfKelch13 in heme-mediated ART activation has not been reported. Here, we show that the purified recombinant PfKelch13 wild-type (WT) protein displays measurable binding affinity for iron and heme, the main effectors for ART activation. The heme-binding property is also exhibited by the native PfKelch13 protein from parasite culture. The two ART-R recombinant PfKelch13 mutants (C580Y and R539T) display weaker heme binding affinities compared to the ART-sensitive WT and A578S mutant proteins, which further translates into reduced yield of heme-ART derivatives when ART is incubated with the heme molecules bound to the mutant PfKelch13 proteins. In conclusion, this study provides the first evidence for ART activation via the heme-binding propensity of PfKelch13. This mechanism may contribute to the modulation of ART-R levels in malaria parasites through a novel function of PfKelch13. Elucidation of heme binding affinity and artemisinin activation by the Plasmodium falciparum Kelch13 protein variants.
一线抗疟药物青蒿素（ART）衍生物的药效是由血红素诱导的内过氧键裂解形成活性血红素-ART 烷氧基自由基和共价血红素-ART 加合物引发的，后者对寄生虫有剧毒。恶性疟原虫含 Kelch 蛋白 Kelch13（PfKekch13）发生突变的抗逆转录病毒寄生虫（ART-R）表现出血红蛋白摄取受损、血红蛋白衍生血红素产量减少，从而降低了 ART 的活化。然而，PfKelch13 直接参与血红素介导的 ART 激活的情况尚未见报道。在这里，我们发现纯化的重组 PfKelch13 野生型（WT）蛋白与铁和血红素（ART 激活的主要效应物）具有可测量的结合亲和力。寄生虫培养物中的原生 PfKelch13 蛋白也具有血红素结合特性。与 ART 敏感的 WT 和 A578S 突变蛋白相比，两个 ART-R 重组 PfKelch13 突变体（C580Y 和 R539T）显示出较弱的血红素结合亲和力，当 ART 与结合到突变 PfKelch13 蛋白上的血红素分子孵育时，这进一步转化为血红素-ART 衍生物产量的减少。总之，本研究首次提供了通过 PfKelch13 的血红素结合倾向激活 ART 的证据。这一机制可能有助于通过 PfKelch13 的新功能调节疟原虫体内的 ART-R 水平。
{"title":"Artemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation","authors":"Abdur Rahman, Sabahat Tamseel, Smritikana Dutta, Nawaal Khan, Mohammad Faaiz, Harshita Rastogi, Jyoti Rani Nath, Kasturi Haldar, Pramit Chowdhury, Ashish, Souvik Bhattacharjee","doi":"10.1038/s42003-024-07178-2","DOIUrl":"10.1038/s42003-024-07178-2","url":null,"abstract":"The potency of frontline antimalarial drug artemisinin (ART) derivatives is triggered by heme-induced cleavage of the endoperoxide bond to form reactive heme-ART alkoxy radicals and covalent heme-ART adducts, which are highly toxic to the parasite. ART-resistant (ART-R) parasites with mutations in the Plasmodium falciparum Kelch-containing protein Kelch13 (PfKekch13) exhibit impaired hemoglobin uptake, reduced yield of hemoglobin-derived heme, and thus decreased ART activation. However, any direct involvement of PfKelch13 in heme-mediated ART activation has not been reported. Here, we show that the purified recombinant PfKelch13 wild-type (WT) protein displays measurable binding affinity for iron and heme, the main effectors for ART activation. The heme-binding property is also exhibited by the native PfKelch13 protein from parasite culture. The two ART-R recombinant PfKelch13 mutants (C580Y and R539T) display weaker heme binding affinities compared to the ART-sensitive WT and A578S mutant proteins, which further translates into reduced yield of heme-ART derivatives when ART is incubated with the heme molecules bound to the mutant PfKelch13 proteins. In conclusion, this study provides the first evidence for ART activation via the heme-binding propensity of PfKelch13. This mechanism may contribute to the modulation of ART-R levels in malaria parasites through a novel function of PfKelch13. Elucidation of heme binding affinity and artemisinin activation by the Plasmodium falciparum Kelch13 protein variants.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":" ","pages":"1-23"},"PeriodicalIF":5.2,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07178-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616176","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 : 2024-11-13DOI: 10.1038/s42003-024-07181-7
Adrián Villastrigo, Steven J. B. Cooper, Barbara Langille, Erinn P. Fagan-Jeffries, William F. Humphreys, Lars Hendrich, Michael Balke
Understanding the profound influence of climatic and tectonic histories on adaptation and speciation is a crucial focus in biology research. While voyages like Humboldt’s expedition shaped our understanding of adaptation, the origin of current biodiversity remains unclear – whether it arose in situ or through dispersal from analogous habitats. Situated in the geologically complex Australopacific region, our study focuses on Limbodessus diving beetles (Dytiscidae), a diverse genus distributed from underground aquifers in Western Australia to alpine meadows in New Guinea. Using low-coverage whole-genome sequencing, we established a time-calibrated phylogenetic tree, elucidating Limbodessus’ origin in the mid-late Miocene, most likely in the Sahul continent (i.e., Australia and New Guinea) and western Pacific archipelagos. Our results provide evidence for parallel colonization and speciation at extreme altitudinal ends, driven by aridification in Australia, influencing subterranean colonization, and in situ diversification of alpine taxa by passive-uplifting of local biota in New Guinea. Furthermore, our findings highlight instances of subterranean speciation in isolated underground aquifers, marked by recurrent independent colonizations of this habitat. This study on Limbodessus diving beetles reveals a mid-late Miocene origin in the Sahul region, with arid-driven subterranean speciation in Australia and alpine diversification in New Guinea through passive uplift.
{"title":"Aridification and major geotectonic landscape change shaped an extraordinary species radiation across a world’s extreme elevational gradient","authors":"Adrián Villastrigo, Steven J. B. Cooper, Barbara Langille, Erinn P. Fagan-Jeffries, William F. Humphreys, Lars Hendrich, Michael Balke","doi":"10.1038/s42003-024-07181-7","DOIUrl":"10.1038/s42003-024-07181-7","url":null,"abstract":"Understanding the profound influence of climatic and tectonic histories on adaptation and speciation is a crucial focus in biology research. While voyages like Humboldt’s expedition shaped our understanding of adaptation, the origin of current biodiversity remains unclear – whether it arose in situ or through dispersal from analogous habitats. Situated in the geologically complex Australopacific region, our study focuses on Limbodessus diving beetles (Dytiscidae), a diverse genus distributed from underground aquifers in Western Australia to alpine meadows in New Guinea. Using low-coverage whole-genome sequencing, we established a time-calibrated phylogenetic tree, elucidating Limbodessus’ origin in the mid-late Miocene, most likely in the Sahul continent (i.e., Australia and New Guinea) and western Pacific archipelagos. Our results provide evidence for parallel colonization and speciation at extreme altitudinal ends, driven by aridification in Australia, influencing subterranean colonization, and in situ diversification of alpine taxa by passive-uplifting of local biota in New Guinea. Furthermore, our findings highlight instances of subterranean speciation in isolated underground aquifers, marked by recurrent independent colonizations of this habitat. This study on Limbodessus diving beetles reveals a mid-late Miocene origin in the Sahul region, with arid-driven subterranean speciation in Australia and alpine diversification in New Guinea through passive uplift.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":" ","pages":"1-11"},"PeriodicalIF":5.2,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07181-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616172","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 : 2024-11-13DOI: 10.1038/s42003-024-07198-y
Cesar C. Ceballos, Lei Ma, Maozhen Qin, Haining Zhong
Several brain neuronal populations transmit both the excitatory and inhibitory neurotransmitters, glutamate, and GABA. However, it remains largely unknown whether these opposing neurotransmitters are co-released simultaneously or are independently transmitted at different times and locations. By recording from acute mouse brain slices, we observed biphasic miniature postsynaptic currents, i.e., minis with time-locked excitatory and inhibitory currents, in striatal spiny projection neurons. This observation cannot be explained by accidental coincidence of monophasic excitatory and inhibitory minis. Interestingly, these biphasic minis could either be an excitatory current leading an inhibitory current or vice versa. Deletion of dopaminergic neurons did not eliminate biphasic minis, indicating that they originate from another source. Importantly, we found that both types of biphasic minis were present in multiple striatal neuronal types and in nine out of ten other brain regions. Overall, co-release of glutamate and GABA appears to be a widespread mode of neurotransmission in the brain. Voltage clamp recording at an intermediate voltage shows that the two opposing neurotransmitters, glutamate and GABA, are co-released by a fraction of synapses in many regions throughout the brain.
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Ganoderic acids (GAs), a class of secondary metabolites produced by the traditional medicinal mushroom Ganoderma, are a group of triterpenoids with superior biological activities. Heat stress (HS) is one of the most important environmental abiotic stresses. Understanding how organisms sense temperature and integrate this information into their metabolism is important for determining how organisms adapt to climate change and for applying this knowledge to breeding. We previously reported that HS induced GA biosynthesis, and phospholipase D (PLD)-mediated phosphatidic acid (PA) was involved in HS-induced GA biosynthesis. We screened a proteome to identify the PA-binding proteins in G. lingzhi. We reported that PA directly interacted with mTOR and positively correlated with the ability of mTOR to promote GA biosynthesis under HS. The PA-activated mTOR pathway promoted the processing of the transcription factor sterol regulatory element-binding protein (SREBP) under HS, which directly activated GA biosynthesis. Our results suggest that SREBP is an intermediate of the PLD-mediated PA-interacting protein mTOR in HS-induced GA biosynthesis. Our report established the link between PLD-mediated PA production and the activation of mTOR and SREBP in the HS response and HS-induced secondary metabolism in filamentous fungi. A study on how organisms sense temperature and integrate this into their metabolism suggests that PLD-mediated PA directly activates mTOR and regulates SREBP to promote the transcription of target genes and GA biosynthesis under heat in G. lingzhi.
灵芝酸（GAs）是由传统药用蘑菇灵芝产生的一类次级代谢产物，是一类具有卓越生物活性的三萜类化合物。热胁迫（HS）是最重要的非生物环境胁迫之一。了解生物如何感知温度并将这一信息整合到其新陈代谢中，对于确定生物如何适应气候变化以及将这一知识应用于育种非常重要。我们以前曾报道过 HS 诱导 GA 的生物合成，而磷脂酶 D（PLD）介导的磷脂酸（PA）参与了 HS 诱导的 GA 生物合成。我们对蛋白质组进行了筛选，以确定灵芝中的 PA 结合蛋白。我们发现 PA 直接与 mTOR 相互作用，并与 mTOR 在 HS 诱导下促进 GA 生物合成的能力呈正相关。PA激活的mTOR通路促进了转录因子甾醇调节元件结合蛋白（SREBP）在HS条件下的加工，从而直接激活了GA的生物合成。我们的研究结果表明，在 HS 诱导的 GA 生物合成过程中，SREBP 是 PLD 介导的 PA 交互蛋白 mTOR 的中间产物。我们的报告建立了 PLD 介导的 PA 产生与 mTOR 和 SREBP 在 HS 响应和 HS 诱导的丝状真菌次生代谢中的激活之间的联系。
{"title":"Phosphatidic acid directly activates mTOR and then regulates SREBP to promote ganoderic acid biosynthesis under heat stress in Ganoderma lingzhi","authors":"Yong-Nan Liu, Yu-Lin Chen, Zi-Juan Zhang, Feng-Yuan Wu, Hao-Jin Wang, Xiao-Ling Wang, Gao-Qiang Liu","doi":"10.1038/s42003-024-07225-y","DOIUrl":"10.1038/s42003-024-07225-y","url":null,"abstract":"Ganoderic acids (GAs), a class of secondary metabolites produced by the traditional medicinal mushroom Ganoderma, are a group of triterpenoids with superior biological activities. Heat stress (HS) is one of the most important environmental abiotic stresses. Understanding how organisms sense temperature and integrate this information into their metabolism is important for determining how organisms adapt to climate change and for applying this knowledge to breeding. We previously reported that HS induced GA biosynthesis, and phospholipase D (PLD)-mediated phosphatidic acid (PA) was involved in HS-induced GA biosynthesis. We screened a proteome to identify the PA-binding proteins in G. lingzhi. We reported that PA directly interacted with mTOR and positively correlated with the ability of mTOR to promote GA biosynthesis under HS. The PA-activated mTOR pathway promoted the processing of the transcription factor sterol regulatory element-binding protein (SREBP) under HS, which directly activated GA biosynthesis. Our results suggest that SREBP is an intermediate of the PLD-mediated PA-interacting protein mTOR in HS-induced GA biosynthesis. Our report established the link between PLD-mediated PA production and the activation of mTOR and SREBP in the HS response and HS-induced secondary metabolism in filamentous fungi. A study on how organisms sense temperature and integrate this into their metabolism suggests that PLD-mediated PA directly activates mTOR and regulates SREBP to promote the transcription of target genes and GA biosynthesis under heat in G. lingzhi.","PeriodicalId":10552,"journal":{"name":"Communications Biology","volume":" ","pages":"1-13"},"PeriodicalIF":5.2,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42003-024-07225-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616282","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}
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