Josseline Ramos-Figueroa, Haoqian Liang, Wilfred A. van der Donk
The continuing discovery of new peptide-aminoacyl-tRNA ligases (PEARLs) has unveiled a diverse array of enzymes with the unique potential to append amino acids to the C terminus of substrate peptides in an aminoacyl-tRNA-dependent manner. To date, PEARLs have been reported that can conjugate Cys, Ala, Trp, Gly, Leu, Asn, and Thr residues, but the basis of peptide substrate and aminoacyl-tRNA recognition is not known. Cell-free expression (CFE) has emerged as a powerful tool to rapidly assay activity of substrate variants, and we used the technique in this study to investigate the peptide substrate specificity of the PEARL <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:msubsup> <mml:mrow> <mml:mi mathvariant="normal">B</mml:mi> <mml:mi mathvariant="normal">h</mml:mi> <mml:mi mathvariant="normal">a</mml:mi> <mml:mi mathvariant="normal">B</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant="normal">C</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant="normal">T</mml:mi> <mml:mi mathvariant="normal">r</mml:mi> <mml:mi mathvariant="normal">p</mml:mi> </mml:mrow> </mml:msubsup> </mml:math> </jats:inline-formula> . This enzyme that adds Trp was discovered previously during genome mining for ribosomally synthesized and posttranslational modified peptides (RiPPs). The enzyme is remarkably tolerant of changes to the C-terminal amino acid of the peptide substrate, and truncation and replacement experiments suggest a minimal sequence requirement. An AlphaFold3 model provided insights into binding interactions of the substrate peptide BhaA-Ala to <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:msubsup> <mml:mrow> <mml:mi mathvariant="normal">B</mml:mi> <mml:mi mathvariant="normal">h</mml:mi> <mml:mi mathvariant="normal">a</mml:mi> <mml:mi mathvariant="normal">B</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant="normal">C</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant="normal">T</mml:mi> <mml:mi mathvariant="normal">r</mml:mi> <mml:mi mathvariant="normal">p</mml:mi> </mml:mrow> </mml:msubsup> </mml:math> </jats:inline-formula> and also generated predictions for tRNA, ATP, and Mg <jats:sup>2+</jats:sup> binding modes that were tested by site-directed mutagenesis. The data suggest that several highly conserved residues in PEARLs recognize the 3′-CCA sequence present in all tRNAs. The minimal sequence required for Trp incorporation by <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:msubsup> <mml:mrow> <mml:mi mathvariant="normal">B</mml:mi> <mml:mi mathvariant="normal">h</mml:mi> <mml:mi mathvariant="normal">a</mml:mi> <mml:mi mathvariant="normal">B</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant="normal">C</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant="normal">T</mml:mi> <mml:mi mathvariant="normal">r</mml:mi> <mml:mi mathvariant="
{"title":"Substrate recognition by a peptide-aminoacyl-tRNA ligase","authors":"Josseline Ramos-Figueroa, Haoqian Liang, Wilfred A. van der Donk","doi":"10.1073/pnas.2423858122","DOIUrl":"https://doi.org/10.1073/pnas.2423858122","url":null,"abstract":"The continuing discovery of new peptide-aminoacyl-tRNA ligases (PEARLs) has unveiled a diverse array of enzymes with the unique potential to append amino acids to the C terminus of substrate peptides in an aminoacyl-tRNA-dependent manner. To date, PEARLs have been reported that can conjugate Cys, Ala, Trp, Gly, Leu, Asn, and Thr residues, but the basis of peptide substrate and aminoacyl-tRNA recognition is not known. Cell-free expression (CFE) has emerged as a powerful tool to rapidly assay activity of substrate variants, and we used the technique in this study to investigate the peptide substrate specificity of the PEARL <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:msubsup> <mml:mrow> <mml:mi mathvariant=\"normal\">B</mml:mi> <mml:mi mathvariant=\"normal\">h</mml:mi> <mml:mi mathvariant=\"normal\">a</mml:mi> <mml:mi mathvariant=\"normal\">B</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant=\"normal\">C</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant=\"normal\">T</mml:mi> <mml:mi mathvariant=\"normal\">r</mml:mi> <mml:mi mathvariant=\"normal\">p</mml:mi> </mml:mrow> </mml:msubsup> </mml:math> </jats:inline-formula> . This enzyme that adds Trp was discovered previously during genome mining for ribosomally synthesized and posttranslational modified peptides (RiPPs). The enzyme is remarkably tolerant of changes to the C-terminal amino acid of the peptide substrate, and truncation and replacement experiments suggest a minimal sequence requirement. An AlphaFold3 model provided insights into binding interactions of the substrate peptide BhaA-Ala to <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:msubsup> <mml:mrow> <mml:mi mathvariant=\"normal\">B</mml:mi> <mml:mi mathvariant=\"normal\">h</mml:mi> <mml:mi mathvariant=\"normal\">a</mml:mi> <mml:mi mathvariant=\"normal\">B</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant=\"normal\">C</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant=\"normal\">T</mml:mi> <mml:mi mathvariant=\"normal\">r</mml:mi> <mml:mi mathvariant=\"normal\">p</mml:mi> </mml:mrow> </mml:msubsup> </mml:math> </jats:inline-formula> and also generated predictions for tRNA, ATP, and Mg <jats:sup>2+</jats:sup> binding modes that were tested by site-directed mutagenesis. The data suggest that several highly conserved residues in PEARLs recognize the 3′-CCA sequence present in all tRNAs. The minimal sequence required for Trp incorporation by <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:msubsup> <mml:mrow> <mml:mi mathvariant=\"normal\">B</mml:mi> <mml:mi mathvariant=\"normal\">h</mml:mi> <mml:mi mathvariant=\"normal\">a</mml:mi> <mml:mi mathvariant=\"normal\">B</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant=\"normal\">C</mml:mi> </mml:mrow> <mml:mrow> <mml:mi mathvariant=\"normal\">T</mml:mi> <mml:mi mathvariant=\"normal\">r</mml:mi> <mml:mi mathvariant=\"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"47 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661473","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}
Sexual dimorphism in immune responses is well documented, but the underlying mechanisms remain incompletely understood. Here, we identified a subset of corticotropin-releasing hormone (CRH) neurons that express androgen receptors (ARs) as key mediators of sex differences in restraint-induced immunosuppression. Mechanistically, androgens directly activate AR-positive CRH neurons, enhancing the hypothalamic–pituitary–adrenal axis activation. This results in elevated corticosterone levels in response to restraint stress, leading to increased immune cell apoptosis and immune organ atrophy in male mice. Conditional knockout of ARs in CRH neurons eliminated this sexual dimorphism, highlighting ARs in CRH neurons as pivotal regulators of sex-specific immune responses to stress.
{"title":"Androgen receptors in corticotropin-releasing hormone neurons mediate the sexual dimorphism in restraint-induced thymic atrophy","authors":"Yutong Meng, Yaning Li, Huating Gu, Ziyao Chen, Xiaoyang Cui, Xiaodong Wang","doi":"10.1073/pnas.2426107122","DOIUrl":"https://doi.org/10.1073/pnas.2426107122","url":null,"abstract":"Sexual dimorphism in immune responses is well documented, but the underlying mechanisms remain incompletely understood. Here, we identified a subset of corticotropin-releasing hormone (CRH) neurons that express androgen receptors (ARs) as key mediators of sex differences in restraint-induced immunosuppression. Mechanistically, androgens directly activate AR-positive CRH neurons, enhancing the hypothalamic–pituitary–adrenal axis activation. This results in elevated corticosterone levels in response to restraint stress, leading to increased immune cell apoptosis and immune organ atrophy in male mice. Conditional knockout of ARs in CRH neurons eliminated this sexual dimorphism, highlighting ARs in CRH neurons as pivotal regulators of sex-specific immune responses to stress.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"40 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661475","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}
Ryosuke Yamamoto, Yui Sahashi, Rieko Shimo-Kon, Miho Sakato-Antoku, Miyuka Suzuki, Leo Luo, Hideaki Tanaka, Takashi Ishikawa, Toshiki Yagi, Stephen M. King, Genji Kurisu, Takahide Kon
Motile cilia are organelles found on many eukaryotic cells that play critical roles in development and fertility. Human CFAP298 has been implicated in the transport/assembly of ciliary dyneins, and defects in this protein cause primary ciliary dyskinesia. However, neither the exact function nor the structure of CFAP298 have been elucidated. Here, we took advantage of Chlamydomonas , a ciliated alga, to study the structure and function of FBB18, an ortholog of CFAP298. Multiple ciliary dyneins were greatly reduced in cilia of Chlamydomonas fbb18 mutants. In addition, we found that both the stability of ciliary dynein heavy chains (HCs) and the association between HCs and intermediate/light chains (IC/LCs) are greatly reduced in fbb18 cytoplasm, strongly suggesting that FBB18 functions in the cytoplasmic assembly (the so-called “preassembly”) of dynein complexes from HC/IC/LCs. Furthermore, X-ray crystallography revealed that FBB18 forms a bilobed structure with globular domains at both ends of the molecule, connected by an α-helical bundle. Unexpectedly, one globular domain shows high similarity to ubiquitin, a small protein critical for the modification of a variety of protein complexes, and this ubiquitin-like domain is indispensable for the molecular function of FBB18. Our results demonstrate that FBB18, a specialized member of the ubiquitin-like protein family, plays a critical role in dynein preassembly, most likely by mediating diverse interactions between dynein HCs, molecular chaperone(s), and other preassembly factor(s) using the ubiquitin-like domain as well as other regions, and by facilitating the proper folding of dynein HCs.
{"title":"Chlamydomonas FBB18 is a ubiquitin-like protein essential for the cytoplasmic preassembly of various ciliary dyneins","authors":"Ryosuke Yamamoto, Yui Sahashi, Rieko Shimo-Kon, Miho Sakato-Antoku, Miyuka Suzuki, Leo Luo, Hideaki Tanaka, Takashi Ishikawa, Toshiki Yagi, Stephen M. King, Genji Kurisu, Takahide Kon","doi":"10.1073/pnas.2423948122","DOIUrl":"https://doi.org/10.1073/pnas.2423948122","url":null,"abstract":"Motile cilia are organelles found on many eukaryotic cells that play critical roles in development and fertility. Human CFAP298 has been implicated in the transport/assembly of ciliary dyneins, and defects in this protein cause primary ciliary dyskinesia. However, neither the exact function nor the structure of CFAP298 have been elucidated. Here, we took advantage of <jats:italic>Chlamydomonas</jats:italic> , a ciliated alga, to study the structure and function of FBB18, an ortholog of CFAP298. Multiple ciliary dyneins were greatly reduced in cilia of <jats:italic>Chlamydomonas fbb18</jats:italic> mutants. In addition, we found that both the stability of ciliary dynein heavy chains (HCs) and the association between HCs and intermediate/light chains (IC/LCs) are greatly reduced in <jats:italic>fbb18</jats:italic> cytoplasm, strongly suggesting that FBB18 functions in the cytoplasmic assembly (the so-called “preassembly”) of dynein complexes from HC/IC/LCs. Furthermore, X-ray crystallography revealed that FBB18 forms a bilobed structure with globular domains at both ends of the molecule, connected by an α-helical bundle. Unexpectedly, one globular domain shows high similarity to ubiquitin, a small protein critical for the modification of a variety of protein complexes, and this ubiquitin-like domain is indispensable for the molecular function of FBB18. Our results demonstrate that FBB18, a specialized member of the ubiquitin-like protein family, plays a critical role in dynein preassembly, most likely by mediating diverse interactions between dynein HCs, molecular chaperone(s), and other preassembly factor(s) using the ubiquitin-like domain as well as other regions, and by facilitating the proper folding of dynein HCs.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"88 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661474","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}
Tian-Chen Zhu, Zhang-Ping He, Shu-Ting Li, Lin Zheng, Xue-Yi Zheng, Xia-Lu Lan, Chun-Hua Qu, Run-Cong Nie, Chao Gu, Li-Ning Huang, Xiao-Xia Cai, Zhi-Cheng Xiang, Dan Xie, Mu-Yan Cai
Poly-ADP-ribose polymerase (PARP) inhibitors are vital therapeutic agents that exploit synthetic lethality, particularly effective in tumors with homologous recombination (HR) defects. However, broadening their clinical utility remains a significant challenge. In this study, we conducted a high-throughput kinase inhibitor screen to identify potential targets exhibiting synthetical lethality with PARP inhibitors. Our results show that thousand and one amino acid protein kinase 1 (TAOK1) plays a pivotal role in the DNA damage response by phosphorylating ubiquitin specific peptidase 7 (USP7), thereby promoting its enzymatic activity and preventing the ubiquitylation and subsequent degradation of RAD51, a crucial protein in the filament formation of HR repair. Notably, genetic depletion or pharmacological inhibition of TAOK1, as well as blocking peptide targeting the USP7 phosphorylation site, impaired USP7 function, leading to RAD51 degradation, disruption of HR repair, and increased tumor cell and sensitivity to PARP inhibition. This study highlights TAOK1 as a critical regulator of HR repair pathway in human cancer cells and presents a therapeutic strategy overcoming resistance to PARPi inhibitors. These findings support the potential clinical application of combining PARP inhibitors with TAOK1 inhibition or peptide treatment to improve therapeutic outcomes.
{"title":"TAOK1 promotes filament formation in HR repair through phosphorylating USP7","authors":"Tian-Chen Zhu, Zhang-Ping He, Shu-Ting Li, Lin Zheng, Xue-Yi Zheng, Xia-Lu Lan, Chun-Hua Qu, Run-Cong Nie, Chao Gu, Li-Ning Huang, Xiao-Xia Cai, Zhi-Cheng Xiang, Dan Xie, Mu-Yan Cai","doi":"10.1073/pnas.2422262122","DOIUrl":"https://doi.org/10.1073/pnas.2422262122","url":null,"abstract":"Poly-ADP-ribose polymerase (PARP) inhibitors are vital therapeutic agents that exploit synthetic lethality, particularly effective in tumors with homologous recombination (HR) defects. However, broadening their clinical utility remains a significant challenge. In this study, we conducted a high-throughput kinase inhibitor screen to identify potential targets exhibiting synthetical lethality with PARP inhibitors. Our results show that thousand and one amino acid protein kinase 1 (TAOK1) plays a pivotal role in the DNA damage response by phosphorylating ubiquitin specific peptidase 7 (USP7), thereby promoting its enzymatic activity and preventing the ubiquitylation and subsequent degradation of RAD51, a crucial protein in the filament formation of HR repair. Notably, genetic depletion or pharmacological inhibition of TAOK1, as well as blocking peptide targeting the USP7 phosphorylation site, impaired USP7 function, leading to RAD51 degradation, disruption of HR repair, and increased tumor cell and sensitivity to PARP inhibition. This study highlights TAOK1 as a critical regulator of HR repair pathway in human cancer cells and presents a therapeutic strategy overcoming resistance to PARPi inhibitors. These findings support the potential clinical application of combining PARP inhibitors with TAOK1 inhibition or peptide treatment to improve therapeutic outcomes.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"19 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661476","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}
Stefanie Muroya, Krishnendu Chatterjee, Thomas A. Henzinger
Quantum hardware is inherently fragile and noisy. We find that the accuracy of traditional quantum error correction algorithms can be improved depending on the hardware. Given different hardware specifications, we automatically synthesize hardware-optimal algorithms for parity correction, qubit resetting, and GHZ (Greenberger–Horne–Zeilinger) state preparation. Using stochastic techniques from computer science, our method presents a computational tool to compute exact accuracy guarantees and synthesize optimal algorithms that are often different from traditional ones. We also show that improvements can be gained with respect to the Qiskit transpiler as we compute the hardware-optimal qubit mapping for the GHZ state-preparation problem.
{"title":"Hardware-optimal quantum algorithms","authors":"Stefanie Muroya, Krishnendu Chatterjee, Thomas A. Henzinger","doi":"10.1073/pnas.2419273122","DOIUrl":"https://doi.org/10.1073/pnas.2419273122","url":null,"abstract":"Quantum hardware is inherently fragile and noisy. We find that the accuracy of traditional quantum error correction algorithms can be improved depending on the hardware. Given different hardware specifications, we automatically synthesize hardware-optimal algorithms for parity correction, qubit resetting, and GHZ (Greenberger–Horne–Zeilinger) state preparation. Using stochastic techniques from computer science, our method presents a computational tool to compute exact accuracy guarantees and synthesize optimal algorithms that are often different from traditional ones. We also show that improvements can be gained with respect to the Qiskit transpiler as we compute the hardware-optimal qubit mapping for the GHZ state-preparation problem.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"88 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661221","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}
Xue Qiao, Alan Houghton, James Reed, Burkhard Steuernagel, Jiahe Zhang, Charlotte Owen, Aymeric Leveau, Anastasia Orme, Thomas Louveau, Rachel Melton, Brande B. H. Wulff, Anne Osbourn
Plants produce diverse specialized metabolites with important ecological functions. It has recently become apparent that the genes for many of these pathways are not dispersed in plant genomes, but rather are arranged like beads on a string in biosynthetic gene clusters (BGCs). Pathways encoded by BGCs are as a rule dedicated linear pathways that do not form parts of wider metabolic networks. In contrast, the genes for the biosynthesis of widely distributed more ancestral metabolites such as carotenoids and anthocyanins are not clustered. Little is known about how these more recently evolved clustered pathways interact with general plant metabolism. We recently characterized a 12-gene BGC for the biosynthesis of the antimicrobial defense compound avenacin A-1, a triterpene glycoside produced by oats. Avenacin A-1 is acylated with the fluorophore N -methyl anthranilate and confers bright blue fluorescence of oat root tips under ultraviolet light. Here, we exploit a suite of >100 avenacin-deficient mutants identified by screening for reduced root fluorescence to identify genes required for the function of this paradigm BGC. Using a combination of mutant chemotyping, biochemical and molecular analysis, and genome resequencing, we identify two nonclustered genes ( Sad4 and Pal2 ) encoding enzymes that synthesize the donors required for avenacin glycosylation and acylation (recruited from the phenylpropanoid and tryptophan pathways). Our finding of these Cluster Auxiliary Enzymes (CAEs) provides insights into the interplay between general plant metabolism and a newly evolved lineage-specific BGC.
{"title":"Comprehensive mutant chemotyping reveals embedding of a lineage-specific biosynthetic gene cluster in wider plant metabolism","authors":"Xue Qiao, Alan Houghton, James Reed, Burkhard Steuernagel, Jiahe Zhang, Charlotte Owen, Aymeric Leveau, Anastasia Orme, Thomas Louveau, Rachel Melton, Brande B. H. Wulff, Anne Osbourn","doi":"10.1073/pnas.2417588122","DOIUrl":"https://doi.org/10.1073/pnas.2417588122","url":null,"abstract":"Plants produce diverse specialized metabolites with important ecological functions. It has recently become apparent that the genes for many of these pathways are not dispersed in plant genomes, but rather are arranged like beads on a string in biosynthetic gene clusters (BGCs). Pathways encoded by BGCs are as a rule dedicated linear pathways that do not form parts of wider metabolic networks. In contrast, the genes for the biosynthesis of widely distributed more ancestral metabolites such as carotenoids and anthocyanins are not clustered. Little is known about how these more recently evolved clustered pathways interact with general plant metabolism. We recently characterized a 12-gene BGC for the biosynthesis of the antimicrobial defense compound avenacin A-1, a triterpene glycoside produced by oats. Avenacin A-1 is acylated with the fluorophore <jats:italic>N</jats:italic> -methyl anthranilate and confers bright blue fluorescence of oat root tips under ultraviolet light. Here, we exploit a suite of >100 avenacin-deficient mutants identified by screening for reduced root fluorescence to identify genes required for the function of this paradigm BGC. Using a combination of mutant chemotyping, biochemical and molecular analysis, and genome resequencing, we identify two nonclustered genes ( <jats:italic>Sad4</jats:italic> and <jats:italic>Pal2</jats:italic> ) encoding enzymes that synthesize the donors required for avenacin glycosylation and acylation (recruited from the phenylpropanoid and tryptophan pathways). Our finding of these Cluster Auxiliary Enzymes (CAEs) provides insights into the interplay between general plant metabolism and a newly evolved lineage-specific BGC.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"1 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661471","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}
Zoltán Taracsák, Margaret E. Hartley, Ray Burgess, Marie Edmonds, Marc-Antoine Longpré, Brian D. Monteleone, Romain Tartèse, Alexandra V. Turchyn
The global sulfur cycle plays a critical role in the redox evolution of Earth’s surface and upper mantle, yet the distribution and origin of sulfur in the mantle remains largely unconstrained. El Hierro is a volcanic island in the Canary archipelago that is fed by sulfur-rich magmas. To constrain the origin of sulfur in these melts, we combine in situ sulfur isotope analyses with regression modeling. We calculate that undegassed El Hierro melts have δ34 S values of 0 ± 2‰. The average δ34 S of undegassed El Hierro melts is 0.3‰ to 1‰ higher than magmas erupting at mid-ocean ridges. Mass balance calculations reveal that El Hierro’s mantle source contains 310 ± 120 μg/g sulfur and that on average 60% of sulfur in the source is of recycled origin. This recycled material should contain >1,800 μg/g sulfur to satisfy isotopic constraints on its mass fraction in the mantle source. The sulfur and oxygen isotopic signature in serpentinites and sediments deviate significantly from the upper mantle, making them unsuitable candidates for the recycled material. An oxidized partial melt of recycled oceanic crust that retained one third of its sulfur budget after subduction zone processing can explain excess sulfur in the Canary Island mantle. Recycled oceanic crust is expected to contain sulfur as sulfide, which is not capable of oxidizing the mantle. The presence of ferric iron in the recycled component is necessary to produce metasomatic melts that are oxidizing enough to carry sufficient sulfur into the mantle source of ocean island basalts.
{"title":"The origin of sulfur in Canary Island magmas and its implications for Earth’s deep sulfur cycle","authors":"Zoltán Taracsák, Margaret E. Hartley, Ray Burgess, Marie Edmonds, Marc-Antoine Longpré, Brian D. Monteleone, Romain Tartèse, Alexandra V. Turchyn","doi":"10.1073/pnas.2416070122","DOIUrl":"https://doi.org/10.1073/pnas.2416070122","url":null,"abstract":"The global sulfur cycle plays a critical role in the redox evolution of Earth’s surface and upper mantle, yet the distribution and origin of sulfur in the mantle remains largely unconstrained. El Hierro is a volcanic island in the Canary archipelago that is fed by sulfur-rich magmas. To constrain the origin of sulfur in these melts, we combine in situ sulfur isotope analyses with regression modeling. We calculate that undegassed El Hierro melts have <jats:italic>δ</jats:italic> <jats:sup>34</jats:sup> S values of 0 ± 2‰. The average <jats:italic>δ</jats:italic> <jats:sup>34</jats:sup> S of undegassed El Hierro melts is 0.3‰ to 1‰ higher than magmas erupting at mid-ocean ridges. Mass balance calculations reveal that El Hierro’s mantle source contains 310 ± 120 μg/g sulfur and that on average 60% of sulfur in the source is of recycled origin. This recycled material should contain >1,800 μg/g sulfur to satisfy isotopic constraints on its mass fraction in the mantle source. The sulfur and oxygen isotopic signature in serpentinites and sediments deviate significantly from the upper mantle, making them unsuitable candidates for the recycled material. An oxidized partial melt of recycled oceanic crust that retained one third of its sulfur budget after subduction zone processing can explain excess sulfur in the Canary Island mantle. Recycled oceanic crust is expected to contain sulfur as sulfide, which is not capable of oxidizing the mantle. The presence of ferric iron in the recycled component is necessary to produce metasomatic melts that are oxidizing enough to carry sufficient sulfur into the mantle source of ocean island basalts.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"2 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661477","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 : 2025-03-18Epub Date: 2025-03-06DOI: 10.1073/pnas.2418978122
Bruce M Jakosky
{"title":"Results from the <i>inSight</i> Mars mission do not require a water-saturated mid crust.","authors":"Bruce M Jakosky","doi":"10.1073/pnas.2418978122","DOIUrl":"https://doi.org/10.1073/pnas.2418978122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 11","pages":"e2418978122"},"PeriodicalIF":9.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573691","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 : 2025-03-18Epub Date: 2025-03-10DOI: 10.1073/pnas.2501894122
Robert A Francis
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Aaron Mychack, Dwayne Evans, Tarah Gilles, Michael J. James, Suzanne Walker
Staphylococcus aureus is a Gram-positive pathogen responsible for numerous antibiotic-resistant infections. Identifying vulnerabilities in S. aureus is crucial for developing new antibiotics to treat these infections. With this in mind, we probed the function of GdpS, a conserved Staphylococcal membrane protein containing a cytoplasmic GGDEF domain. These domains are canonically involved in cyclic-di-GMP signaling processes, but S. aureus is not known to make cyclic-di-GMP. Using a transposon screen, we found that loss of GdpS is lethal when combined with disruption in synthesis of the glycolipid anchor of a cell surface polymer called lipoteichoic acid (LTA) or with deletion of genes important in cell division. Taking advantage of a small molecule that inhibits LTA glycolipid anchor synthesis, we selected for suppressors of Δ gdpS lethality. The most prevalent suppressors were hypermorphic alleles of dgkB , which encodes a soluble diacylglycerol (DAG) kinase required to recycle DAG to phosphatidylglycerol. By following up on these suppressors, we found that the GGDEF domain of GdpS interacts directly with DgkB, orienting its active site at the membrane to promote DAG recycling. DAG kinase hypermorphs also suppressed the lethality caused by combined loss of gdpS and cell division factors, highlighting the importance of lipid homeostasis for cell division. GdpS’ positive regulation of DAG kinase function was dependent on the GGDEF domain but not its catalytic residues. As the sole conserved GGDEF-domain protein in Staphylococci, GdpS promotes an enzymatic process independent of cyclic-di-GMP signaling, revealing a new function for the ubiquitously conserved GGDEF domain.
{"title":"Staphylococcus aureus uses a GGDEF protein to recruit diacylglycerol kinase to the membrane for lipid recycling","authors":"Aaron Mychack, Dwayne Evans, Tarah Gilles, Michael J. James, Suzanne Walker","doi":"10.1073/pnas.2414696122","DOIUrl":"https://doi.org/10.1073/pnas.2414696122","url":null,"abstract":"<jats:italic>Staphylococcus aureus</jats:italic> is a Gram-positive pathogen responsible for numerous antibiotic-resistant infections. Identifying vulnerabilities in <jats:italic>S. aureus</jats:italic> is crucial for developing new antibiotics to treat these infections. With this in mind, we probed the function of GdpS, a conserved Staphylococcal membrane protein containing a cytoplasmic GGDEF domain. These domains are canonically involved in cyclic-di-GMP signaling processes, but <jats:italic>S. aureus</jats:italic> is not known to make cyclic-di-GMP. Using a transposon screen, we found that loss of GdpS is lethal when combined with disruption in synthesis of the glycolipid anchor of a cell surface polymer called lipoteichoic acid (LTA) or with deletion of genes important in cell division. Taking advantage of a small molecule that inhibits LTA glycolipid anchor synthesis, we selected for suppressors of Δ <jats:italic>gdpS</jats:italic> lethality. The most prevalent suppressors were hypermorphic alleles of <jats:italic>dgkB</jats:italic> , which encodes a soluble diacylglycerol (DAG) kinase required to recycle DAG to phosphatidylglycerol. By following up on these suppressors, we found that the GGDEF domain of GdpS interacts directly with DgkB, orienting its active site at the membrane to promote DAG recycling. DAG kinase hypermorphs also suppressed the lethality caused by combined loss of <jats:italic>gdpS</jats:italic> and cell division factors, highlighting the importance of lipid homeostasis for cell division. GdpS’ positive regulation of DAG kinase function was dependent on the GGDEF domain but not its catalytic residues. As the sole conserved GGDEF-domain protein in Staphylococci, GdpS promotes an enzymatic process independent of cyclic-di-GMP signaling, revealing a new function for the ubiquitously conserved GGDEF domain.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"28 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653404","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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