Pub Date : 2024-08-28DOI: 10.1016/j.cell.2024.08.004
Tao Long, Dongyu Li, Goncalo Vale, Yaoyukun Jiang, Philip Schmiege, Zhongyue J. Yang, Jeffrey G. McDonald, Xiaochun Li
In mammalian cells, two phosphatidylserine (PS) synthases drive PS synthesis. Gain-of-function mutations in the Ptdss1 gene lead to heightened PS production, causing Lenz-Majewski syndrome (LMS). Recently, pharmacological inhibition of PSS1 has been shown to suppress tumorigenesis. Here, we report the cryo-EM structures of wild-type human PSS1 (PSS1WT), the LMS-causing Pro269Ser mutant (PSS1P269S), and PSS1WT in complex with its inhibitor DS55980254. PSS1 contains 10 transmembrane helices (TMs), with TMs 4–8 forming a catalytic core in the luminal leaflet. These structures revealed a working mechanism of PSS1 akin to the postulated mechanisms of the membrane-bound O-acyltransferase family. Additionally, we showed that both PS and DS55980254 can allosterically inhibit PSS1 and that inhibition by DS55980254 activates the SREBP pathways, thus enhancing the expression of LDL receptors and increasing cellular LDL uptake. This work uncovers a mechanism of mammalian PS synthesis and suggests that selective PSS1 inhibitors have the potential to lower blood cholesterol levels.
{"title":"Molecular insights into human phosphatidylserine synthase 1 reveal its inhibition promotes LDL uptake","authors":"Tao Long, Dongyu Li, Goncalo Vale, Yaoyukun Jiang, Philip Schmiege, Zhongyue J. Yang, Jeffrey G. McDonald, Xiaochun Li","doi":"10.1016/j.cell.2024.08.004","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.004","url":null,"abstract":"<p>In mammalian cells, two phosphatidylserine (PS) synthases drive PS synthesis. Gain-of-function mutations in the <em>Ptdss1</em> gene lead to heightened PS production, causing Lenz-Majewski syndrome (LMS). Recently, pharmacological inhibition of PSS1 has been shown to suppress tumorigenesis. Here, we report the cryo-EM structures of wild-type human PSS1 (PSS1<sup>WT</sup>), the LMS-causing Pro269Ser mutant (PSS1<sup>P269S</sup>), and PSS1<sup>WT</sup> in complex with its inhibitor DS55980254. PSS1 contains 10 transmembrane helices (TMs), with TMs 4–8 forming a catalytic core in the luminal leaflet. These structures revealed a working mechanism of PSS1 akin to the postulated mechanisms of the membrane-bound <em>O</em>-acyltransferase family. Additionally, we showed that both PS and DS55980254 can allosterically inhibit PSS1 and that inhibition by DS55980254 activates the SREBP pathways, thus enhancing the expression of LDL receptors and increasing cellular LDL uptake. This work uncovers a mechanism of mammalian PS synthesis and suggests that selective PSS1 inhibitors have the potential to lower blood cholesterol levels.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.cell.2024.07.053
Judit J. Penzes, Martin Holm, Samantha A. Yost, Jason T. Kaelber
We use cryoelectron microscopy (cryo-EM) as a sequence- and culture-independent diagnostic tool to identify the etiological agent of an agricultural pandemic. For the past 4 years, American insect-rearing facilities have experienced a distinctive larval pathology and colony collapse of farmed Zophobas morio (superworm). By means of cryo-EM, we discovered the causative agent: a densovirus that we named Zophobas morio black wasting virus (ZmBWV). We confirmed the etiology of disease by fulfilling Koch’s postulates and characterizing strains from across the United States. ZmBWV is a member of the family Parvoviridae with a 5,542 nt genome, and we describe intersubunit interactions explaining its expanded internal volume relative to human parvoviruses. Cryo-EM structures at resolutions up to 2.1 Å revealed single-strand DNA (ssDNA) ordering at the capsid inner surface pinned by base-binding pockets in the capsid inner surface. Also, we demonstrated the prophylactic potential of non-pathogenic strains to provide cross-protection in vivo.
{"title":"Cryo-EM-based discovery of a pathogenic parvovirus causing epidemic mortality by black wasting disease in farmed beetles","authors":"Judit J. Penzes, Martin Holm, Samantha A. Yost, Jason T. Kaelber","doi":"10.1016/j.cell.2024.07.053","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.053","url":null,"abstract":"<p>We use cryoelectron microscopy (cryo-EM) as a sequence- and culture-independent diagnostic tool to identify the etiological agent of an agricultural pandemic. For the past 4 years, American insect-rearing facilities have experienced a distinctive larval pathology and colony collapse of farmed <em>Zophobas morio</em> (superworm). By means of cryo-EM, we discovered the causative agent: a densovirus that we named <em>Zophobas morio</em> black wasting virus (ZmBWV). We confirmed the etiology of disease by fulfilling Koch’s postulates and characterizing strains from across the United States. ZmBWV is a member of the family <em>Parvoviridae</em> with a 5,542 nt genome, and we describe intersubunit interactions explaining its expanded internal volume relative to human parvoviruses. Cryo-EM structures at resolutions up to 2.1 Å revealed single-strand DNA (ssDNA) ordering at the capsid inner surface pinned by base-binding pockets in the capsid inner surface. Also, we demonstrated the prophylactic potential of non-pathogenic strains to provide cross-protection <em>in vivo</em>.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1016/j.cell.2024.07.047
Guangyan Wu, Tianji Ma, Clare E. Hancock, Santiago Gonzalez, Binod Aryal, Sharon Vaz, Gabrielle Chan, Madison Palarca-Wong, Nick Allen, Chan-I. Chung, Xiaokun Shu, Qili Liu
Animals defend a target level for their fundamental needs, including food, water, and sleep. Deviation from the target range, or “setpoint,” triggers motivated behaviors to eliminate that difference. Whether and how the setpoint itself is encoded remains enigmatic for all motivated behaviors. Employing a high-throughput feeding assay in Drosophila, we demonstrate that the protein intake setpoint is set to different values in male, virgin female, and mated female flies to meet their varying protein demands. Leveraging this setpoint variability, we found, remarkably, that the information on the intake setpoint is stored within the protein hunger neurons as the resting membrane potential. Two RFamide G protein-coupled receptor (GPCR) pathways, by tuning the resting membrane potential in opposite directions, coordinately program and adjust the protein intake setpoint. Together, our studies map the protein intake setpoint to a single trackable physiological parameter and elucidate the cellular and molecular mechanisms underlying setpoint determination and modulation.
动物对食物、水和睡眠等基本需求都有一个目标值。偏离目标范围或 "设定点 "会引发动机行为,以消除这种差异。对于所有动机行为来说,设定点本身是否以及如何编码仍然是个谜。我们利用果蝇的高通量喂养试验证明,雄蝇、处子雌蝇和交配雌蝇的蛋白质摄入设定值是不同的,以满足它们对蛋白质的不同需求。利用这种设定值的可变性,我们发现,摄入设定值的信息以静息膜电位的形式储存在蛋白质饥饿神经元中。两个射频酰胺 G 蛋白偶联受体(GPCR)通路通过向相反方向调节静息膜电位,协调地编程和调整蛋白质摄入设定点。我们的研究共同将蛋白质摄入量设定点映射为一个可跟踪的生理参数,并阐明了设定点确定和调节的细胞和分子机制。
{"title":"Opposing GPCR signaling programs protein intake setpoint in Drosophila","authors":"Guangyan Wu, Tianji Ma, Clare E. Hancock, Santiago Gonzalez, Binod Aryal, Sharon Vaz, Gabrielle Chan, Madison Palarca-Wong, Nick Allen, Chan-I. Chung, Xiaokun Shu, Qili Liu","doi":"10.1016/j.cell.2024.07.047","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.047","url":null,"abstract":"<p>Animals defend a target level for their fundamental needs, including food, water, and sleep. Deviation from the target range, or “setpoint,” triggers motivated behaviors to eliminate that difference. Whether and how the setpoint itself is encoded remains enigmatic for all motivated behaviors. Employing a high-throughput feeding assay in <em>Drosophila</em>, we demonstrate that the protein intake setpoint is set to different values in male, virgin female, and mated female flies to meet their varying protein demands. Leveraging this setpoint variability, we found, remarkably, that the information on the intake setpoint is stored within the protein hunger neurons as the resting membrane potential. Two RFamide G protein-coupled receptor (GPCR) pathways, by tuning the resting membrane potential in opposite directions, coordinately program and adjust the protein intake setpoint. Together, our studies map the protein intake setpoint to a single trackable physiological parameter and elucidate the cellular and molecular mechanisms underlying setpoint determination and modulation.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1016/j.cell.2024.08.002
Ke Liang, Xiechao Zhan, Yuxin Li, Yi Yang, Yanqiu Xie, Zeyu Jin, Xiaoyan Xu, Wenwen Zhang, Yang Lu, Sheng Zhang, Yilong Zou, Shan Feng, Jianping Wu, Zhen Yan
The protein import motor in chloroplasts plays a pivotal role in their biogenesis and homeostasis by driving the translocation of preproteins into chloroplasts. While the Ycf2-FtsHi complex serves as the import motor in land plants, its evolutionary conservation, specialization, and mechanisms across photosynthetic organisms are largely unexplored. Here, we isolated and determined the cryogenic electron microscopy (cryo-EM) structures of the native Ycf2-FtsHi complex from Chlamydomonas reinhardtii, uncovering a complex composed of up to 19 subunits, including multiple green-algae-specific components. The heterohexameric AAA+ ATPase motor module is tilted, potentially facilitating preprotein handover from the translocon at the inner chloroplast membrane (TIC) complex. Preprotein interacts with Ycf2-FtsHi and enhances its ATPase activity in vitro. Integrating Ycf2-FtsHi and translocon at the outer chloroplast membrane (TOC)-TIC supercomplex structures reveals insights into their physical and functional interplay during preprotein translocation. By comparing these findings with those from land plants, our study establishes a structural foundation for understanding the assembly, function, evolutionary conservation, and diversity of chloroplast protein import motors.
{"title":"Conservation and specialization of the Ycf2-FtsHi chloroplast protein import motor in green algae","authors":"Ke Liang, Xiechao Zhan, Yuxin Li, Yi Yang, Yanqiu Xie, Zeyu Jin, Xiaoyan Xu, Wenwen Zhang, Yang Lu, Sheng Zhang, Yilong Zou, Shan Feng, Jianping Wu, Zhen Yan","doi":"10.1016/j.cell.2024.08.002","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.002","url":null,"abstract":"<p>The protein import motor in chloroplasts plays a pivotal role in their biogenesis and homeostasis by driving the translocation of preproteins into chloroplasts. While the Ycf2-FtsHi complex serves as the import motor in land plants, its evolutionary conservation, specialization, and mechanisms across photosynthetic organisms are largely unexplored. Here, we isolated and determined the cryogenic electron microscopy (cryo-EM) structures of the native Ycf2-FtsHi complex from <em>Chlamydomonas reinhardtii</em>, uncovering a complex composed of up to 19 subunits, including multiple green-algae-specific components. The heterohexameric AAA+ ATPase motor module is tilted, potentially facilitating preprotein handover from the translocon at the inner chloroplast membrane (TIC) complex. Preprotein interacts with Ycf2-FtsHi and enhances its ATPase activity <em>in vitro</em>. Integrating Ycf2-FtsHi and translocon at the outer chloroplast membrane (TOC)-TIC supercomplex structures reveals insights into their physical and functional interplay during preprotein translocation. By comparing these findings with those from land plants, our study establishes a structural foundation for understanding the assembly, function, evolutionary conservation, and diversity of chloroplast protein import motors.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1016/j.cell.2024.07.057
Samuel J. Hobbs, Jason Nomburg, Jennifer A. Doudna, Philip J. Kranzusch
Animal and bacterial cells sense and defend against viral infections using evolutionarily conserved antiviral signaling pathways. Here, we show that viruses overcome host signaling using mechanisms of immune evasion that are directly shared across the eukaryotic and prokaryotic kingdoms of life. Structures of animal poxvirus proteins that inhibit host cGAS-STING signaling demonstrate architectural and catalytic active-site homology shared with bacteriophage Acb1 proteins, which inactivate CBASS anti-phage defense. In bacteria, phage Acb1 proteins are viral enzymes that degrade host cyclic nucleotide immune signals. Structural comparisons of poxvirus protein-2′3′-cGAMP and phage Acb1-3′3′-cGAMP complexes reveal a universal mechanism of host nucleotide immune signal degradation and explain kingdom-specific additions that enable viral adaptation. Chimeric bacteriophages confirm that animal poxvirus proteins are sufficient to evade immune signaling in bacteria. Our findings identify a mechanism of immune evasion conserved between animal and bacterial viruses and define shared rules that explain host-virus interactions across multiple kingdoms of life.
{"title":"Animal and bacterial viruses share conserved mechanisms of immune evasion","authors":"Samuel J. Hobbs, Jason Nomburg, Jennifer A. Doudna, Philip J. Kranzusch","doi":"10.1016/j.cell.2024.07.057","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.057","url":null,"abstract":"<p>Animal and bacterial cells sense and defend against viral infections using evolutionarily conserved antiviral signaling pathways. Here, we show that viruses overcome host signaling using mechanisms of immune evasion that are directly shared across the eukaryotic and prokaryotic kingdoms of life. Structures of animal poxvirus proteins that inhibit host cGAS-STING signaling demonstrate architectural and catalytic active-site homology shared with bacteriophage Acb1 proteins, which inactivate CBASS anti-phage defense. In bacteria, phage Acb1 proteins are viral enzymes that degrade host cyclic nucleotide immune signals. Structural comparisons of poxvirus protein-2′3′-cGAMP and phage Acb1-3′3′-cGAMP complexes reveal a universal mechanism of host nucleotide immune signal degradation and explain kingdom-specific additions that enable viral adaptation. Chimeric bacteriophages confirm that animal poxvirus proteins are sufficient to evade immune signaling in bacteria. Our findings identify a mechanism of immune evasion conserved between animal and bacterial viruses and define shared rules that explain host-virus interactions across multiple kingdoms of life.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1016/j.cell.2024.07.048
Sundaresh Shankar, Junhua Pan, Pan Yang, Yuemin Bian, Gábor Oroszlán, Zishuo Yu, Purba Mukherjee, David J. Filman, James M. Hogle, Mrinal Shekhar, Donald M. Coen, Jonathan Abraham
DNA polymerases are important drug targets, and many structural studies have captured them in distinct conformations. However, a detailed understanding of the impact of polymerase conformational dynamics on drug resistance is lacking. We determined cryoelectron microscopy (cryo-EM) structures of DNA-bound herpes simplex virus polymerase holoenzyme in multiple conformations and interacting with antivirals in clinical use. These structures reveal how the catalytic subunit Pol and the processivity factor UL42 bind DNA to promote processive DNA synthesis. Unexpectedly, in the absence of an incoming nucleotide, we observed Pol in multiple conformations with the closed state sampled by the fingers domain. Drug-bound structures reveal how antivirals may selectively bind enzymes that more readily adopt the closed conformation. Molecular dynamics simulations and the cryo-EM structure of a drug-resistant mutant indicate that some resistance mutations modulate conformational dynamics rather than directly impacting drug binding, thus clarifying mechanisms that drive drug selectivity.
DNA 聚合酶是重要的药物靶标,许多结构研究都捕捉到了它们的不同构象。然而,人们对聚合酶构象动态对耐药性的影响还缺乏详细的了解。我们测定了与 DNA 结合的单纯疱疹病毒聚合酶全酶在多种构象下与临床使用的抗病毒药物相互作用的冷冻电子显微镜(cryo-EM)结构。这些结构揭示了催化亚基 Pol 和过程因子 UL42 如何结合 DNA 以促进过程性 DNA 合成。出乎意料的是,在没有输入核苷酸的情况下,我们观察到 Pol 有多种构象,手指结构域采样的是封闭状态。药物结合结构揭示了抗病毒药物如何选择性地结合更容易采用封闭构象的酶。分子动力学模拟和耐药性突变体的低温电子显微镜结构表明,一些耐药性突变会改变构象动力学,而不是直接影响药物结合,从而阐明了驱动药物选择性的机制。
{"title":"Viral DNA polymerase structures reveal mechanisms of antiviral drug resistance","authors":"Sundaresh Shankar, Junhua Pan, Pan Yang, Yuemin Bian, Gábor Oroszlán, Zishuo Yu, Purba Mukherjee, David J. Filman, James M. Hogle, Mrinal Shekhar, Donald M. Coen, Jonathan Abraham","doi":"10.1016/j.cell.2024.07.048","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.048","url":null,"abstract":"<p>DNA polymerases are important drug targets, and many structural studies have captured them in distinct conformations. However, a detailed understanding of the impact of polymerase conformational dynamics on drug resistance is lacking. We determined cryoelectron microscopy (cryo-EM) structures of DNA-bound herpes simplex virus polymerase holoenzyme in multiple conformations and interacting with antivirals in clinical use. These structures reveal how the catalytic subunit Pol and the processivity factor UL42 bind DNA to promote processive DNA synthesis. Unexpectedly, in the absence of an incoming nucleotide, we observed Pol in multiple conformations with the closed state sampled by the fingers domain. Drug-bound structures reveal how antivirals may selectively bind enzymes that more readily adopt the closed conformation. Molecular dynamics simulations and the cryo-EM structure of a drug-resistant mutant indicate that some resistance mutations modulate conformational dynamics rather than directly impacting drug binding, thus clarifying mechanisms that drive drug selectivity.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1016/j.cell.2024.08.003
Ke Liang, Zeyu Jin, Xiechao Zhan, Yuxin Li, Qikui Xu, Yanqiu Xie, Yi Yang, Shaojie Wang, Jianping Wu, Zhen Yan
Chloroplast proteins are imported via the translocon at the outer chloroplast membrane (TOC)-translocon at the inner chloroplast membrane (TIC) supercomplex, driven by an ATPase motor. The Ycf2-FtsHi complex has been identified as the chloroplast import motor. However, its assembly and cooperation with the TIC complex during preprotein translocation remain unclear. Here, we present the structures of the Ycf2-FtsHi and TIC complexes from Arabidopsis and an ultracomplex formed between them from Pisum. The Ycf2-FtsHi structure reveals a heterohexameric AAA+ ATPase motor module with characteristic features. Four previously uncharacterized components of Ycf2-FtsHi were identified, which aid in complex assembly and anchoring of the motor module at a tilted angle relative to the membrane. When considering the structures of the TIC complex and the TIC-Ycf2-FtsHi ultracomplex together, it becomes evident that the tilted motor module of Ycf2-FtsHi enables its close contact with the TIC complex, thereby facilitating efficient preprotein translocation. Our study provides valuable structural insights into the chloroplast protein import process in land plants.
{"title":"Structural insights into the chloroplast protein import in land plants","authors":"Ke Liang, Zeyu Jin, Xiechao Zhan, Yuxin Li, Qikui Xu, Yanqiu Xie, Yi Yang, Shaojie Wang, Jianping Wu, Zhen Yan","doi":"10.1016/j.cell.2024.08.003","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.003","url":null,"abstract":"<p>Chloroplast proteins are imported via the translocon at the outer chloroplast membrane (TOC)-translocon at the inner chloroplast membrane (TIC) supercomplex, driven by an ATPase motor. The Ycf2-FtsHi complex has been identified as the chloroplast import motor. However, its assembly and cooperation with the TIC complex during preprotein translocation remain unclear. Here, we present the structures of the Ycf2-FtsHi and TIC complexes from <em>Arabidopsis</em> and an ultracomplex formed between them from <em>Pisum</em>. The Ycf2-FtsHi structure reveals a heterohexameric AAA+ ATPase motor module with characteristic features. Four previously uncharacterized components of Ycf2-FtsHi were identified, which aid in complex assembly and anchoring of the motor module at a tilted angle relative to the membrane. When considering the structures of the TIC complex and the TIC-Ycf2-FtsHi ultracomplex together, it becomes evident that the tilted motor module of Ycf2-FtsHi enables its close contact with the TIC complex, thereby facilitating efficient preprotein translocation. Our study provides valuable structural insights into the chloroplast protein import process in land plants.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1016/j.cell.2024.07.052
Alexander A. Cohen, Jennifer R. Keeffe, Ariën Schiepers, Sandra E. Dross, Allison J. Greaney, Annie V. Rorick, Han Gao, Priyanthi N.P. Gnanapragasam, Chengcheng Fan, Anthony P. West, Arlene I. Ramsingh, Jesse H. Erasmus, Janice D. Pata, Hiromi Muramatsu, Norbert Pardi, Paulo J.C. Lin, Scott Baxter, Rita Cruz, Martina Quintanar-Audelo, Ellis Robb, Pamela J. Bjorkman
Immunization with mosaic-8b (nanoparticles presenting 8 SARS-like betacoronavirus [sarbecovirus] receptor-binding domains [RBDs]) elicits more broadly cross-reactive antibodies than homotypic SARS-CoV-2 RBD-only nanoparticles and protects against sarbecoviruses. To investigate original antigenic sin (OAS) effects on mosaic-8b efficacy, we evaluated the effects of prior COVID-19 vaccinations in non-human primates and mice on anti-sarbecovirus responses elicited by mosaic-8b, admix-8b (8 homotypics), or homotypic SARS-CoV-2 immunizations, finding the greatest cross-reactivity for mosaic-8b. As demonstrated by molecular fate mapping, in which antibodies from specific cohorts of B cells are differentially detected, B cells primed by WA1 spike mRNA-LNP dominated antibody responses after RBD-nanoparticle boosting. While mosaic-8b- and homotypic-nanoparticles boosted cross-reactive antibodies, de novo antibodies were predominantly induced by mosaic-8b, and these were specific for variant RBDs with increased identity to RBDs on mosaic-8b. These results inform OAS mechanisms and support using mosaic-8b to protect COVID-19-vaccinated/infected humans against as-yet-unknown SARS-CoV-2 variants and animal sarbecoviruses with human spillover potential.
{"title":"Mosaic sarbecovirus nanoparticles elicit cross-reactive responses in pre-vaccinated animals","authors":"Alexander A. Cohen, Jennifer R. Keeffe, Ariën Schiepers, Sandra E. Dross, Allison J. Greaney, Annie V. Rorick, Han Gao, Priyanthi N.P. Gnanapragasam, Chengcheng Fan, Anthony P. West, Arlene I. Ramsingh, Jesse H. Erasmus, Janice D. Pata, Hiromi Muramatsu, Norbert Pardi, Paulo J.C. Lin, Scott Baxter, Rita Cruz, Martina Quintanar-Audelo, Ellis Robb, Pamela J. Bjorkman","doi":"10.1016/j.cell.2024.07.052","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.052","url":null,"abstract":"<p>Immunization with mosaic-8b (nanoparticles presenting 8 SARS-like betacoronavirus [sarbecovirus] receptor-binding domains [RBDs]) elicits more broadly cross-reactive antibodies than homotypic SARS-CoV-2 RBD-only nanoparticles and protects against sarbecoviruses. To investigate original antigenic sin (OAS) effects on mosaic-8b efficacy, we evaluated the effects of prior COVID-19 vaccinations in non-human primates and mice on anti-sarbecovirus responses elicited by mosaic-8b, admix-8b (8 homotypics), or homotypic SARS-CoV-2 immunizations, finding the greatest cross-reactivity for mosaic-8b. As demonstrated by molecular fate mapping, in which antibodies from specific cohorts of B cells are differentially detected, B cells primed by WA1 spike mRNA-LNP dominated antibody responses after RBD-nanoparticle boosting. While mosaic-8b- and homotypic-nanoparticles boosted cross-reactive antibodies, <em>de novo</em> antibodies were predominantly induced by mosaic-8b, and these were specific for variant RBDs with increased identity to RBDs on mosaic-8b. These results inform OAS mechanisms and support using mosaic-8b to protect COVID-19-vaccinated/infected humans against as-yet-unknown SARS-CoV-2 variants and animal sarbecoviruses with human spillover potential.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142084999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1016/j.cell.2024.08.001
Justin L. Engel, Xiao Zhang, Mingming Wu, Yan Wang, Jose Espejo Valle-Inclán, Qing Hu, Kidist S. Woldehawariat, Mathijs A. Sanders, Agata Smogorzewska, Jin Chen, Isidro Cortés-Ciriano, Roger S. Lo, Peter Ly
Chromothripsis describes the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei. Although micronuclei accumulate DNA double-strand breaks and replication defects throughout interphase, how chromosomes undergo shattering remains unresolved. Using CRISPR-Cas9 screens, we identify a non-canonical role of the Fanconi anemia (FA) pathway as a driver of chromothripsis. Inactivation of the FA pathway suppresses chromosome shattering during mitosis without impacting interphase-associated defects within micronuclei. Mono-ubiquitination of FANCI-FANCD2 by the FA core complex promotes its mitotic engagement with under-replicated micronuclear chromosomes. The structure-selective SLX4-XPF-ERCC1 endonuclease subsequently induces large-scale nucleolytic cleavage of persistent DNA replication intermediates, which stimulates POLD3-dependent mitotic DNA synthesis to prime shattered fragments for reassembly in the ensuing cell cycle. Notably, FA-pathway-induced chromothripsis generates complex genomic rearrangements and extrachromosomal DNA that confer acquired resistance to anti-cancer therapies. Our findings demonstrate how pathological activation of a central DNA repair mechanism paradoxically triggers cancer genome evolution through chromothripsis.
染色体破碎(Chromothripsis)是指被困在微核中的错误分离的染色体发生灾难性破碎。虽然微核在整个间期都会积累 DNA 双链断裂和复制缺陷,但染色体是如何发生破碎的仍未解决。通过 CRISPR-Cas9 筛选,我们确定了范可尼贫血症(FA)通路作为染色体破碎驱动因素的非经典作用。FA通路的失活抑制了有丝分裂过程中的染色体破碎,但不会影响微核内的间期相关缺陷。FA核心复合物对FANCI-FANCD2的单泛素化促进了FANCI-FANCD2与复制不足的小核染色体的有丝分裂啮合。随后,结构选择性 SLX4-XPF-ERCC1 内切酶诱导对持续存在的 DNA 复制中间体进行大规模核溶解切割,从而刺激 POLD3 依赖性有丝分裂 DNA 合成,使破碎的片段在随后的细胞周期中重新组合。值得注意的是,FA 途径诱导的染色体分裂会产生复杂的基因组重排和染色体外 DNA,从而对抗癌疗法产生获得性抗性。我们的研究结果表明,病理激活中心DNA修复机制是如何通过染色体三分裂矛盾地引发癌症基因组进化的。
{"title":"The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance","authors":"Justin L. Engel, Xiao Zhang, Mingming Wu, Yan Wang, Jose Espejo Valle-Inclán, Qing Hu, Kidist S. Woldehawariat, Mathijs A. Sanders, Agata Smogorzewska, Jin Chen, Isidro Cortés-Ciriano, Roger S. Lo, Peter Ly","doi":"10.1016/j.cell.2024.08.001","DOIUrl":"https://doi.org/10.1016/j.cell.2024.08.001","url":null,"abstract":"<p>Chromothripsis describes the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei. Although micronuclei accumulate DNA double-strand breaks and replication defects throughout interphase, how chromosomes undergo shattering remains unresolved. Using CRISPR-Cas9 screens, we identify a non-canonical role of the Fanconi anemia (FA) pathway as a driver of chromothripsis. Inactivation of the FA pathway suppresses chromosome shattering during mitosis without impacting interphase-associated defects within micronuclei. Mono-ubiquitination of FANCI-FANCD2 by the FA core complex promotes its mitotic engagement with under-replicated micronuclear chromosomes. The structure-selective SLX4-XPF-ERCC1 endonuclease subsequently induces large-scale nucleolytic cleavage of persistent DNA replication intermediates, which stimulates POLD3-dependent mitotic DNA synthesis to prime shattered fragments for reassembly in the ensuing cell cycle. Notably, FA-pathway-induced chromothripsis generates complex genomic rearrangements and extrachromosomal DNA that confer acquired resistance to anti-cancer therapies. Our findings demonstrate how pathological activation of a central DNA repair mechanism paradoxically triggers cancer genome evolution through chromothripsis.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1016/j.cell.2024.07.043
Yvonne Y. Chen, Charles L. Evavold, Matthias Mann, Emily R. Davenport, Margaret McFall-Ngai, Magda Bienko, Hiroki R. Ueda, Lin Tian, Nikki Tjahjono, Polina Anikeeva, Jun-Jie Gogo Liu, Tara L. Deans, Xiaohua Shen
We asked researchers from a range of disciplines across biology, engineering, and medicine to describe a current technological need. The goal is to provide a sample of the various technological gaps that exist and inspire future research projects.
{"title":"What tool or method do you wish existed?","authors":"Yvonne Y. Chen, Charles L. Evavold, Matthias Mann, Emily R. Davenport, Margaret McFall-Ngai, Magda Bienko, Hiroki R. Ueda, Lin Tian, Nikki Tjahjono, Polina Anikeeva, Jun-Jie Gogo Liu, Tara L. Deans, Xiaohua Shen","doi":"10.1016/j.cell.2024.07.043","DOIUrl":"https://doi.org/10.1016/j.cell.2024.07.043","url":null,"abstract":"<p>We asked researchers from a range of disciplines across biology, engineering, and medicine to describe a current technological need. The goal is to provide a sample of the various technological gaps that exist and inspire future research projects.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":null,"pages":null},"PeriodicalIF":64.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142023045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}