A 2°C climate-warming scenario is expected to further exacerbate average crop losses by 3%–13%, yet few heat-tolerant staple-crop varieties are available toward meeting future food demands. Here, we develop high-efficiency prime-editing tools to precisely knockin a 10-bp heat-shock element (HSE) into promoters of cell-wall-invertase genes (CWINs) in elite rice and tomato cultivars. HSE insertion endows CWINs with heat-responsive upregulation in both controlled and field environments to enhance carbon partitioning to grain and fruits, resulting in per-plot yield increases of 25% in rice cultivar Zhonghua11 and 33% in tomato cultivar Ailsa Craig over heat-stressed controls, without fruit quality penalties. Up to 41% of heat-induced grain losses were rescued in rice. Beyond a prime-editing system for tweaking gene expression by efficiently delivering bespoke changes into crop genomes, we demonstrate broad and robust utility for targeted knockin of cis-regulatory elements to optimize source-sink relations and boost crop climate resilience.
{"title":"Engineering source-sink relations by prime editing confers heat-stress resilience in tomato and rice","authors":"Huanchang Lou, Shujia Li, Zihang Shi, Yupan Zou, Yueqin Zhang, Xiaozhen Huang, Dandan Yang, Yongfang Yang, Zuoyao Li, Cao Xu","doi":"10.1016/j.cell.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.005","url":null,"abstract":"A 2°C climate-warming scenario is expected to further exacerbate average crop losses by 3%–13%, yet few heat-tolerant staple-crop varieties are available toward meeting future food demands. Here, we develop high-efficiency prime-editing tools to precisely knockin a 10-bp heat-shock element (HSE) into promoters of cell-wall-invertase genes (<em>CWINs</em>) in elite rice and tomato cultivars. HSE insertion endows <em>CWINs</em> with heat-responsive upregulation in both controlled and field environments to enhance carbon partitioning to grain and fruits, resulting in per-plot yield increases of 25% in rice cultivar Zhonghua11 and 33% in tomato cultivar Ailsa Craig over heat-stressed controls, without fruit quality penalties. Up to 41% of heat-induced grain losses were rescued in rice. Beyond a prime-editing system for tweaking gene expression by efficiently delivering bespoke changes into crop genomes, we demonstrate broad and robust utility for targeted knockin of <em>cis</em>-regulatory elements to optimize source-sink relations and boost crop climate resilience.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"41 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816155","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 : 2024-12-12DOI: 10.1016/j.cell.2024.11.016
Giulia Irene Maria Pasquesi, Holly Allen, Atma Ivancevic, Arturo Barbachano-Guerrero, Olivia Joyner, Kejun Guo, David M. Simpson, Keala Gapin, Isabella Horton, Lily L. Nguyen, Qing Yang, Cody J. Warren, Liliana D. Florea, Benjamin G. Bitler, Mario L. Santiago, Sara L. Sawyer, Edward B. Chuong
Innate immune signaling is essential for clearing pathogens and damaged cells and must be tightly regulated to avoid excessive inflammation or autoimmunity. Here, we found that the alternative splicing of exons derived from transposable elements is a key mechanism controlling immune signaling in human cells. By analyzing long-read transcriptome datasets, we identified numerous transposon exonization events predicted to generate functional protein variants of immune genes, including the type I interferon receptor IFNAR2. We demonstrated that the transposon-derived isoform of IFNAR2 is more highly expressed than the canonical isoform in almost all tissues and functions as a decoy receptor that potently inhibits interferon signaling, including in cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our findings uncover a primate-specific axis controlling interferon signaling and show how a transposon exonization event can be co-opted for immune regulation.
{"title":"Regulation of human interferon signaling by transposon exonization","authors":"Giulia Irene Maria Pasquesi, Holly Allen, Atma Ivancevic, Arturo Barbachano-Guerrero, Olivia Joyner, Kejun Guo, David M. Simpson, Keala Gapin, Isabella Horton, Lily L. Nguyen, Qing Yang, Cody J. Warren, Liliana D. Florea, Benjamin G. Bitler, Mario L. Santiago, Sara L. Sawyer, Edward B. Chuong","doi":"10.1016/j.cell.2024.11.016","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.016","url":null,"abstract":"Innate immune signaling is essential for clearing pathogens and damaged cells and must be tightly regulated to avoid excessive inflammation or autoimmunity. Here, we found that the alternative splicing of exons derived from transposable elements is a key mechanism controlling immune signaling in human cells. By analyzing long-read transcriptome datasets, we identified numerous transposon exonization events predicted to generate functional protein variants of immune genes, including the type I interferon receptor IFNAR2. We demonstrated that the transposon-derived isoform of IFNAR2 is more highly expressed than the canonical isoform in almost all tissues and functions as a decoy receptor that potently inhibits interferon signaling, including in cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our findings uncover a primate-specific axis controlling interferon signaling and show how a transposon exonization event can be co-opted for immune regulation.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"29 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809590","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 : 2024-12-12DOI: 10.1016/j.cell.2024.11.015
Charlotte Bunne, Yusuf Roohani, Yanay Rosen, Ankit Gupta, Xikun Zhang, Marcel Roed, Theo Alexandrov, Mohammed AlQuraishi, Patricia Brennan, Daniel B. Burkhardt, Andrea Califano, Jonah Cool, Abby F. Dernburg, Kirsty Ewing, Emily B. Fox, Matthias Haury, Amy E. Herr, Eric Horvitz, Patrick D. Hsu, Viren Jain, Stephen R. Quake
Cells are essential to understanding health and disease, yet traditional models fall short of modeling and simulating their function and behavior. Advances in AI and omics offer groundbreaking opportunities to create an AI virtual cell (AIVC), a multi-scale, multi-modal large-neural-network-based model that can represent and simulate the behavior of molecules, cells, and tissues across diverse states. This Perspective provides a vision on their design and how collaborative efforts to build AIVCs will transform biological research by allowing high-fidelity simulations, accelerating discoveries, and guiding experimental studies, offering new opportunities for understanding cellular functions and fostering interdisciplinary collaborations in open science.
{"title":"How to build the virtual cell with artificial intelligence: Priorities and opportunities","authors":"Charlotte Bunne, Yusuf Roohani, Yanay Rosen, Ankit Gupta, Xikun Zhang, Marcel Roed, Theo Alexandrov, Mohammed AlQuraishi, Patricia Brennan, Daniel B. Burkhardt, Andrea Califano, Jonah Cool, Abby F. Dernburg, Kirsty Ewing, Emily B. Fox, Matthias Haury, Amy E. Herr, Eric Horvitz, Patrick D. Hsu, Viren Jain, Stephen R. Quake","doi":"10.1016/j.cell.2024.11.015","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.015","url":null,"abstract":"Cells are essential to understanding health and disease, yet traditional models fall short of modeling and simulating their function and behavior. Advances in AI and omics offer groundbreaking opportunities to create an AI virtual cell (AIVC), a multi-scale, multi-modal large-neural-network-based model that can represent and simulate the behavior of molecules, cells, and tissues across diverse states. This Perspective provides a vision on their design and how collaborative efforts to build AIVCs will transform biological research by allowing high-fidelity simulations, accelerating discoveries, and guiding experimental studies, offering new opportunities for understanding cellular functions and fostering interdisciplinary collaborations in open science.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"88 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809970","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 : 2024-12-11DOI: 10.1016/j.cell.2024.11.022
Jake F. Watson, Victor Vargas-Barroso, Rebecca J. Morse-Mora, Andrea Navas-Olive, Mojtaba R. Tavakoli, Johann G. Danzl, Matthias Tomschik, Karl Rössler, Peter Jonas
Our brain has remarkable computational power, generating sophisticated behaviors, storing memories over an individual’s lifetime, and producing higher cognitive functions. However, little of our neuroscience knowledge covers the human brain. Is this organ truly unique, or is it a scaled version of the extensively studied rodent brain? Combining multicellular patch-clamp recording with expansion-based superresolution microscopy and full-scale modeling, we determined the cellular and microcircuit properties of the human hippocampal CA3 region, a fundamental circuit for memory storage. In contrast to neocortical networks, human hippocampal CA3 displayed sparse connectivity, providing a circuit architecture that maximizes associational power. Human synapses showed unique reliability, high precision, and long integration times, exhibiting both species- and circuit-specific properties. Together with expanded neuronal numbers, these circuit characteristics greatly enhanced the memory storage capacity of CA3. Our results reveal distinct microcircuit properties of the human hippocampus and begin to unravel the inner workings of our most complex organ.
{"title":"Human hippocampal CA3 uses specific functional connectivity rules for efficient associative memory","authors":"Jake F. Watson, Victor Vargas-Barroso, Rebecca J. Morse-Mora, Andrea Navas-Olive, Mojtaba R. Tavakoli, Johann G. Danzl, Matthias Tomschik, Karl Rössler, Peter Jonas","doi":"10.1016/j.cell.2024.11.022","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.022","url":null,"abstract":"Our brain has remarkable computational power, generating sophisticated behaviors, storing memories over an individual’s lifetime, and producing higher cognitive functions. However, little of our neuroscience knowledge covers the human brain. Is this organ truly unique, or is it a scaled version of the extensively studied rodent brain? Combining multicellular patch-clamp recording with expansion-based superresolution microscopy and full-scale modeling, we determined the cellular and microcircuit properties of the human hippocampal CA3 region, a fundamental circuit for memory storage. In contrast to neocortical networks, human hippocampal CA3 displayed sparse connectivity, providing a circuit architecture that maximizes associational power. Human synapses showed unique reliability, high precision, and long integration times, exhibiting both species- and circuit-specific properties. Together with expanded neuronal numbers, these circuit characteristics greatly enhanced the memory storage capacity of CA3. Our results reveal distinct microcircuit properties of the human hippocampus and begin to unravel the inner workings of our most complex organ.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"200 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804861","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 : 2024-12-11DOI: 10.1016/j.cell.2024.11.011
Yago A. Arribas, Blandine Baudon, Maxime Rotival, Guadalupe Suárez, Pierre-Emmanuel Bonté, Vanessa Casas, Apollinaire Roubert, Paul Klein, Elisa Bonnin, Basma Mchich, Patricia Legoix, Sylvain Baulande, Benjamin Sadacca, Julien Diharce, Joshua J. Waterfall, Catherine Etchebest, Montserrat Carrascal, Christel Goudot, Lluís Quintana-Murci, Marianne Burbage, Sebastian Amigorena
Alternative splicing enhances protein diversity in different ways, including through exonization of transposable elements (TEs). Recent transcriptomic analyses identified thousands of unannotated spliced transcripts with exonizing TEs, but their contribution to the proteome and biological relevance remains unclear. Here, we use transcriptome assembly, ribosome profiling, and proteomics to describe a population of 1,227 unannotated TE exonizing isoforms generated by mRNA splicing and recurrent in human populations. Despite being shorter and lowly expressed, these isoforms are shared between individuals and efficiently translated. Functional analyses show stable expression, specific cellular localization, and, in some cases, modified functions. Exonized TEs are rich in ancient genes, whereas the involved splice sites are recent and can be evolutionarily conserved. In addition, exonized TEs contribute to the secondary structure of the emerging isoforms, supporting their functional relevance. We conclude that TE-spliced isoforms represent a diversity reservoir of functional proteins on which natural selection can act.
{"title":"Transposable element exonization generates a reservoir of evolving and functional protein isoforms","authors":"Yago A. Arribas, Blandine Baudon, Maxime Rotival, Guadalupe Suárez, Pierre-Emmanuel Bonté, Vanessa Casas, Apollinaire Roubert, Paul Klein, Elisa Bonnin, Basma Mchich, Patricia Legoix, Sylvain Baulande, Benjamin Sadacca, Julien Diharce, Joshua J. Waterfall, Catherine Etchebest, Montserrat Carrascal, Christel Goudot, Lluís Quintana-Murci, Marianne Burbage, Sebastian Amigorena","doi":"10.1016/j.cell.2024.11.011","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.011","url":null,"abstract":"Alternative splicing enhances protein diversity in different ways, including through exonization of transposable elements (TEs). Recent transcriptomic analyses identified thousands of unannotated spliced transcripts with exonizing TEs, but their contribution to the proteome and biological relevance remains unclear. Here, we use transcriptome assembly, ribosome profiling, and proteomics to describe a population of 1,227 unannotated TE exonizing isoforms generated by mRNA splicing and recurrent in human populations. Despite being shorter and lowly expressed, these isoforms are shared between individuals and efficiently translated. Functional analyses show stable expression, specific cellular localization, and, in some cases, modified functions. Exonized TEs are rich in ancient genes, whereas the involved splice sites are recent and can be evolutionarily conserved. In addition, exonized TEs contribute to the secondary structure of the emerging isoforms, supporting their functional relevance. We conclude that TE-spliced isoforms represent a diversity reservoir of functional proteins on which natural selection can act.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"2 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804864","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 : 2024-12-11DOI: 10.1016/j.cell.2024.11.021
Bibekananda Sahoo, Zongjun Mou, Wei Liu, George Dubyak, Xinghong Dai
Ninjurin-1 (NINJ1) is an active executioner of plasma membrane rupture (PMR), a process previously thought to be a passive osmotic lysis event in lytic cell death. Ninjurin-2 (NINJ2) is a close paralog of NINJ1 but cannot mediate PMR. Using cryogenic electron microscopy (cryo-EM), we show that NINJ1 and NINJ2 both assemble into linear filaments that are hydrophobic on one side but hydrophilic on the other. This structural feature and other evidence point to a PMR mechanism by which NINJ1 filaments wrap around and solubilize membrane fragments and, less frequently, form pores in the plasma membrane. In contrast to the straight NINJ1 filament, the NINJ2 filament is curved toward the intracellular space, preventing its circularization or even assembly on a relatively flat membrane to mediate PMR. Mutagenesis studies further demonstrate that the NINJ2 filament curvature is induced by strong association with lipids, particularly a cholesterol molecule, at the cytoplasmic leaflet of the lipid bilayer.
{"title":"How NINJ1 mediates plasma membrane rupture and why NINJ2 cannot","authors":"Bibekananda Sahoo, Zongjun Mou, Wei Liu, George Dubyak, Xinghong Dai","doi":"10.1016/j.cell.2024.11.021","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.021","url":null,"abstract":"Ninjurin-1 (NINJ1) is an active executioner of plasma membrane rupture (PMR), a process previously thought to be a passive osmotic lysis event in lytic cell death. Ninjurin-2 (NINJ2) is a close paralog of NINJ1 but cannot mediate PMR. Using cryogenic electron microscopy (cryo-EM), we show that NINJ1 and NINJ2 both assemble into linear filaments that are hydrophobic on one side but hydrophilic on the other. This structural feature and other evidence point to a PMR mechanism by which NINJ1 filaments wrap around and solubilize membrane fragments and, less frequently, form pores in the plasma membrane. In contrast to the straight NINJ1 filament, the NINJ2 filament is curved toward the intracellular space, preventing its circularization or even assembly on a relatively flat membrane to mediate PMR. Mutagenesis studies further demonstrate that the NINJ2 filament curvature is induced by strong association with lipids, particularly a cholesterol molecule, at the cytoplasmic leaflet of the lipid bilayer.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"10 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804868","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 : 2024-12-09DOI: 10.1016/j.cell.2024.11.009
Wenbin Mei, Schayan Faraj Tabrizi, Christopher Godina, Anthea F. Lovisa, Karolin Isaksson, Helena Jernström, Sohail F. Tavazoie
Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 (PCSK9) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival—uncovering a hereditary basis underlying breast cancer metastasis.
识别有转移性复发风险的患者是一项关键的医疗需求。我们在多种乳腺癌患者队列中发现了一种常见的蛋白转化酶subtilisin/kexin type 9 (PCSK9) （rs562556, V474I）的错意种系变异，该变异与生存率降低有关。这种功能获得的单核苷酸变异在小鼠中的遗传模型显示，它可以促进乳腺癌转移。相反，在多种乳腺癌模型中，宿主PCSK9缺失减少了转移性定植。宿主PCSK9通过靶向肿瘤低密度脂蛋白受体相关蛋白1 （LRP1）受体，抑制促进转移的基因XAF1和USP18，促进肺转移起始事件，增强转移增殖能力。抗体介导的PCSK9治疗性抑制在多种模型中抑制乳腺癌转移。在一项大型瑞典早期乳腺癌队列研究中，rs562556纯合子在15年时远处转移性复发的风险为22%，而非纯合子的风险为2%。我们的研究结果表明，一种常见的遗传基因改变控制着乳腺癌的转移，并预测了乳腺癌的生存——揭示了乳腺癌转移的遗传基础。
{"title":"A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor","authors":"Wenbin Mei, Schayan Faraj Tabrizi, Christopher Godina, Anthea F. Lovisa, Karolin Isaksson, Helena Jernström, Sohail F. Tavazoie","doi":"10.1016/j.cell.2024.11.009","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.009","url":null,"abstract":"Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 (<em>PCSK9</em>) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes <em>XAF1</em> and <em>USP18</em>. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival—uncovering a hereditary basis underlying breast cancer metastasis.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"35 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793816","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 : 2024-12-09DOI: 10.1016/j.cell.2024.11.006
Benedikt Goretzki, Maryam Khoshouei, Martin Schröder, Patrick Penner, Luca Egger, Christine Stephan, Dayana Argoti, Nele Dierlamm, Jimena Maria Rada, Sandra Kapps, Catrin Swantje Müller, Zacharias Thiel, Merve Mutlu, Claude Tschopp, David Furkert, Felix Freuler, Simon Haenni, Laurent Tenaillon, Britta Knapp, Alexandra Hinniger, César Fernández
Broad-complex, tramtrack, and bric-à-brac domain (BTB) and CNC homolog 1 (BACH1) is a key regulator of the cellular oxidative stress response and an oncogene that undergoes tight post-translational control by two distinct F-box ubiquitin ligases, SCFFBXO22 and SCFFBXL17. However, how both ligases recognize BACH1 under oxidative stress is unclear. In our study, we elucidate the mechanism by which FBXO22 recognizes a quaternary degron in a domain-swapped β-sheet of the BACH1 BTB dimer. Cancer-associated mutations and cysteine modifications destabilize the degron and impair FBXO22 binding but simultaneously expose an otherwise shielded degron in the dimer interface, allowing FBXL17 to recognize BACH1 as a monomer. These findings shed light on a ligase switch mechanism that enables post-translational regulation of BACH1 by complementary ligases depending on the stability of its BTB domain. Our results provide mechanistic insights into the oxidative stress response and may spur therapeutic approaches for targeting oxidative stress-related disorders and cancer.
{"title":"Dual BACH1 regulation by complementary SCF-type E3 ligases","authors":"Benedikt Goretzki, Maryam Khoshouei, Martin Schröder, Patrick Penner, Luca Egger, Christine Stephan, Dayana Argoti, Nele Dierlamm, Jimena Maria Rada, Sandra Kapps, Catrin Swantje Müller, Zacharias Thiel, Merve Mutlu, Claude Tschopp, David Furkert, Felix Freuler, Simon Haenni, Laurent Tenaillon, Britta Knapp, Alexandra Hinniger, César Fernández","doi":"10.1016/j.cell.2024.11.006","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.006","url":null,"abstract":"Broad-complex, tramtrack, and bric-à-brac domain (BTB) and CNC homolog 1 (BACH1) is a key regulator of the cellular oxidative stress response and an oncogene that undergoes tight post-translational control by two distinct F-box ubiquitin ligases, SCF<sup>FBXO22</sup> and SCF<sup>FBXL17</sup>. However, how both ligases recognize BACH1 under oxidative stress is unclear. In our study, we elucidate the mechanism by which FBXO22 recognizes a quaternary degron in a domain-swapped β-sheet of the BACH1 BTB dimer. Cancer-associated mutations and cysteine modifications destabilize the degron and impair FBXO22 binding but simultaneously expose an otherwise shielded degron in the dimer interface, allowing FBXL17 to recognize BACH1 as a monomer. These findings shed light on a ligase switch mechanism that enables post-translational regulation of BACH1 by complementary ligases depending on the stability of its BTB domain. Our results provide mechanistic insights into the oxidative stress response and may spur therapeutic approaches for targeting oxidative stress-related disorders and cancer.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793564","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 : 2024-12-06DOI: 10.1016/j.cell.2024.11.002
Svenja K. Tetzlaff, Ekin Reyhan, Nikolas Layer, C. Peter Bengtson, Alina Heuer, Julian Schroers, Anton J. Faymonville, Atefeh Pourkhalili Langeroudi, Nina Drewa, Elijah Keifert, Julia Wagner, Stella J. Soyka, Marc C. Schubert, Nirosan Sivapalan, Rangel L. Pramatarov, Verena Buchert, Tim Wageringel, Elena Grabis, Niklas Wißmann, Obada T. Alhalabi, Varun Venkataramani
Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain, engaging in widespread functional communication, with cholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor-cell-state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasiveness. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.
{"title":"Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing","authors":"Svenja K. Tetzlaff, Ekin Reyhan, Nikolas Layer, C. Peter Bengtson, Alina Heuer, Julian Schroers, Anton J. Faymonville, Atefeh Pourkhalili Langeroudi, Nina Drewa, Elijah Keifert, Julia Wagner, Stella J. Soyka, Marc C. Schubert, Nirosan Sivapalan, Rangel L. Pramatarov, Verena Buchert, Tim Wageringel, Elena Grabis, Niklas Wißmann, Obada T. Alhalabi, Varun Venkataramani","doi":"10.1016/j.cell.2024.11.002","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.002","url":null,"abstract":"Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain, engaging in widespread functional communication, with cholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor-cell-state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasiveness. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"82 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782648","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}
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