首页 > 最新文献

PLoS Biology最新文献

英文 中文
Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides. 导致结核病的分枝杆菌保留了从祖先那里获得的生物合成化学性质多样的萜烯核苷的基因。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-30 eCollection Date: 2024-09-01 DOI: 10.1371/journal.pbio.3002813
Jacob A Mayfield, Sahadevan Raman, Alexandrea K Ramnarine, Vivek K Mishra, Annie D Huang, Sandrine Dudoit, Jeffrey Buter, Tan-Yun Cheng, David C Young, Yashodhan M Nair, Isobel G Ouellet, Braden T Griebel, Shuyi Ma, David R Sherman, Ludovic Mallet, Kyu Y Rhee, Adriaan J Minnaard, D Branch Moody

Mycobacterium tuberculosis (Mtb) releases the unusual terpene nucleoside 1-tuberculosinyladenosine (1-TbAd) to block lysosomal function and promote survival in human macrophages. Using conventional approaches, we found that genes Rv3377c and Rv3378c, but not Rv3376, were necessary for 1-TbAd biosynthesis. Here, we introduce linear models for mass spectrometry (limms) software as a next-generation lipidomics tool to study the essential functions of lipid biosynthetic enzymes on a whole-cell basis. Using limms, whole-cell lipid profiles deepened the phenotypic landscape of comparative mass spectrometry experiments and identified a large family of approximately 100 terpene nucleoside metabolites downstream of Rv3378c. We validated the identity of previously unknown adenine-, adenosine-, and lipid-modified tuberculosinol-containing molecules using synthetic chemistry and collisional mass spectrometry, including comprehensive profiling of bacterial lipids that fragment to adenine. We tracked terpene nucleoside genotypes and lipid phenotypes among Mycobacterium tuberculosis complex (MTC) species that did or did not evolve to productively infect either human or nonhuman mammals. Although 1-TbAd biosynthesis genes were thought to be restricted to the MTC, we identified the locus in unexpected species outside the MTC. Sequence analysis of the locus showed nucleotide usage characteristic of plasmids from plant-associated bacteria, clarifying the origin and timing of horizontal gene transfer to a pre-MTC progenitor. The data demonstrated correlation between high level terpene nucleoside biosynthesis and mycobacterial competence for human infection, and 2 mechanisms of 1-TbAd biosynthesis loss. Overall, the selective gain and evolutionary retention of tuberculosinyl metabolites in modern species that cause human TB suggest a role in human TB disease, and the newly discovered molecules represent candidate disease-specific biomarkers.

结核分枝杆菌(Mtb)释放出不寻常的萜烯核苷 1-结核苷基腺苷(1-TbAd),阻断溶酶体功能,促进人类巨噬细胞的存活。利用传统方法,我们发现基因 Rv3377c 和 Rv3378c 是 1-TbAd 生物合成所必需的,但 Rv3376 不是。在这里,我们引入了线性质谱模型(limms)软件,作为新一代脂质组学工具,用于研究全细胞脂质生物合成酶的基本功能。利用 limms,全细胞脂质图谱深化了比较质谱实验的表型图谱,并确定了 Rv3378c 下游约 100 个萜烯核苷代谢物的大家族。我们利用合成化学和碰撞质谱法验证了先前未知的腺嘌呤、腺苷和脂质修饰的含结核苷醇分子的身份,包括全面剖析了以腺嘌呤为片段的细菌脂质。我们追踪了结核分枝杆菌复合体(MTC)物种中的萜烯核苷基因型和脂质表型,无论这些物种是否进化到能有效感染人类或非人类哺乳动物。尽管 1-TbAd 生物合成基因被认为仅限于 MTC,但我们在 MTC 以外的意外物种中发现了该基因座。对该基因座的序列分析表明,核苷酸的使用具有来自植物相关细菌质粒的特征,从而明确了横向基因转移到前 MTC 祖先的起源和时间。数据显示了高水平萜烯核苷生物合成与分枝杆菌感染人类的能力之间的相关性,以及 1-TbAd 生物合成丧失的两种机制。总之,在导致人类结核病的现代物种中,结核苷代谢物的选择性增殖和进化保留表明了其在人类结核病中的作用,新发现的分子代表了候选的疾病特异性生物标记物。
{"title":"Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides.","authors":"Jacob A Mayfield, Sahadevan Raman, Alexandrea K Ramnarine, Vivek K Mishra, Annie D Huang, Sandrine Dudoit, Jeffrey Buter, Tan-Yun Cheng, David C Young, Yashodhan M Nair, Isobel G Ouellet, Braden T Griebel, Shuyi Ma, David R Sherman, Ludovic Mallet, Kyu Y Rhee, Adriaan J Minnaard, D Branch Moody","doi":"10.1371/journal.pbio.3002813","DOIUrl":"10.1371/journal.pbio.3002813","url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb) releases the unusual terpene nucleoside 1-tuberculosinyladenosine (1-TbAd) to block lysosomal function and promote survival in human macrophages. Using conventional approaches, we found that genes Rv3377c and Rv3378c, but not Rv3376, were necessary for 1-TbAd biosynthesis. Here, we introduce linear models for mass spectrometry (limms) software as a next-generation lipidomics tool to study the essential functions of lipid biosynthetic enzymes on a whole-cell basis. Using limms, whole-cell lipid profiles deepened the phenotypic landscape of comparative mass spectrometry experiments and identified a large family of approximately 100 terpene nucleoside metabolites downstream of Rv3378c. We validated the identity of previously unknown adenine-, adenosine-, and lipid-modified tuberculosinol-containing molecules using synthetic chemistry and collisional mass spectrometry, including comprehensive profiling of bacterial lipids that fragment to adenine. We tracked terpene nucleoside genotypes and lipid phenotypes among Mycobacterium tuberculosis complex (MTC) species that did or did not evolve to productively infect either human or nonhuman mammals. Although 1-TbAd biosynthesis genes were thought to be restricted to the MTC, we identified the locus in unexpected species outside the MTC. Sequence analysis of the locus showed nucleotide usage characteristic of plasmids from plant-associated bacteria, clarifying the origin and timing of horizontal gene transfer to a pre-MTC progenitor. The data demonstrated correlation between high level terpene nucleoside biosynthesis and mycobacterial competence for human infection, and 2 mechanisms of 1-TbAd biosynthesis loss. Overall, the selective gain and evolutionary retention of tuberculosinyl metabolites in modern species that cause human TB suggest a role in human TB disease, and the newly discovered molecules represent candidate disease-specific biomarkers.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structure of the Nmd4-Upf1 complex supports conservation of the nonsense-mediated mRNA decay pathway between yeast and humans. Nmd4-Upf1复合物的结构支持酵母和人类之间无义介导的mRNA衰变途径的保护。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-27 eCollection Date: 2024-09-01 DOI: 10.1371/journal.pbio.3002821
Irène Barbarin-Bocahu, Nathalie Ulryck, Amandine Rigobert, Nadia Ruiz Gutierrez, Laurence Decourty, Mouna Raji, Bhumika Garkhal, Hervé Le Hir, Cosmin Saveanu, Marc Graille

The nonsense-mediated mRNA decay (NMD) pathway clears eukaryotic cells of mRNAs containing premature termination codons (PTCs) or normal stop codons located in specific contexts. It therefore plays an important role in gene expression regulation. The precise molecular mechanism of the NMD pathway has long been considered to differ substantially from yeast to metazoa, despite the involvement of universally conserved factors such as the central ATP-dependent RNA-helicase Upf1. Here, we describe the crystal structure of the yeast Upf1 bound to its recently identified but yet uncharacterized partner Nmd4, show that Nmd4 stimulates Upf1 ATPase activity and that this interaction contributes to the elimination of NMD substrates. We also demonstrate that a region of Nmd4 critical for the interaction with Upf1 in yeast is conserved in the metazoan SMG6 protein, another major NMD factor. We show that this conserved region is involved in the interaction of SMG6 with UPF1 and that mutations in this region affect the levels of endogenous human NMD substrates. Our results support the universal conservation of the NMD mechanism in eukaryotes.

无义介导的mRNA衰变(NMD)途径可清除真核细胞中含有过早终止密码子(PTC)或位于特定位置的正常终止密码子的mRNA。因此,它在基因表达调控中发挥着重要作用。长期以来,人们一直认为 NMD 通路的确切分子机制在酵母和后生动物之间存在很大差异,尽管有普遍保守的因子参与其中,如中心 ATP 依赖性 RNA 螺旋酶 Upf1。 在这里,我们描述了酵母 Upf1 与最近发现但尚未定性的伙伴 Nmd4 结合的晶体结构,表明 Nmd4 可刺激 Upf1 的 ATP 酶活性,并且这种相互作用有助于消除 NMD 底物。我们还证明,Nmd4 在酵母中与 Upf1 相互作用的关键区域在后生动物 SMG6 蛋白(另一种主要 NMD 因子)中是保守的。我们表明,这一保守区域参与了 SMG6 与 UPF1 的相互作用,而且该区域的突变会影响内源性人类 NMD 底物的水平。我们的研究结果支持真核生物普遍保留 NMD 机制。
{"title":"Structure of the Nmd4-Upf1 complex supports conservation of the nonsense-mediated mRNA decay pathway between yeast and humans.","authors":"Irène Barbarin-Bocahu, Nathalie Ulryck, Amandine Rigobert, Nadia Ruiz Gutierrez, Laurence Decourty, Mouna Raji, Bhumika Garkhal, Hervé Le Hir, Cosmin Saveanu, Marc Graille","doi":"10.1371/journal.pbio.3002821","DOIUrl":"10.1371/journal.pbio.3002821","url":null,"abstract":"<p><p>The nonsense-mediated mRNA decay (NMD) pathway clears eukaryotic cells of mRNAs containing premature termination codons (PTCs) or normal stop codons located in specific contexts. It therefore plays an important role in gene expression regulation. The precise molecular mechanism of the NMD pathway has long been considered to differ substantially from yeast to metazoa, despite the involvement of universally conserved factors such as the central ATP-dependent RNA-helicase Upf1. Here, we describe the crystal structure of the yeast Upf1 bound to its recently identified but yet uncharacterized partner Nmd4, show that Nmd4 stimulates Upf1 ATPase activity and that this interaction contributes to the elimination of NMD substrates. We also demonstrate that a region of Nmd4 critical for the interaction with Upf1 in yeast is conserved in the metazoan SMG6 protein, another major NMD factor. We show that this conserved region is involved in the interaction of SMG6 with UPF1 and that mutations in this region affect the levels of endogenous human NMD substrates. Our results support the universal conservation of the NMD mechanism in eukaryotes.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Little impact of new mutations on mammalian trait variation. 新突变对哺乳动物性状变异的影响很小。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-27 eCollection Date: 2024-09-01 DOI: 10.1371/journal.pbio.3002825
Beth L Dumont

New mutations provide the source of all genetic variation but their impact on trait variation remains poorly understood. A new study published in PLOS Biology addresses this question, finding that new mutations exert only weak effects on some traits in mice.

新突变是所有遗传变异的来源,但人们对它们对性状变异的影响仍然知之甚少。发表在《公共科学图书馆生物学》(PLOS Biology)上的一项新研究解决了这一问题,研究发现新突变对小鼠的某些性状只产生微弱的影响。
{"title":"Little impact of new mutations on mammalian trait variation.","authors":"Beth L Dumont","doi":"10.1371/journal.pbio.3002825","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002825","url":null,"abstract":"<p><p>New mutations provide the source of all genetic variation but their impact on trait variation remains poorly understood. A new study published in PLOS Biology addresses this question, finding that new mutations exert only weak effects on some traits in mice.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11432828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
SPOT: A machine learning model that predicts specific substrates for transport proteins. SPOT:预测转运蛋白特定底物的机器学习模型。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-26 eCollection Date: 2024-09-01 DOI: 10.1371/journal.pbio.3002807
Alexander Kroll, Nico Niebuhr, Gregory Butler, Martin J Lercher

Transport proteins play a crucial role in cellular metabolism and are central to many aspects of molecular biology and medicine. Determining the function of transport proteins experimentally is challenging, as they become unstable when isolated from cell membranes. Machine learning-based predictions could provide an efficient alternative. However, existing methods are limited to predicting a small number of specific substrates or broad transporter classes. These limitations stem partly from using small data sets for model training and a choice of input features that lack sufficient information about the prediction problem. Here, we present SPOT, the first general machine learning model that can successfully predict specific substrates for arbitrary transport proteins, achieving an accuracy above 92% on independent and diverse test data covering widely different transporters and a broad range of metabolites. SPOT uses Transformer Networks to represent transporters and substrates numerically. To overcome the problem of missing negative data for training, it augments a large data set of known transporter-substrate pairs with carefully sampled random molecules as non-substrates. SPOT not only predicts specific transporter-substrate pairs, but also outperforms previously published models designed to predict broad substrate classes for individual transport proteins. We provide a web server and Python function that allows users to explore the substrate scope of arbitrary transporters.

转运蛋白在细胞新陈代谢中起着至关重要的作用,是分子生物学和医学许多方面的核心。通过实验确定转运蛋白的功能具有挑战性,因为当它们从细胞膜中分离出来时会变得不稳定。基于机器学习的预测可以提供一种有效的替代方法。然而,现有方法仅限于预测少量特定底物或广泛的转运体类别。这些局限性部分源于使用较小的数据集进行模型训练,以及对输入特征的选择缺乏有关预测问题的足够信息。在这里,我们提出了 SPOT,这是第一个能成功预测任意转运蛋白特定底物的通用机器学习模型,在独立和多样化的测试数据上达到了 92% 以上的准确率,这些数据涵盖了多种不同的转运体和广泛的代谢物。SPOT 使用变形网络(Transformer Networks)对转运体和底物进行数字表示。为了克服训练中缺失负数据的问题,SPOT 利用精心采样的随机分子作为非底物,增强了已知转运体-底物对的大型数据集。SPOT 不仅能预测特定的转运体-底物配对,其性能也优于之前发表的旨在预测单个转运蛋白广泛底物类别的模型。我们提供了一个网络服务器和 Python 函数,允许用户探索任意转运体的底物范围。
{"title":"SPOT: A machine learning model that predicts specific substrates for transport proteins.","authors":"Alexander Kroll, Nico Niebuhr, Gregory Butler, Martin J Lercher","doi":"10.1371/journal.pbio.3002807","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002807","url":null,"abstract":"<p><p>Transport proteins play a crucial role in cellular metabolism and are central to many aspects of molecular biology and medicine. Determining the function of transport proteins experimentally is challenging, as they become unstable when isolated from cell membranes. Machine learning-based predictions could provide an efficient alternative. However, existing methods are limited to predicting a small number of specific substrates or broad transporter classes. These limitations stem partly from using small data sets for model training and a choice of input features that lack sufficient information about the prediction problem. Here, we present SPOT, the first general machine learning model that can successfully predict specific substrates for arbitrary transport proteins, achieving an accuracy above 92% on independent and diverse test data covering widely different transporters and a broad range of metabolites. SPOT uses Transformer Networks to represent transporters and substrates numerically. To overcome the problem of missing negative data for training, it augments a large data set of known transporter-substrate pairs with carefully sampled random molecules as non-substrates. SPOT not only predicts specific transporter-substrate pairs, but also outperforms previously published models designed to predict broad substrate classes for individual transport proteins. We provide a web server and Python function that allows users to explore the substrate scope of arbitrary transporters.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Polygenic scores for complex traits are associated with changes in concentration of circulating lipid species. 复杂性状的多基因评分与循环脂质浓度的变化有关。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-26 eCollection Date: 2024-09-01 DOI: 10.1371/journal.pbio.3002830
Rubina Tabassum, Nina Mars, Pietro Della Briotta Parolo, Mathias J Gerl, Christian Klose, Matti Pirinen, Kai Simons, Elisabeth Widén, Samuli Ripatti

Understanding perturbations in circulating lipid levels that often occur years or decades before clinical symptoms may enhance our understanding of disease mechanisms and provide novel intervention opportunities. Here, we assessed if polygenic scores (PGSs) for complex traits could detect lipid dysfunctions related to the traits and provide new biological insights. We constructed genome-wide PGSs (approximately 1 million genetic variants) for 50 complex traits in 7,169 Finnish individuals with routine clinical lipid profiles and lipidomics measurements (179 lipid species). We identified 678 associations (P < 9.0 × 10-5) involving 26 traits and 142 lipids. Most of these associations were also validated with the actual phenotype measurements where available (89.5% of 181 associations where the trait was available), suggesting that these associations represent early signs of physiological changes of the traits. We detected many known relationships (e.g., PGS for body mass index (BMI) and lysophospholipids, PGS for type 2 diabetes and triacyglycerols) and those that suggested potential target for prevention strategies (e.g., PGS for venous thromboembolism and arachidonic acid). We also found association of PGS for favorable adiposity with increased sphingomyelins levels, suggesting a probable role of sphingomyelins in increased risk for certain disease, e.g., venous thromboembolism as reported previously, in favorable adiposity despite its favorable metabolic effect. Altogether, our study provides a comprehensive characterization of lipidomic alterations in genetic predisposition for a wide range of complex traits. The study also demonstrates potential of PGSs for complex traits to capture early, presymptomatic lipid alterations, highlighting its utility in understanding disease mechanisms and early disease detection.

循环血脂水平的扰动往往发生在临床症状出现之前的几年或几十年,了解这种扰动可能会加深我们对疾病机理的理解,并提供新的干预机会。在此,我们评估了复杂性状的多基因评分(PGS)能否检测出与性状相关的血脂功能障碍,并提供新的生物学见解。我们对 7,169 名芬兰人的 50 个复杂性状构建了全基因组 PGSs(约 100 万个遗传变异),并进行了常规临床血脂分析和脂质组学测量(179 种脂质)。我们发现了涉及 26 个性状和 142 种血脂的 678 种关联(P < 9.0 × 10-5)。这些关联中的大多数还与实际的表型测量结果进行了验证(181 种关联中 89.5% 的性状是可用的),这表明这些关联代表了性状生理变化的早期迹象。我们发现了许多已知的关系(如 PGS 与体重指数 (BMI) 和溶血磷脂的关系、PGS 与 2 型糖尿病和三酰甘油的关系)以及那些提示潜在预防策略目标的关系(如 PGS 与静脉血栓栓塞症和花生四烯酸的关系)。我们还发现有利脂肪的 PGS 与鞘磷脂水平升高有关,这表明尽管鞘磷脂具有良好的代谢作用,但它可能会增加某些疾病的风险,如之前报道的静脉血栓栓塞。总之,我们的研究全面描述了各种复杂性状遗传易感性的脂质体改变。该研究还证明了针对复杂性状的 PGSs 在捕捉早期、无症状血脂改变方面的潜力,突出了其在了解疾病机制和早期疾病检测方面的实用性。
{"title":"Polygenic scores for complex traits are associated with changes in concentration of circulating lipid species.","authors":"Rubina Tabassum, Nina Mars, Pietro Della Briotta Parolo, Mathias J Gerl, Christian Klose, Matti Pirinen, Kai Simons, Elisabeth Widén, Samuli Ripatti","doi":"10.1371/journal.pbio.3002830","DOIUrl":"10.1371/journal.pbio.3002830","url":null,"abstract":"<p><p>Understanding perturbations in circulating lipid levels that often occur years or decades before clinical symptoms may enhance our understanding of disease mechanisms and provide novel intervention opportunities. Here, we assessed if polygenic scores (PGSs) for complex traits could detect lipid dysfunctions related to the traits and provide new biological insights. We constructed genome-wide PGSs (approximately 1 million genetic variants) for 50 complex traits in 7,169 Finnish individuals with routine clinical lipid profiles and lipidomics measurements (179 lipid species). We identified 678 associations (P < 9.0 × 10-5) involving 26 traits and 142 lipids. Most of these associations were also validated with the actual phenotype measurements where available (89.5% of 181 associations where the trait was available), suggesting that these associations represent early signs of physiological changes of the traits. We detected many known relationships (e.g., PGS for body mass index (BMI) and lysophospholipids, PGS for type 2 diabetes and triacyglycerols) and those that suggested potential target for prevention strategies (e.g., PGS for venous thromboembolism and arachidonic acid). We also found association of PGS for favorable adiposity with increased sphingomyelins levels, suggesting a probable role of sphingomyelins in increased risk for certain disease, e.g., venous thromboembolism as reported previously, in favorable adiposity despite its favorable metabolic effect. Altogether, our study provides a comprehensive characterization of lipidomic alterations in genetic predisposition for a wide range of complex traits. The study also demonstrates potential of PGSs for complex traits to capture early, presymptomatic lipid alterations, highlighting its utility in understanding disease mechanisms and early disease detection.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
An estimate of fitness reduction from mutation accumulation in a mammal allows assessment of the consequences of relaxed selection. 通过估算哺乳动物因突变积累而导致的体能下降,可以评估宽松选择的后果。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-26 eCollection Date: 2024-09-01 DOI: 10.1371/journal.pbio.3002795
Jobran Chebib, Anika Jonas, Eugenio López-Cortegano, Sven Künzel, Diethard Tautz, Peter D Keightley

Each generation, spontaneous mutations introduce heritable changes that tend to reduce fitness in populations of highly adapted living organisms. This erosion of fitness is countered by natural selection, which keeps deleterious mutations at low frequencies and ultimately removes most of them from the population. The classical way of studying the impact of spontaneous mutations is via mutation accumulation (MA) experiments, where lines of small effective population size are bred for many generations in conditions where natural selection is largely removed. Such experiments in microbes, invertebrates, and plants have generally demonstrated that fitness decays as a result of MA. However, the phenotypic consequences of MA in vertebrates are largely unknown, because no replicated MA experiment has previously been carried out. This gap in our knowledge is relevant for human populations, where societal changes have reduced the strength of natural selection, potentially allowing deleterious mutations to accumulate. Here, we study the impact of spontaneous MA on the mean and genetic variation for quantitative and fitness-related traits in the house mouse using the MA experimental design, with a cryopreserved control to account for environmental influences. We show that variation for morphological and life history traits accumulates at a sufficiently high rate to maintain genetic variation and selection response. Weight and tail length measures decrease significantly between 0.04% and 0.3% per generation with narrow confidence intervals. Fitness proxy measures (litter size and surviving offspring) decrease on average by about 0.2% per generation, but with confidence intervals overlapping zero. When extrapolated to humans, our results imply that the rate of fitness loss should not be of concern in the foreseeable future.

每一代,自发突变都会带来可遗传的变化,这些变化往往会降低高度适应性生物种群的适应性。自然选择可以抵消这种对适应性的侵蚀,它将有害突变保持在较低频率,并最终从种群中清除大部分有害突变。研究自发突变影响的经典方法是突变累积(MA)实验,即在自然选择基本消失的条件下,对有效种群规模较小的品系进行多代培育。在微生物、无脊椎动物和植物中进行的此类实验普遍表明,突变累积会导致适存度下降。然而,在脊椎动物中,MA 的表型后果在很大程度上是未知的,因为以前没有进行过重复的 MA 实验。我们的这一知识空白与人类种群有关,因为社会变迁降低了自然选择的强度,可能会导致有害突变的积累。在这里,我们使用 MA 实验设计研究了自发 MA 对家鼠数量性状和体能相关性状的平均值和遗传变异的影响,并使用低温保存的对照来考虑环境影响。我们的研究表明,形态和生活史性状的变异积累速度足以维持遗传变异和选择反应。体重和尾长在每代 0.04% 到 0.3% 之间显著下降,置信区间较窄。体能替代指标(窝产仔数和存活后代数)平均每代下降约 0.2%,但置信区间为零。推断人类的情况,我们的结果表明,在可预见的未来,体能损失的速度不应引起人们的关注。
{"title":"An estimate of fitness reduction from mutation accumulation in a mammal allows assessment of the consequences of relaxed selection.","authors":"Jobran Chebib, Anika Jonas, Eugenio López-Cortegano, Sven Künzel, Diethard Tautz, Peter D Keightley","doi":"10.1371/journal.pbio.3002795","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002795","url":null,"abstract":"<p><p>Each generation, spontaneous mutations introduce heritable changes that tend to reduce fitness in populations of highly adapted living organisms. This erosion of fitness is countered by natural selection, which keeps deleterious mutations at low frequencies and ultimately removes most of them from the population. The classical way of studying the impact of spontaneous mutations is via mutation accumulation (MA) experiments, where lines of small effective population size are bred for many generations in conditions where natural selection is largely removed. Such experiments in microbes, invertebrates, and plants have generally demonstrated that fitness decays as a result of MA. However, the phenotypic consequences of MA in vertebrates are largely unknown, because no replicated MA experiment has previously been carried out. This gap in our knowledge is relevant for human populations, where societal changes have reduced the strength of natural selection, potentially allowing deleterious mutations to accumulate. Here, we study the impact of spontaneous MA on the mean and genetic variation for quantitative and fitness-related traits in the house mouse using the MA experimental design, with a cryopreserved control to account for environmental influences. We show that variation for morphological and life history traits accumulates at a sufficiently high rate to maintain genetic variation and selection response. Weight and tail length measures decrease significantly between 0.04% and 0.3% per generation with narrow confidence intervals. Fitness proxy measures (litter size and surviving offspring) decrease on average by about 0.2% per generation, but with confidence intervals overlapping zero. When extrapolated to humans, our results imply that the rate of fitness loss should not be of concern in the foreseeable future.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Placebo effects beyond dopamine. 多巴胺之外的安慰剂效应
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-25 eCollection Date: 2024-09-01 DOI: 10.1371/journal.pbio.3002812
Karin B Jensen

The role of dopamine in reward expectancy has led to the hypothesis that it is crucial for forming treatment expectations and placebo effects. However, a new study in PLOS Biology presents robust evidence against the causal role of dopamine in these processes.

多巴胺在奖赏预期中的作用导致了一种假设,即多巴胺对于形成治疗预期和安慰剂效应至关重要。然而,《公共科学图书馆生物学》(PLOS Biology)杂志上的一项新研究提出了强有力的证据,反驳了多巴胺在这些过程中的因果作用。
{"title":"Placebo effects beyond dopamine.","authors":"Karin B Jensen","doi":"10.1371/journal.pbio.3002812","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002812","url":null,"abstract":"<p><p>The role of dopamine in reward expectancy has led to the hypothesis that it is crucial for forming treatment expectations and placebo effects. However, a new study in PLOS Biology presents robust evidence against the causal role of dopamine in these processes.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The conserved protein adaptors CALM/AP180 and FCHo1/2 cooperatively recruit Eps15 to promote the initiation of clathrin-mediated endocytosis in yeast. 保守的蛋白适配体CALM/AP180和FCHo1/2协同招募Eps15,以促进酵母中凝集素介导的内吞作用的启动。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-24 eCollection Date: 2024-09-01 DOI: 10.1371/journal.pbio.3002833
Yidi Sun, Albert Yeam, Jonathan Kuo, Yuichiro Iwamoto, Gean Hu, David G Drubin

Clathrin-mediated endocytosis (CME) is a critical trafficking process that begins when an elaborate endocytic protein network is established at the plasma membrane. Interaction of early endocytic proteins with anionic phospholipids and/or cargo has been suggested to trigger CME initiation. However, the exact mechanism by which CME sites are initiated has not been fully elucidated. In the budding yeast Saccharomyces cerevisiae, higher levels of anionic phospholipids and cargo molecules exist in the newly formed daughter cell compared to the levels in the mother cell during polarized growth. Taking advantage of this asymmetry, we quantitatively compared CME proteins in S. cerevisiae mother versus daughter cells, observing differences in the dynamics and composition of key endocytic proteins. Our results show that CME site initiation occurs preferentially on regions of the plasma membrane with a relatively higher density of endocytic cargo and/or acidic phospholipids. Furthermore, our combined live cell-imaging and yeast genetics analysis provided evidence for a molecular mechanism in which CME sites are initiated when Yap1801 and Yap1802 (yeast CALM/AP180) and Syp1 (yeast FCHo1/2) coordinate with anionic phospholipids and cargo molecules to trigger Ede1 (yeast Eps15)-centric CME initiation complex assembly at the plasma membrane.

凝集素介导的内吞作用(CME)是一个关键的转运过程,当一个复杂的内吞蛋白网络在质膜上建立起来时,这一过程就开始了。有人认为,早期内吞蛋白与阴离子磷脂和/或货物的相互作用触发了 CME 的启动。然而,CME 位点启动的确切机制尚未完全阐明。在出芽酵母(Saccharomyces cerevisiae)中,在极化生长过程中,新形成的子细胞中阴离子磷脂和货物分子的含量高于母细胞。利用这种不对称性,我们定量比较了酿酒酵母母细胞和子细胞中的 CME 蛋白,观察到关键内细胞蛋白的动态和组成存在差异。我们的结果表明,CME 位点的启动优先发生在质膜上内吞货物和/或酸性磷脂密度相对较高的区域。此外,我们结合活细胞成像和酵母遗传学分析,证明了一种分子机制,即当Yap1801和Yap1802(酵母CALM/AP180)以及Syp1(酵母FCHo1/2)与阴离子磷脂和货物分子协调,触发以Ede1(酵母Eps15)为中心的CME启动复合物在质膜上组装时,CME位点就启动了。
{"title":"The conserved protein adaptors CALM/AP180 and FCHo1/2 cooperatively recruit Eps15 to promote the initiation of clathrin-mediated endocytosis in yeast.","authors":"Yidi Sun, Albert Yeam, Jonathan Kuo, Yuichiro Iwamoto, Gean Hu, David G Drubin","doi":"10.1371/journal.pbio.3002833","DOIUrl":"10.1371/journal.pbio.3002833","url":null,"abstract":"<p><p>Clathrin-mediated endocytosis (CME) is a critical trafficking process that begins when an elaborate endocytic protein network is established at the plasma membrane. Interaction of early endocytic proteins with anionic phospholipids and/or cargo has been suggested to trigger CME initiation. However, the exact mechanism by which CME sites are initiated has not been fully elucidated. In the budding yeast Saccharomyces cerevisiae, higher levels of anionic phospholipids and cargo molecules exist in the newly formed daughter cell compared to the levels in the mother cell during polarized growth. Taking advantage of this asymmetry, we quantitatively compared CME proteins in S. cerevisiae mother versus daughter cells, observing differences in the dynamics and composition of key endocytic proteins. Our results show that CME site initiation occurs preferentially on regions of the plasma membrane with a relatively higher density of endocytic cargo and/or acidic phospholipids. Furthermore, our combined live cell-imaging and yeast genetics analysis provided evidence for a molecular mechanism in which CME sites are initiated when Yap1801 and Yap1802 (yeast CALM/AP180) and Syp1 (yeast FCHo1/2) coordinate with anionic phospholipids and cargo molecules to trigger Ede1 (yeast Eps15)-centric CME initiation complex assembly at the plasma membrane.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11451990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Wnt target gene activation requires β-catenin separation into biomolecular condensates. Wnt靶基因的激活需要β-catenin分离成生物分子凝聚体。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-24 eCollection Date: 2024-09-01 DOI: 10.1371/journal.pbio.3002368
Richard A Stewart, Zhihao Ding, Ung Seop Jeon, Lauren B Goodman, Jeannine J Tran, John P Zientko, Malavika Sabu, Ken M Cadigan

The Wnt/β-catenin signaling pathway plays numerous essential roles in animal development and tissue/stem cell maintenance. The activation of genes regulated by Wnt/β-catenin signaling requires the nuclear accumulation of β-catenin, a transcriptional co-activator. β-catenin is recruited to many Wnt-regulated enhancers through direct binding to T-cell factor/lymphoid enhancer factor (TCF/LEF) family transcription factors. β-catenin has previously been reported to form phase-separated biomolecular condensates (BMCs), which was implicated as a component of β-catenin's mechanism of action. This function required aromatic amino acid residues in the intrinsically disordered regions (IDRs) at the N- and C-termini of the protein. In this report, we further explore a role for β-catenin BMCs in Wnt target gene regulation. We find that β-catenin BMCs are miscible with LEF1 BMCs in vitro and in cultured cells. We characterized a panel of β-catenin mutants with different combinations of aromatic residue mutations in human cell culture and Drosophila melanogaster. Our data support a model in which aromatic residues across both IDRs contribute to BMC formation and signaling activity. Although different Wnt targets have different sensitivities to loss of β-catenin's aromatic residues, the activation of every target examined was compromised by aromatic substitution. These mutants are not defective in nuclear import or co-immunoprecipitation with several β-catenin binding partners. In addition, residues in the N-terminal IDR with no previously known role in signaling are clearly required for the activation of various Wnt readouts. Consistent with this, deletion of the N-terminal IDR results in a loss of signaling activity, which can be rescued by the addition of heterologous IDRs enriched in aromatic residues. Overall, our work supports a model in which the ability of β-catenin to form biomolecular condensates in the nucleus is tightly linked to its function as a transcriptional co-regulator.

Wnt/β-catenin信号通路在动物发育和组织/干细胞维持中发挥着许多重要作用。激活受 Wnt/β-catenin 信号调控的基因需要β-catenin(一种转录共激活因子)的核积累。β-catenin通过与T细胞因子/淋巴细胞增强因子(TCF/LEF)家族转录因子直接结合,被招募到许多Wnt调控的增强子上。据报道,β-catenin 可形成相分离的生物分子凝集物(BMC),这被认为是 β-catenin 作用机制的一个组成部分。这一功能需要蛋白质 N 端和 C 端内在无序区(IDR)中的芳香族氨基酸残基。在本报告中,我们进一步探讨了β-catenin BMC在Wnt靶基因调控中的作用。我们发现,在体外和培养细胞中,β-catenin BMC 与 LEF1 BMC 是混杂的。我们在人类细胞培养和黑腹果蝇中鉴定了一组具有不同芳香残基突变组合的β-catenin突变体。我们的数据支持这样一个模型,即两个 IDR 的芳香残基都有助于 BMC 的形成和信号活性。虽然不同的 Wnt 靶标对β-catenin芳香残基的缺失有不同的敏感性,但芳香取代会影响所研究的每个靶标的激活。这些突变体在核导入或与β-catenin的几个结合伙伴共免疫沉淀方面没有缺陷。此外,N-末端 IDR 的残基以前在信号传导中没有已知的作用,但在激活各种 Wnt 读出时显然是必需的。与此相一致的是,缺失 N 端 IDR 会导致信号活性丧失,而添加富含芳香族残基的异源 IDR 则可以挽救信号活性。总之,我们的工作支持这样一个模型,即β-catenin在细胞核中形成生物分子凝聚体的能力与其作为转录协同调控因子的功能密切相关。
{"title":"Wnt target gene activation requires β-catenin separation into biomolecular condensates.","authors":"Richard A Stewart, Zhihao Ding, Ung Seop Jeon, Lauren B Goodman, Jeannine J Tran, John P Zientko, Malavika Sabu, Ken M Cadigan","doi":"10.1371/journal.pbio.3002368","DOIUrl":"10.1371/journal.pbio.3002368","url":null,"abstract":"<p><p>The Wnt/β-catenin signaling pathway plays numerous essential roles in animal development and tissue/stem cell maintenance. The activation of genes regulated by Wnt/β-catenin signaling requires the nuclear accumulation of β-catenin, a transcriptional co-activator. β-catenin is recruited to many Wnt-regulated enhancers through direct binding to T-cell factor/lymphoid enhancer factor (TCF/LEF) family transcription factors. β-catenin has previously been reported to form phase-separated biomolecular condensates (BMCs), which was implicated as a component of β-catenin's mechanism of action. This function required aromatic amino acid residues in the intrinsically disordered regions (IDRs) at the N- and C-termini of the protein. In this report, we further explore a role for β-catenin BMCs in Wnt target gene regulation. We find that β-catenin BMCs are miscible with LEF1 BMCs in vitro and in cultured cells. We characterized a panel of β-catenin mutants with different combinations of aromatic residue mutations in human cell culture and Drosophila melanogaster. Our data support a model in which aromatic residues across both IDRs contribute to BMC formation and signaling activity. Although different Wnt targets have different sensitivities to loss of β-catenin's aromatic residues, the activation of every target examined was compromised by aromatic substitution. These mutants are not defective in nuclear import or co-immunoprecipitation with several β-catenin binding partners. In addition, residues in the N-terminal IDR with no previously known role in signaling are clearly required for the activation of various Wnt readouts. Consistent with this, deletion of the N-terminal IDR results in a loss of signaling activity, which can be rescued by the addition of heterologous IDRs enriched in aromatic residues. Overall, our work supports a model in which the ability of β-catenin to form biomolecular condensates in the nucleus is tightly linked to its function as a transcriptional co-regulator.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist. 一项全基因组阵列 CRISPR 筛选发现,PLSCR1 是 SARS-CoV-2 进入人体的内在屏障,而最近的病毒变种已经进化到可以抵御这一屏障。
IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-24 eCollection Date: 2024-09-01 DOI: 10.1371/journal.pbio.3002767
Jérémie Le Pen, Gabrielle Paniccia, Volker Kinast, Marcela Moncada-Velez, Alison W Ashbrook, Michael Bauer, H-Heinrich Hoffmann, Ana Pinharanda, Inna Ricardo-Lax, Ansgar F Stenzel, Edwin A Rosado-Olivieri, Kenneth H Dinnon, William C Doyle, Catherine A Freije, Seon-Hui Hong, Danyel Lee, Tyler Lewy, Joseph M Luna, Avery Peace, Carltin Schmidt, William M Schneider, Roni Winkler, Elaine Z Yip, Chloe Larson, Timothy McGinn, Miriam-Rose Menezes, Lavoisier Ramos-Espiritu, Priyam Banerjee, John T Poirier, Francisco J Sànchez-Rivera, Aurélie Cobat, Qian Zhang, Jean-Laurent Casanova, Thomas S Carroll, J Fraser Glickman, Eleftherios Michailidis, Brandon Razooky, Margaret R MacDonald, Charles M Rice

Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of Coronavirus Disease 2019 (COVID-19) patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 overexpression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently.

干扰素(IFN)在宿主-病毒相互作用的调控和进化过程中发挥着至关重要的作用。在这里,我们在有 IFN 和没有 IFN 的情况下进行了全基因组阵列 CRISPR 基因敲除筛选,以确定影响严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)感染的人类基因。然后,我们从包括我们自己的研究在内的 67 项大规模研究中筛选出与 SARS-CoV-2 相互作用的基因,并对其进行了综合分析。我们在冠状病毒病 2019(COVID-19)患者的人类基因研究和细胞培养的功能基因筛选中发现了 28 个高度相关的基因,其中许多基因与 IFN 通路有关。其中包括 IFN 刺激基因 PLSCR1。PLSCR1 不需要 IFN 诱导来限制 SARS-CoV-2,也不参与 IFN 信号转导。相反,PLSCR1 专门限制尖峰介导的 SARS-CoV-2 进入。过表达 TMPRSS2 可减轻 PLSCR1 介导的限制,这表明 PLSCR1 主要限制内细胞进入途径。此外,最近的 SARS-CoV-2 变体通过目前尚未确定的机制绕过了 PLSCR1 的屏障。最后,我们研究了存在于人类中的 PLSCR1 变体的功能影响,并讨论了最近报道的 PLSCR1 与严重 COVID-19 之间的关联。
{"title":"A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist.","authors":"Jérémie Le Pen, Gabrielle Paniccia, Volker Kinast, Marcela Moncada-Velez, Alison W Ashbrook, Michael Bauer, H-Heinrich Hoffmann, Ana Pinharanda, Inna Ricardo-Lax, Ansgar F Stenzel, Edwin A Rosado-Olivieri, Kenneth H Dinnon, William C Doyle, Catherine A Freije, Seon-Hui Hong, Danyel Lee, Tyler Lewy, Joseph M Luna, Avery Peace, Carltin Schmidt, William M Schneider, Roni Winkler, Elaine Z Yip, Chloe Larson, Timothy McGinn, Miriam-Rose Menezes, Lavoisier Ramos-Espiritu, Priyam Banerjee, John T Poirier, Francisco J Sànchez-Rivera, Aurélie Cobat, Qian Zhang, Jean-Laurent Casanova, Thomas S Carroll, J Fraser Glickman, Eleftherios Michailidis, Brandon Razooky, Margaret R MacDonald, Charles M Rice","doi":"10.1371/journal.pbio.3002767","DOIUrl":"10.1371/journal.pbio.3002767","url":null,"abstract":"<p><p>Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of Coronavirus Disease 2019 (COVID-19) patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 overexpression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11486371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
PLoS Biology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1