首页 > 最新文献

Cell Discovery最新文献

英文 中文
Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control 精氨酸-eIF5A 轴对通过翻译控制激活肌肉干细胞至关重要
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-10 DOI: 10.1038/s41421-024-00712-w
Qianying Zhang, Wanhong Han, Rimao Wu, Shixian Deng, Jiemiao Meng, Yuanping Yang, Lili Li, Mingwei Sun, Heng Ai, Yingxi Chen, Qinyao Liu, Tian Gao, Xingchen Niu, Haixia Liu, Li Zhang, Dan Zhang, Meihong Chen, Pengbin Yin, Licheng Zhang, Peifu Tang, Dahai Zhu, Yong Zhang, Hu Li

Adult skeletal muscle stem cells, also known satellite cells (SCs), are quiescent and activate in response to injury. However, the activation mechanisms of quiescent SCs (QSCs) remain largely unknown. Here, we investigated the metabolic regulation of SC activation by identifying regulatory metabolites that promote SC activation. Using targeted metabolomics, we found that spermidine acts as a regulatory metabolite to promote SC activation and muscle regeneration in mice. Mechanistically, spermidine activates SCs via generating hypusinated eIF5A. Using SC-specific eIF5A-knockout (KO) and Myod-KO mice, we further found that eIF5A is required for spermidine-mediated SC activation by controlling MyoD translation. More significantly, depletion of eIF5A in SCs results in impaired muscle regeneration in mice. Together, the findings of our study define a novel mechanism that is essential for SC activation and acts via spermidine-eIF5A-mediated MyoD translation. Our findings suggest that the spermidine-eIF5A axis represents a promising pharmacological target in efforts to activate endogenous SCs for the treatment of muscular disease.

成人骨骼肌干细胞又称卫星细胞(SCs),具有静止状态,在受伤时会激活。然而,静止骨骼肌干细胞(QSCs)的活化机制在很大程度上仍不为人知。在这里,我们通过鉴定促进SC活化的调控代谢物,研究了SC活化的代谢调控。通过靶向代谢组学研究,我们发现亚精胺是促进小鼠SC活化和肌肉再生的调节代谢物。从机理上讲,亚精胺通过产生高浓度的 eIF5A 来激活 SC。通过使用 SC 特异性 eIF5A 基因敲除(KO)和 Myod-KO 小鼠,我们进一步发现 eIF5A 是通过控制 MyoD 翻译来实现亚精胺介导的 SC 激活的必要条件。更重要的是,消耗 SC 中的 eIF5A 会导致小鼠肌肉再生能力受损。总之,我们的研究结果确定了一种新的机制,它对 SC 的活化至关重要,并通过精胺-eIF5A 介导的 MyoD 翻译发挥作用。我们的研究结果表明,精胺-eIF5A 轴是激活内源性 SCs 治疗肌肉疾病的一个很有前景的药理靶点。
{"title":"Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control","authors":"Qianying Zhang, Wanhong Han, Rimao Wu, Shixian Deng, Jiemiao Meng, Yuanping Yang, Lili Li, Mingwei Sun, Heng Ai, Yingxi Chen, Qinyao Liu, Tian Gao, Xingchen Niu, Haixia Liu, Li Zhang, Dan Zhang, Meihong Chen, Pengbin Yin, Licheng Zhang, Peifu Tang, Dahai Zhu, Yong Zhang, Hu Li","doi":"10.1038/s41421-024-00712-w","DOIUrl":"https://doi.org/10.1038/s41421-024-00712-w","url":null,"abstract":"<p>Adult skeletal muscle stem cells, also known satellite cells (SCs), are quiescent and activate in response to injury. However, the activation mechanisms of quiescent SCs (QSCs) remain largely unknown. Here, we investigated the metabolic regulation of SC activation by identifying regulatory metabolites that promote SC activation. Using targeted metabolomics, we found that spermidine acts as a regulatory metabolite to promote SC activation and muscle regeneration in mice. Mechanistically, spermidine activates SCs via generating hypusinated eIF5A. Using SC-specific <i>eIF5A</i>-knockout (KO) and <i>Myod</i>-KO mice, we further found that eIF5A is required for spermidine-mediated SC activation by controlling MyoD translation. More significantly, depletion of eIF5A in SCs results in impaired muscle regeneration in mice. Together, the findings of our study define a novel mechanism that is essential for SC activation and acts via spermidine-eIF5A-mediated MyoD translation. Our findings suggest that the spermidine-eIF5A axis represents a promising pharmacological target in efforts to activate endogenous SCs for the treatment of muscular disease.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"400 1","pages":""},"PeriodicalIF":33.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180176","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}
引用次数: 0
A conditional protein diffusion model generates artificial programmable endonuclease sequences with enhanced activity 条件蛋白质扩散模型可生成具有更强活性的人工可编程内切酶序列
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-10 DOI: 10.1038/s41421-024-00728-2
Bingxin Zhou, Lirong Zheng, Banghao Wu, Kai Yi, Bozitao Zhong, Yang Tan, Qian Liu, Pietro Liò, Liang Hong

Deep learning-based methods for generating functional proteins address the growing need for novel biocatalysts, allowing for precise tailoring of functionalities to meet specific requirements. This advancement leads to the development of highly efficient and specialized proteins with diverse applications across scientific, technological, and biomedical fields. This study establishes a pipeline for protein sequence generation with a conditional protein diffusion model, namely CPDiffusion, to create diverse sequences of proteins with enhanced functions. CPDiffusion accommodates protein-specific conditions, such as secondary structures and highly conserved amino acids. Without relying on extensive training data, CPDiffusion effectively captures highly conserved residues and sequence features for specific protein families. We applied CPDiffusion to generate artificial sequences of Argonaute (Ago) proteins based on the backbone structures of wild-type (WT) Kurthia massiliensis Ago (KmAgo) and Pyrococcus furiosus Ago (PfAgo), which are complex multi-domain programmable endonucleases. The generated sequences deviate by up to nearly 400 amino acids from their WT templates. Experimental tests demonstrated that the majority of the generated proteins for both KmAgo and PfAgo show unambiguous activity in DNA cleavage, with many of them exhibiting superior activity as compared to the WT. These findings underscore CPDiffusion’s remarkable success rate in generating novel sequences for proteins with complex structures and functions in a single step, leading to enhanced activity. This approach facilitates the design of enzymes with multi-domain molecular structures and intricate functions through in silico generation and screening, all accomplished without the need for supervision from labeled data.

基于深度学习的功能蛋白质生成方法满足了对新型生物催化剂日益增长的需求,可精确定制功能以满足特定要求。这一进步促使人们开发出高效、特异的蛋白质,并在科学、技术和生物医学领域得到广泛应用。本研究利用条件蛋白质扩散模型(即 CPDiffusion)建立了蛋白质序列生成管道,以创建具有增强功能的多样化蛋白质序列。CPDiffusion 可满足蛋白质的特定条件,如二级结构和高度保守的氨基酸。CPDiffusion 无需依赖大量训练数据,就能有效捕捉特定蛋白质家族的高度保守残基和序列特征。我们根据野生型(WT)Kurthia massiliensis Ago(KmAgo)和Pyrococcus furiosus Ago(PfAgo)的骨架结构,应用CPDiffusion生成了Argonaute(Ago)蛋白的人工序列。生成的序列与它们的 WT 模板最多相差近 400 个氨基酸。实验测试表明,生成的大多数 KmAgo 和 PfAgo 蛋白在 DNA 切割方面都表现出明确的活性,其中许多蛋白的活性比 WT 蛋白更强。这些发现突出表明,CPDiffusion 在为具有复杂结构和功能的蛋白质生成新序列方面取得了显著的成功,从而提高了活性。这种方法有助于通过硅学生成和筛选设计具有多域分子结构和复杂功能的酶,而这一切都不需要标记数据的监督。
{"title":"A conditional protein diffusion model generates artificial programmable endonuclease sequences with enhanced activity","authors":"Bingxin Zhou, Lirong Zheng, Banghao Wu, Kai Yi, Bozitao Zhong, Yang Tan, Qian Liu, Pietro Liò, Liang Hong","doi":"10.1038/s41421-024-00728-2","DOIUrl":"https://doi.org/10.1038/s41421-024-00728-2","url":null,"abstract":"<p>Deep learning-based methods for generating functional proteins address the growing need for novel biocatalysts, allowing for precise tailoring of functionalities to meet specific requirements. This advancement leads to the development of highly efficient and specialized proteins with diverse applications across scientific, technological, and biomedical fields. This study establishes a pipeline for protein sequence generation with a conditional protein diffusion model, namely CPDiffusion, to create diverse sequences of proteins with enhanced functions. CPDiffusion accommodates protein-specific conditions, such as secondary structures and highly conserved amino acids. Without relying on extensive training data, CPDiffusion effectively captures highly conserved residues and sequence features for specific protein families. We applied CPDiffusion to generate artificial sequences of Argonaute (Ago) proteins based on the backbone structures of wild-type (WT) <i>Kurthia massiliensis</i> Ago (KmAgo) and <i>Pyrococcus furiosus</i> Ago (PfAgo), which are complex multi-domain programmable endonucleases. The generated sequences deviate by up to nearly 400 amino acids from their WT templates. Experimental tests demonstrated that the majority of the generated proteins for both KmAgo and PfAgo show unambiguous activity in DNA cleavage, with many of them exhibiting superior activity as compared to the WT. These findings underscore CPDiffusion’s remarkable success rate in generating novel sequences for proteins with complex structures and functions in a single step, leading to enhanced activity. This approach facilitates the design of enzymes with multi-domain molecular structures and intricate functions through in silico generation and screening, all accomplished without the need for supervision from labeled data.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"77 1","pages":""},"PeriodicalIF":33.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180175","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}
引用次数: 0
Single-cell and spatial proteo-transcriptomic profiling reveals immune infiltration heterogeneity associated with neuroendocrine features in small cell lung cancer. 单细胞和空间蛋白质转录组特征分析揭示了与小细胞肺癌神经内分泌特征相关的免疫浸润异质性。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-04 DOI: 10.1038/s41421-024-00703-x
Ying Jin, Yuefeng Wu, Alexandre Reuben, Liang Zhu, Carl M Gay, Qingzhe Wu, Xintong Zhou, Haomin Mo, Qi Zheng, Junyu Ren, Zhaoyuan Fang, Teng Peng, Nan Wang, Liang Ma, Yun Fan, Hai Song, Jianjun Zhang, Ming Chen

Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 pathologically defined spatial compartments (pan-CK-positive tumor nest; CD45/CD3-positive tumor stroma; para-tumor). Our study depicted the spatial transcriptomic and proteomic TIME architecture of SCLC, indicating clear intra-tumor heterogeneity dictated via canonical neuroendocrine subtyping markers; revealed the enrichment of innate immune cells and functionally impaired B cells in tumor nest and suggested potentially important immunoregulatory roles of monocytes/macrophages. We identified RE1 silencing factor (REST) as a potential biomarker for SCLC associated with low neuroendocrine features, more active anti-tumor immunity, and prolonged survival.

小细胞肺癌(SCLC)是一种侵袭性肺神经内分泌恶性肿瘤,其特点是肿瘤免疫微环境(TIME)寒冷、免疫疗法获益有限且生存率低。目前尚未对 SCLC 中与抗肿瘤免疫显著相关的 TIME 空间异质性进行系统研究。我们对来自 44 例未接受治疗的局限期 SCLC 肿瘤的 132 个组织芯片核进行了超高倍数字空间谱分析。结合来自本地队列的单细胞 RNA 序列数据和已发表的 SCLC 数据,我们建立了一个空间蛋白质转录组图谱,涵盖了 18,000 多个基因和 60 个关键免疫肿瘤学蛋白,这些蛋白参与了影响肿瘤发生、免疫调节和癌症代谢的信号通路,横跨 3 个病理学定义的空间分区(pan-CK 阳性瘤巢;CD45/CD3 阳性肿瘤基质;瘤旁)。我们的研究描绘了SCLC的空间转录组和蛋白质组TIME结构,表明通过典型神经内分泌亚型标志物决定的肿瘤内异质性;揭示了先天性免疫细胞和功能受损的B细胞在肿瘤巢中的富集,并提出了单核细胞/巨噬细胞潜在的重要免疫调节作用。我们发现RE1沉默因子(REST)是SCLC的潜在生物标志物,它与低神经内分泌特征、更活跃的抗肿瘤免疫和生存期延长有关。
{"title":"Single-cell and spatial proteo-transcriptomic profiling reveals immune infiltration heterogeneity associated with neuroendocrine features in small cell lung cancer.","authors":"Ying Jin, Yuefeng Wu, Alexandre Reuben, Liang Zhu, Carl M Gay, Qingzhe Wu, Xintong Zhou, Haomin Mo, Qi Zheng, Junyu Ren, Zhaoyuan Fang, Teng Peng, Nan Wang, Liang Ma, Yun Fan, Hai Song, Jianjun Zhang, Ming Chen","doi":"10.1038/s41421-024-00703-x","DOIUrl":"10.1038/s41421-024-00703-x","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 pathologically defined spatial compartments (pan-CK-positive tumor nest; CD45/CD3-positive tumor stroma; para-tumor). Our study depicted the spatial transcriptomic and proteomic TIME architecture of SCLC, indicating clear intra-tumor heterogeneity dictated via canonical neuroendocrine subtyping markers; revealed the enrichment of innate immune cells and functionally impaired B cells in tumor nest and suggested potentially important immunoregulatory roles of monocytes/macrophages. We identified RE1 silencing factor (REST) as a potential biomarker for SCLC associated with low neuroendocrine features, more active anti-tumor immunity, and prolonged survival.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"93"},"PeriodicalIF":13.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11375181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131908","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
Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation. 人类 ABCD3 介导的过氧物酶体酰基-CoA 转运的结构性启示。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-03 DOI: 10.1038/s41421-024-00722-8
Yang Li, Zhi-Peng Chen, Da Xu, Liang Wang, Meng-Ting Cheng, Cong-Zhao Zhou, Yuxing Chen, Wen-Tao Hou

Human ABC transporters ABCD1-3 are all localized on the peroxisomal membrane and participate in the β-oxidation of fatty acyl-CoAs, but they differ from each other in substrate specificity. The transport of branched-chain fatty acids from cytosol to peroxisome is specifically driven by ABCD3, dysfunction of which causes severe liver diseases such as hepatosplenomegaly. Here we report two cryogenic electron microscopy (cryo-EM) structures of ABCD3 bound to phytanoyl-CoA and ATP at resolutions of 2.9 Å and 3.2 Å, respectively. A pair of phytanoyl-CoA molecules were observed in ABCD3, each binding to one transmembrane domain (TMD), which is distinct from our previously reported structure of ABCD1, where each fatty acyl-CoA molecule strongly crosslinks two TMDs. Upon ATP binding, ABCD3 exhibits a conformation that is open towards the peroxisomal matrix, leaving two extra densities corresponding to two CoA molecules deeply embedded in the translocation cavity. Structural analysis combined with substrate-stimulated ATPase activity assays indicated that the present structures might represent two states of ABCD3 in the transport cycle. These findings advance our understanding of fatty acid oxidation and the molecular pathology of related diseases.

人类 ABC 转运体 ABCD1-3 都定位于过氧物酶体膜上,参与脂肪酰基-CoAs 的β-氧化,但它们在底物特异性上有所不同。支链脂肪酸从细胞质到过氧物酶体的转运是由 ABCD3 特别驱动的,ABCD3 的功能障碍会导致严重的肝病,如肝脾肿大。在这里,我们报告了 ABCD3 与植烷酰-CoA 和 ATP 结合的两个低温电子显微镜(cryo-EM)结构,分辨率分别为 2.9 Å 和 3.2 Å。在 ABCD3 中观察到一对植物酰基-CoA 分子,每个分子与一个跨膜结构域(TMD)结合,这与我们之前报道的 ABCD1 结构不同,在 ABCD1 中,每个脂肪酰基-CoA 分子与两个跨膜结构域强烈交联。与 ATP 结合后,ABCD3 呈现出一种向过氧物酶体基质开放的构象,留下两个额外的密度,对应于深深嵌入转运腔的两个 CoA 分子。结构分析与底物刺激 ATPase 活性测定相结合表明,目前的结构可能代表了 ABCD3 在转运循环中的两种状态。这些发现加深了我们对脂肪酸氧化及相关疾病分子病理学的理解。
{"title":"Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation.","authors":"Yang Li, Zhi-Peng Chen, Da Xu, Liang Wang, Meng-Ting Cheng, Cong-Zhao Zhou, Yuxing Chen, Wen-Tao Hou","doi":"10.1038/s41421-024-00722-8","DOIUrl":"10.1038/s41421-024-00722-8","url":null,"abstract":"<p><p>Human ABC transporters ABCD1-3 are all localized on the peroxisomal membrane and participate in the β-oxidation of fatty acyl-CoAs, but they differ from each other in substrate specificity. The transport of branched-chain fatty acids from cytosol to peroxisome is specifically driven by ABCD3, dysfunction of which causes severe liver diseases such as hepatosplenomegaly. Here we report two cryogenic electron microscopy (cryo-EM) structures of ABCD3 bound to phytanoyl-CoA and ATP at resolutions of 2.9 Å and 3.2 Å, respectively. A pair of phytanoyl-CoA molecules were observed in ABCD3, each binding to one transmembrane domain (TMD), which is distinct from our previously reported structure of ABCD1, where each fatty acyl-CoA molecule strongly crosslinks two TMDs. Upon ATP binding, ABCD3 exhibits a conformation that is open towards the peroxisomal matrix, leaving two extra densities corresponding to two CoA molecules deeply embedded in the translocation cavity. Structural analysis combined with substrate-stimulated ATPase activity assays indicated that the present structures might represent two states of ABCD3 in the transport cycle. These findings advance our understanding of fatty acid oxidation and the molecular pathology of related diseases.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"92"},"PeriodicalIF":13.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119104","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
Molecular mechanism of prolactin-releasing peptide recognition and signaling via its G protein-coupled receptor. 催乳素释放肽通过其 G 蛋白偶联受体识别和传递信号的分子机制。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-03 DOI: 10.1038/s41421-024-00724-6
Yang Li, Qingning Yuan, Xinheng He, Yumu Zhang, Chongzhao You, Canrong Wu, Jingru Li, H Eric Xu, Li-Hua Zhao

Prolactin-releasing peptide (PrRP) is an RF-amide neuropeptide that binds and activates its cognate G protein-coupled receptor, prolactin-releasing peptide receptor (PrRPR), also known as GPR10. PrRP and PrRPR are highly conserved across mammals and involved in regulating a range of physiological processes, including stress response, appetite regulation, pain modulation, cardiovascular function, and potentially reproductive functions. Here we present cryo-electron microscopy structures of PrRP-bound PrRPR coupled to Gq or Gi heterotrimer, unveiling distinct molecular determinants underlying the specific recognition of the ligand's C-terminal RF-amide motif. We identify a conserved polar pocket that accommodates the C-terminal amide shared by RF-amide peptides. Structural comparison with neuropeptide Y receptors reveals both similarities and differences in engaging the essential RF/RY-amide motifs. Our findings demonstrate the general mechanism governing RF-amide motif recognition by PrRPR and RF-amide peptide receptors, and provide a foundation for elucidating activation mechanisms and developing selective drugs targeting this important peptide-receptor system.

催乳素释放肽(PrRP)是一种射频酰胺神经肽,可结合并激活其同源的 G 蛋白偶联受体--催乳素释放肽受体(PrRPR),也称为 GPR10。PrRP 和 PrRPR 在哺乳动物中高度保守,参与调节一系列生理过程,包括应激反应、食欲调节、疼痛调节、心血管功能以及潜在的生殖功能。在这里,我们展示了与 Gq 或 Gi 异源三聚体偶联的 PrRP 结合的 PrRPR 的冷冻电子显微镜结构,揭示了特异性识别配体 C 端 RF-amide motif 的独特分子决定因素。我们发现了一个保守的极性口袋,可容纳 RF-amide 肽共有的 C 端酰胺。通过与神经肽 Y 受体的结构比较,我们发现了与 RF/RY-amide 重要基团结合的相似之处和不同之处。我们的研究结果证明了 PrRPR 和 RF-amide 肽受体识别 RF-amide 主题的一般机制,为阐明激活机制和开发针对这一重要肽受体系统的选择性药物奠定了基础。
{"title":"Molecular mechanism of prolactin-releasing peptide recognition and signaling via its G protein-coupled receptor.","authors":"Yang Li, Qingning Yuan, Xinheng He, Yumu Zhang, Chongzhao You, Canrong Wu, Jingru Li, H Eric Xu, Li-Hua Zhao","doi":"10.1038/s41421-024-00724-6","DOIUrl":"10.1038/s41421-024-00724-6","url":null,"abstract":"<p><p>Prolactin-releasing peptide (PrRP) is an RF-amide neuropeptide that binds and activates its cognate G protein-coupled receptor, prolactin-releasing peptide receptor (PrRPR), also known as GPR10. PrRP and PrRPR are highly conserved across mammals and involved in regulating a range of physiological processes, including stress response, appetite regulation, pain modulation, cardiovascular function, and potentially reproductive functions. Here we present cryo-electron microscopy structures of PrRP-bound PrRPR coupled to G<sub>q</sub> or G<sub>i</sub> heterotrimer, unveiling distinct molecular determinants underlying the specific recognition of the ligand's C-terminal RF-amide motif. We identify a conserved polar pocket that accommodates the C-terminal amide shared by RF-amide peptides. Structural comparison with neuropeptide Y receptors reveals both similarities and differences in engaging the essential RF/RY-amide motifs. Our findings demonstrate the general mechanism governing RF-amide motif recognition by PrRPR and RF-amide peptide receptors, and provide a foundation for elucidating activation mechanisms and developing selective drugs targeting this important peptide-receptor system.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"91"},"PeriodicalIF":13.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119102","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
PCaseek: ultraspecific urinary tumor DNA detection using deep learning for prostate cancer diagnosis and Gleason grading. PCaseek:利用深度学习进行超特异性尿液肿瘤 DNA 检测,用于前列腺癌诊断和格里森分级。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-09-03 DOI: 10.1038/s41421-024-00710-y
Gaojie Li, Ye Wang, Ying Wang, Baojun Wang, Yuan Liang, Ping Wang, Yudan He, Xiaoshan Hu, Guojun Liu, Zhentao Lei, Bao Zhang, Yue Shi, Xu Gao, Xu Zhang, Weimin Ci
{"title":"PCaseek: ultraspecific urinary tumor DNA detection using deep learning for prostate cancer diagnosis and Gleason grading.","authors":"Gaojie Li, Ye Wang, Ying Wang, Baojun Wang, Yuan Liang, Ping Wang, Yudan He, Xiaoshan Hu, Guojun Liu, Zhentao Lei, Bao Zhang, Yue Shi, Xu Gao, Xu Zhang, Weimin Ci","doi":"10.1038/s41421-024-00710-y","DOIUrl":"10.1038/s41421-024-00710-y","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"90"},"PeriodicalIF":13.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119103","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
Gut microbiota-derived indole-3-acetic acid suppresses high myopia progression by promoting type I collagen synthesis. 肠道微生物群衍生的吲哚-3-乙酸通过促进 I 型胶原蛋白的合成抑制高度近视的发展。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-27 DOI: 10.1038/s41421-024-00709-5
Hao Li, Yu Du, Kaiwen Cheng, Yuxi Chen, Ling Wei, Yujun Pei, Xiaoyu Wang, Lan Wang, Ye Zhang, Xiaoxin Hu, Yi Lu, Xiangjia Zhu

High myopia (HM) is a leading cause of blindness worldwide with currently no effective interventions available. A major hurdle lies in its often isolated perception as a purely ocular morbidity, disregarding potential systemic implications. Recent evidence suggests the existence of a gut-eye axis; however, the role of gut microbiota in the pathogenesis of HM remains largely unexplored. Herein, we provide a potential crosstalk among HM's gut dysbiosis, microbial metabolites, and scleral remodeling. Utilizing 16S rRNA gene sequencing, we observed an altered gut microbiota profile in HM patients with a significant reduction in probiotic abundance compared with healthy controls. Subsequent targeted metabolic profiling revealed a notable decrease in plasma levels of the gut microbiota-derived metabolite indole-3-acetic acid (3-IAA) among HM patients, which is closely associated with the reduced probiotics, both negatively correlated with HM severity. Genetic analyses determined that gut microbiota are causally associated with myopia risk. Importantly, when mice subjected to HM modeling receive fecal microbiota transplantation from healthy donors, there is an increase in 3-IAA plasma levels and simultaneous retardation of HM progression along with better maintenance of collagen type I alpha 1 (COL1A1) expression in the sclera. Furthermore, 3-IAA gavage achieves similar effects. Mechanistic investigations confirm the transcriptional activation of COL1A1 by 3-IAA via promoting the enrichment of SP1 to its promoter. Together, our findings provide novel insights into the gut microbiota-eye axis in the pathogenesis of HM and propose new strategies for HM intervention by remodeling the gut microbiota and indole supplementation.

高度近视(HM)是全球致盲的主要原因之一,目前尚无有效的干预措施。其主要障碍在于人们往往将其孤立地视为一种纯粹的眼部疾病,而忽视了其潜在的系统性影响。最近的证据表明存在肠道-眼睛轴;然而,肠道微生物群在 HM 发病机制中的作用在很大程度上仍未被探索。在此,我们提供了 HM 的肠道菌群失调、微生物代谢产物和巩膜重塑之间的潜在串联关系。通过 16S rRNA 基因测序,我们观察到 HM 患者的肠道微生物群谱发生了改变,与健康对照组相比,益生菌丰度显著降低。随后的靶向代谢谱分析显示,HM 患者的血浆中肠道微生物群衍生代谢物吲哚-3-乙酸(3-IAA)水平明显下降,这与益生菌的减少密切相关,两者均与 HM 的严重程度呈负相关。遗传分析表明,肠道微生物群与近视风险存在因果关系。重要的是,当 HM 模型小鼠接受来自健康捐赠者的粪便微生物群移植时,血浆中的 3-IAA 水平会增加,同时会延缓 HM 的发展,更好地维持巩膜中 I 型胶原蛋白α1(COL1A1)的表达。此外,灌胃 3-IAA 也能达到类似的效果。机理研究证实,3-IAA 通过促进 SP1 向其启动子富集而激活了 COL1A1 的转录。总之,我们的研究结果提供了有关 HM 发病机制中肠道微生物-眼睛轴的新见解,并提出了通过重塑肠道微生物群和补充吲哚来干预 HM 的新策略。
{"title":"Gut microbiota-derived indole-3-acetic acid suppresses high myopia progression by promoting type I collagen synthesis.","authors":"Hao Li, Yu Du, Kaiwen Cheng, Yuxi Chen, Ling Wei, Yujun Pei, Xiaoyu Wang, Lan Wang, Ye Zhang, Xiaoxin Hu, Yi Lu, Xiangjia Zhu","doi":"10.1038/s41421-024-00709-5","DOIUrl":"10.1038/s41421-024-00709-5","url":null,"abstract":"<p><p>High myopia (HM) is a leading cause of blindness worldwide with currently no effective interventions available. A major hurdle lies in its often isolated perception as a purely ocular morbidity, disregarding potential systemic implications. Recent evidence suggests the existence of a gut-eye axis; however, the role of gut microbiota in the pathogenesis of HM remains largely unexplored. Herein, we provide a potential crosstalk among HM's gut dysbiosis, microbial metabolites, and scleral remodeling. Utilizing 16S rRNA gene sequencing, we observed an altered gut microbiota profile in HM patients with a significant reduction in probiotic abundance compared with healthy controls. Subsequent targeted metabolic profiling revealed a notable decrease in plasma levels of the gut microbiota-derived metabolite indole-3-acetic acid (3-IAA) among HM patients, which is closely associated with the reduced probiotics, both negatively correlated with HM severity. Genetic analyses determined that gut microbiota are causally associated with myopia risk. Importantly, when mice subjected to HM modeling receive fecal microbiota transplantation from healthy donors, there is an increase in 3-IAA plasma levels and simultaneous retardation of HM progression along with better maintenance of collagen type I alpha 1 (COL1A1) expression in the sclera. Furthermore, 3-IAA gavage achieves similar effects. Mechanistic investigations confirm the transcriptional activation of COL1A1 by 3-IAA via promoting the enrichment of SP1 to its promoter. Together, our findings provide novel insights into the gut microbiota-eye axis in the pathogenesis of HM and propose new strategies for HM intervention by remodeling the gut microbiota and indole supplementation.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"89"},"PeriodicalIF":13.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11347609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072138","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
Postsynaptic lncRNA Sera/Pkm2 pathway orchestrates the transition from social competition to rank by remodeling the neural ensemble in mPFC. 突触后lncRNA Sera/Pkm2通路通过重塑mPFC的神经组合,协调从社会竞争到等级的转变。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-20 DOI: 10.1038/s41421-024-00706-8
Ling-Shuang Zhu, Chuan Lai, Chao-Wen Zhou, Hui-Yang Chen, Zhi-Qiang Liu, Ziyuan Guo, Hengye Man, Hui-Yun Du, Youming Lu, Feng Hu, Zhiye Chen, Kai Shu, Ling-Qiang Zhu, Dan Liu

Individuals' continuous success in competitive interactions with conspecifics strongly affects their social hierarchy. Medial prefrontal cortex (mPFC) is the key brain region mediating both social competition and hierarchy. However, the molecular regulatory mechanisms underlying the neural ensemble in the mPFC remains unclear. Here, we demonstrate that in excitatory neurons of prelimbic cortex (PL), lncRNA Sera remodels the utilization of Pkm Exon9 and Exon10, resulting in a decrease in the Pkm1/2 ratio in highly competitive mice. By employing a tet-on/off system, we disrupt or rebuild the normal Pkm1/2 ratio by controlling the expression of Pkm2 in PL excitatory neurons. We find that long-term Pkm2 modulation induces timely competition alteration and hysteretic rank change, through phosphorylating the Ser845 site of GluA1. Together, this study uncovers a crucial role of lncRNA Sera/Pkm2 pathway in the transition of social competition to rank by remodeling neural ensemble in mPFC.

个体在与同类的竞争性互动中不断取得成功会对其社会等级产生强烈影响。内侧前额叶皮层(mPFC)是介导社会竞争和等级制度的关键脑区。然而,mPFC神经集合的分子调控机制仍不清楚。在这里,我们证明了在前边缘皮层(PL)的兴奋性神经元中,lncRNA Sera重塑了Pkm Exon9和Exon10的利用,导致高度竞争性小鼠的Pkm1/2比率下降。通过使用 tet-on/off 系统,我们控制了 PL 兴奋神经元中 Pkm2 的表达,从而破坏或重建了正常的 Pkm1/2 比率。我们发现,通过磷酸化 GluA1 的 Ser845 位点,长期的 Pkm2 调节可诱导及时的竞争改变和滞后等级变化。综上所述,本研究发现了lncRNA Sera/Pkm2通路通过重塑mPFC中的神经组合,在社会竞争向等级过渡中的关键作用。
{"title":"Postsynaptic lncRNA Sera/Pkm2 pathway orchestrates the transition from social competition to rank by remodeling the neural ensemble in mPFC.","authors":"Ling-Shuang Zhu, Chuan Lai, Chao-Wen Zhou, Hui-Yang Chen, Zhi-Qiang Liu, Ziyuan Guo, Hengye Man, Hui-Yun Du, Youming Lu, Feng Hu, Zhiye Chen, Kai Shu, Ling-Qiang Zhu, Dan Liu","doi":"10.1038/s41421-024-00706-8","DOIUrl":"10.1038/s41421-024-00706-8","url":null,"abstract":"<p><p>Individuals' continuous success in competitive interactions with conspecifics strongly affects their social hierarchy. Medial prefrontal cortex (mPFC) is the key brain region mediating both social competition and hierarchy. However, the molecular regulatory mechanisms underlying the neural ensemble in the mPFC remains unclear. Here, we demonstrate that in excitatory neurons of prelimbic cortex (PL), lncRNA Sera remodels the utilization of Pkm Exon9 and Exon10, resulting in a decrease in the Pkm1/2 ratio in highly competitive mice. By employing a tet-on/off system, we disrupt or rebuild the normal Pkm1/2 ratio by controlling the expression of Pkm2 in PL excitatory neurons. We find that long-term Pkm2 modulation induces timely competition alteration and hysteretic rank change, through phosphorylating the Ser845 site of GluA1. Together, this study uncovers a crucial role of lncRNA Sera/Pkm2 pathway in the transition of social competition to rank by remodeling neural ensemble in mPFC.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"87"},"PeriodicalIF":13.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11333582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003714","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
Structural insight into 6-OH-FAD-dependent activation of hFSP1 for ferroptosis suppression. 从结构上洞察 6-OH-FAD 依赖性激活 hFSP1 以抑制铁变态反应。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-20 DOI: 10.1038/s41421-024-00723-7
Hongying Lan, Yu Gao, Ting Hong, Zihan Chang, Zhengyang Zhao, Yanfeng Wang, Feng Wang
{"title":"Structural insight into 6-OH-FAD-dependent activation of hFSP1 for ferroptosis suppression.","authors":"Hongying Lan, Yu Gao, Ting Hong, Zihan Chang, Zhengyang Zhao, Yanfeng Wang, Feng Wang","doi":"10.1038/s41421-024-00723-7","DOIUrl":"10.1038/s41421-024-00723-7","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"88"},"PeriodicalIF":13.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11333494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003715","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
Prediction of overall survival in stage II and III colon cancer through machine learning of rapidly-acquired proteomics. 通过对快速获得的蛋白质组学进行机器学习,预测 II 期和 III 期结肠癌患者的总生存期。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-13 DOI: 10.1038/s41421-024-00707-7
Kailun Xu, Xiaoyang Yin, Hui Chen, Yuhui Huang, Xi Zheng, Biting Zhou, Xue Cai, Huanhuan Gao, Miaomiao Tian, Sijun Hu, Shu Zheng, Changzheng Yuan, Yongzhan Nie, Tiannan Guo, Yingkuan Shao
{"title":"Prediction of overall survival in stage II and III colon cancer through machine learning of rapidly-acquired proteomics.","authors":"Kailun Xu, Xiaoyang Yin, Hui Chen, Yuhui Huang, Xi Zheng, Biting Zhou, Xue Cai, Huanhuan Gao, Miaomiao Tian, Sijun Hu, Shu Zheng, Changzheng Yuan, Yongzhan Nie, Tiannan Guo, Yingkuan Shao","doi":"10.1038/s41421-024-00707-7","DOIUrl":"10.1038/s41421-024-00707-7","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"85"},"PeriodicalIF":13.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970695","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
Cell Discovery
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