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Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis. 成骨细胞系的承诺、分化、骨形成和稳态的细胞信号和转录调控。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-02 DOI: 10.1038/s41421-024-00689-6
Siyu Zhu, Wei Chen, Alasdair Masson, Yi-Ping Li

The initiation of osteogenesis primarily occurs as mesenchymal stem cells undergo differentiation into osteoblasts. This differentiation process plays a crucial role in bone formation and homeostasis and is regulated by two intricate processes: cell signal transduction and transcriptional gene expression. Various essential cell signaling pathways, including Wnt, BMP, TGF-β, Hedgehog, PTH, FGF, Ephrin, Notch, Hippo, and Piezo1/2, play a critical role in facilitating osteoblast differentiation, bone formation, and bone homeostasis. Key transcriptional factors in this differentiation process include Runx2, Cbfβ, Runx1, Osterix, ATF4, SATB2, and TAZ/YAP. Furthermore, a diverse array of epigenetic factors also plays critical roles in osteoblast differentiation, bone formation, and homeostasis at the transcriptional level. This review provides an overview of the latest developments and current comprehension concerning the pathways of cell signaling, regulation of hormones, and transcriptional regulation of genes involved in the commitment and differentiation of osteoblast lineage, as well as in bone formation and maintenance of homeostasis. The paper also reviews epigenetic regulation of osteoblast differentiation via mechanisms, such as histone and DNA modifications. Additionally, we summarize the latest developments in osteoblast biology spurred by recent advancements in various modern technologies and bioinformatics. By synthesizing these insights into a comprehensive understanding of osteoblast differentiation, this review provides further clarification of the mechanisms underlying osteoblast lineage commitment, differentiation, and bone formation, and highlights potential new therapeutic applications for the treatment of bone diseases.

成骨的启动主要发生在间充质干细胞分化成成骨细胞的过程中。这一分化过程在骨形成和稳态中起着至关重要的作用,并受两个复杂过程的调控:细胞信号传导和转录基因表达。各种重要的细胞信号通路,包括 Wnt、BMP、TGF-β、Hedgehog、PTH、FGF、Ephrin、Notch、Hippo 和 Piezo1/2,在促进成骨细胞分化、骨形成和骨稳态中发挥着关键作用。这一分化过程中的关键转录因子包括 Runx2、Cbfβ、Runx1、Osterix、ATF4、SATB2 和 TAZ/YAP。此外,一系列不同的表观遗传因子也在成骨细胞分化、骨形成和转录水平的平衡中发挥着关键作用。这篇综述概述了细胞信号传导途径、激素调控、参与成骨细胞系的承诺和分化的基因转录调控以及骨形成和维持稳态的最新进展和目前的理解。本文还回顾了通过组蛋白和 DNA 修饰等机制对成骨细胞分化的表观遗传调控。此外,我们还总结了成骨细胞生物学在各种现代技术和生物信息学的推动下取得的最新进展。这篇综述将这些见解综合为对成骨细胞分化的全面理解,进一步阐明了成骨细胞系承诺、分化和骨形成的内在机制,并强调了治疗骨病的潜在新疗法应用。
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引用次数: 0
Structural basis for the inhibition mechanism of LAT1-4F2hc complex by JPH203. JPH203 抑制 LAT1-4F2hc 复合物机制的结构基础。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-02 DOI: 10.1038/s41421-024-00697-6
Ziwei Hu, Renhong Yan
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引用次数: 0
A pan-KRAS degrader for the treatment of KRAS-mutant cancers. 用于治疗 KRAS 突变癌症的泛 KRAS 降解剂。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-28 DOI: 10.1038/s41421-024-00699-4
Jie Yang, Qiao-Li Wang, Guan-Nan Wang, Jia-Cong Ye, Zi-Qian Li, Jing-Yun Wang, Zhao-Hui Liang, Shu-Xin Li, Cong Sun, Wen-Ting Liao, Yi-Jun Gao, Jing Wang, Yong Mao, Chunjing Yu, Guo-Kai Feng, Mu-Sheng Zeng

KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.

KRAS 突变在多种致命癌症中非常普遍,这些突变形式的 KRAS 在推动癌症进展和产生抗药性方面发挥着至关重要的作用。虽然针对特定 KRAS 突变体的小分子药物的开发取得了进展,但不可药用突变体的存在和二次突变的出现仍给 KRAS 突变癌症的临床治疗带来了挑战。在这项研究中,我们开发了一种名为肿瘤靶向 KRAS 降解剂(TKD)的新型分子工具,它能有效靶向多种 KRAS 突变体。TKD由一个KRAS结合纳米抗体、一个选择性靶向癌细胞的细胞穿透肽和一个溶酶体结合基团组成。我们的数据显示,TKD可选择性地与癌细胞中的KRAS结合,并通过溶酶体依赖过程有效地诱导KRAS降解。在功能上,TKD能抑制肿瘤生长,且无明显副作用,并能增强PD-1抗体和西妥昔单抗的抗肿瘤作用。这项研究不仅为开发针对 "不可药用 "蛋白的药物提供了一种策略,而且揭示了 TKD 是一种治疗 KRAS 突变癌症的有前途的疗法。
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引用次数: 0
Structural and functional insights into the helicase protein E5 of Mpox virus. 对 Mpox 病毒螺旋酶蛋白 E5 结构和功能的深入研究。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-25 DOI: 10.1038/s41421-024-00680-1
Weizhen Zhang, Yusong Liu, Mengquan Yang, Jie Yang, Zhiwei Shao, Yanqing Gao, Xinran Jiang, Ruixue Cui, Yixi Zhang, Xin Zhao, Qiyuan Shao, Chulei Cao, Huili Li, Linxi Li, Hehua Liu, Haishan Gao, Jianhua Gan

Mpox virus (MPXV) can cause mpox in humans. Due to its quick and wide spread in the past two years, mpox has turned into a significant public health concern. Helicase E5 is a multi-domain protein; its primer synthesis and DNA unwinding activity are required for genome uncoating and DNA replication of MPXV. However, the in vitro DNA unwinding activity has never been demonstrated. Here, we report the structural and biochemical studies of MPXV E5, showing that the full-length protein adopts an auto-inhibited conformation. Truncation of the N-terminus can recover the in vitro unwinding activity of E5 towards the forked DNA. Further structural analysis reveals that MPXV E5 shares a conserved mechanism in DNA unwinding and primer synthesis with the homologous proteins. These findings not only advance our understanding on the function of MPXV E5, but also provide a solid basis for the development of anti-poxvirus drugs.

痘病毒(MPXV)可导致人类感染痘。由于痘病毒在过去两年中迅速广泛传播,痘病毒已成为一个重大的公共卫生问题。螺旋酶 E5 是一种多域蛋白,其引物合成和 DNA 解旋活性是 MPXV 的基因组解衣和 DNA 复制所必需的。然而,体外 DNA 解旋活性尚未得到证实。在此,我们报告了对 MPXV E5 的结构和生化研究,结果表明全长蛋白采用了自动抑制构象。截断 N 端可以恢复 E5 对分叉 DNA 的体外解旋活性。进一步的结构分析表明,MPXV E5 与同源蛋白在 DNA 解旋和引物合成方面有着相同的机制。这些发现不仅加深了我们对 MPXV E5 功能的理解,而且为开发抗痘病毒药物提供了坚实的基础。
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引用次数: 0
Molecular recognition of the atypical chemokine-like peptide GPR15L by its cognate receptor GPR15. 其同源受体 GPR15 对非典型趋化因子样肽 GPR15L 的分子识别。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-25 DOI: 10.1038/s41421-024-00698-5
Zhongyuan Zhang, You Zheng, Lu Xu, Yang Yue, Kexin Xu, Fei Li, Fei Xu
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引用次数: 0
TMC6 functions as a GPCR-like receptor to sense noxious heat via Gαq signaling. TMC6 作为一种类似 GPCR 的受体,通过 Gαq 信号传导来感知有害热量。
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-18 DOI: 10.1038/s41421-024-00678-9
Chen Zhang, Fang Tong, Bin Zhou, Mingdong He, Shuai Liu, Xiaomeng Zhou, Qiang Ma, Tianyu Feng, Wan-Jie Du, Huan Yang, Hao Xu, Lei Xiao, Zhen-Zhong Xu, Cheng Zhu, Ruiqi Wu, Yan-Qing Wang, Qingjian Han

Thermosensation is vital for the survival, propagation, and adaption of all organisms, but its mechanism is not fully understood yet. Here, we find that TMC6, a membrane protein of unknown function, is highly expressed in dorsal root ganglion (DRG) neurons and functions as a Gαq-coupled G protein-coupled receptor (GPCR)-like receptor to sense noxious heat. TMC6-deficient mice display a substantial impairment in noxious heat sensation while maintaining normal perception of cold, warmth, touch, and mechanical pain. Further studies show that TMC6 interacts with Gαq via its intracellular C-terminal region spanning Ser780 to Pro810. Specifically disrupting such interaction using polypeptide in DRG neurons, genetically ablating Gαq, or pharmacologically blocking Gαq-coupled GPCR signaling can replicate the phenotype of TMC6 deficient mice regarding noxious heat sensation. Noxious heat stimulation triggers intracellular calcium release from the endoplasmic reticulum (ER) of TMC6- but not control vector-transfected HEK293T cell, which can be significantly inhibited by blocking PLC or IP3R. Consistently, noxious heat-induced intracellular Ca2+ release from ER and action potentials of DRG neurons largely reduced when ablating TMC6 or blocking Gαq/PLC/IP3R signaling pathway as well. In summary, our findings indicate that TMC6 can directly function as a Gαq-coupled GPCR-like receptor sensing noxious heat.

热感觉对所有生物的生存、传播和适应至关重要,但其机制尚未完全清楚。在这里,我们发现 TMC6 是一种功能未知的膜蛋白,在背根神经节(DRG)神经元中高度表达,并作为一种类似 Gαq 的 G 蛋白偶联受体(GPCR)来感知有害热。缺失 TMC6 的小鼠在对冷、暖、触觉和机械痛的感知保持正常的同时,对有害热的感觉却表现出严重的障碍。进一步的研究表明,TMC6 通过跨越 Ser780 至 Pro810 的胞内 C 端区域与 Gαq 相互作用。在DRG神经元中使用多肽、基因消融Gαq或药物阻断Gαq耦合GPCR信号传导来具体破坏这种相互作用,可以复制TMC6缺失小鼠在痛热感觉方面的表型。毒性热刺激会触发细胞内钙从TMC6转染的HEK293T细胞内质网(ER)释放,而不是对照载体转染的HEK293T细胞。同样,当消融 TMC6 或阻断 Gαq/PLC/IP3R 信号通路时,有害热诱导的细胞内 Ca2+ 从 ER 的释放和 DRG 神经元的动作电位也会大大降低。总之,我们的研究结果表明,TMC6 可直接作为 Gαq 偶联的 GPCR 样受体感知有害热。
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引用次数: 0
Structural basis of connexin-36 gap junction channel inhibition. 连接蛋白-36 间隙连接通道抑制作用的结构基础
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-18 DOI: 10.1038/s41421-024-00691-y
Xinyue Ding, Simone Aureli, Anand Vaithia, Pia Lavriha, Dina Schuster, Basavraj Khanppnavar, Xiaodan Li, Thorsten B Blum, Paola Picotti, Francesco L Gervasio, Volodymyr M Korkhov
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引用次数: 0
Clathrin mediates membrane fission and budding by constricting membrane pores. Clathrin 通过收缩膜孔介导膜裂变和出芽。
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-11 DOI: 10.1038/s41421-024-00677-w
Lisi Wei, Xiaoli Guo, Ehud Haimov, Kazuki Obashi, Sung Hoon Lee, Wonchul Shin, Min Sun, Chung Yu Chan, Jiansong Sheng, Zhen Zhang, Ammar Mohseni, Sudhriti Ghosh Dastidar, Xin-Sheng Wu, Xin Wang, Sue Han, Gianvito Arpino, Bo Shi, Maryam Molakarimi, Jessica Matthias, Christian A Wurm, Lin Gan, Justin W Taraska, Michael M Kozlov, Ling-Gang Wu

Membrane budding, which underlies fundamental processes like endocytosis, intracellular trafficking, and viral infection, is thought to involve membrane coat-forming proteins, including the most observed clathrin, to form Ω-shape profiles and helix-forming proteins like dynamin to constrict Ω-profiles' pores and thus mediate fission. Challenging this fundamental concept, we report that polymerized clathrin is required for Ω-profiles' pore closure and that clathrin around Ω-profiles' base/pore region mediates pore constriction/closure in neuroendocrine chromaffin cells. Mathematical modeling suggests that clathrin polymerization at Ω-profiles' base/pore region generates forces from its intrinsically curved shape to constrict/close the pore. This new fission function may exert broader impacts than clathrin's well-known coat-forming function during clathrin (coat)-dependent endocytosis, because it underlies not only clathrin (coat)-dependent endocytosis, but also diverse endocytic modes, including ultrafast, fast, slow, bulk, and overshoot endocytosis previously considered clathrin (coat)-independent in chromaffin cells. It mediates kiss-and-run fusion (fusion pore closure) previously considered bona fide clathrin-independent, and limits the vesicular content release rate. Furthermore, analogous to results in chromaffin cells, we found that clathrin is essential for fast and slow endocytosis at hippocampal synapses where clathrin was previously considered dispensable, suggesting clathrin in mediating synaptic vesicle endocytosis and fission. These results suggest that clathrin and likely other intrinsically curved coat proteins are a new class of fission proteins underlying vesicle budding and fusion. The half-a-century concept and studies that attribute vesicle-coat contents' function to Ω-profile formation and classify budding as coat-protein (e.g., clathrin)-dependent or -independent may need to be re-defined and re-examined by considering clathrin's pivotal role in pore constriction/closure.

膜萌发是内吞、细胞内贩运和病毒感染等基本过程的基础,一般认为膜衣形成蛋白(包括观察到最多的凝集蛋白)参与膜萌发以形成Ω形轮廓,而螺旋形成蛋白(如达能蛋白)则收缩Ω形轮廓的孔,从而介导裂变。我们对这一基本概念提出了质疑,并报告说Ω-profiles孔的关闭需要聚合的凝集蛋白,而且在神经内分泌嗜铬细胞中,Ω-profiles基底/孔区域周围的凝集蛋白介导孔的收缩/关闭。数学模型表明,Ω-profiles基底/孔区的凝集素聚合产生的力来自其固有的弯曲形状,从而使孔道收缩/关闭。这种新的裂变功能可能比凝集素在凝集素(外皮)依赖性内吞过程中众所周知的外皮形成功能产生更广泛的影响,因为它不仅是凝集素(外皮)依赖性内吞的基础,也是多种内吞模式的基础,包括超快、快速、慢速、大体积和超调内吞,以前在绒毛膜细胞中被认为是凝集素(外皮)依赖性内吞。它介导了以前被认为真正不依赖于凝集素的 "接吻-奔跑 "融合(融合孔关闭),并限制了囊泡内容物的释放速度。此外,与在绒毛膜细胞中的结果类似,我们发现在海马突触的快速和慢速内吞过程中,凝集素是必不可少的,而以前认为凝集素是可有可无的。这些结果表明,凝集素和其他可能的内在弯曲衣壳蛋白是一类新的裂变蛋白,是囊泡出芽和融合的基础。半个世纪以来,将囊泡包被内容物的功能归因于Ω轮廓的形成,并将出芽分为包被蛋白(如凝集蛋白)依赖型或不依赖型的概念和研究可能需要重新定义,并通过考虑凝集蛋白在孔收缩/关闭中的关键作用来重新审视。
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引用次数: 0
Single-cell sequencing depicts tumor architecture and empowers clinical decision in metastatic conjunctival melanoma. 单细胞测序描绘肿瘤结构,为转移性结膜黑色素瘤的临床决策提供依据。
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-11 DOI: 10.1038/s41421-024-00683-y
Hanhan Shi, Hao Tian, Tianyu Zhu, Qili Liao, Chang Liu, Peng Yuan, Yongyun Li, Jie Yang, Chunyan Zong, Shichong Jia, Jing Ruan, Shengfang Ge, Renbing Jia, Peiwei Chai, Shiqiong Xu, Xianqun Fan

Conjunctival melanoma (CoM) is a potentially devastating tumor that can lead to distant metastasis. Despite various therapeutic strategies for distant metastatic CoM, the clinical outcomes remain unfavorable. Herein, we performed single-cell RNA sequencing (scRNA-seq) of 47,017 cells obtained from normal conjunctival samples (n = 3) and conjunctival melanomas (n = 7). Notably, we noticed a higher abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME), correlated with enhanced angiogenic capacity and increased VEGFR expression in distal metastatic CoM. Additionally, we observed a significant decrease in the proportion of total CD8+ T cells and an increase in the proportion of naive CD8+ T cells, contributing to a relatively quiescent immunological environment in distal metastatic CoM. These findings were confirmed through the analyses of 70,303 single-cell transcriptomes of 7 individual CoM samples, as well as spatially resolved proteomes of an additional 10 samples of CoMs. Due to the increase of VEGFR-mediated angiogenesis and a less active T cell environment in distal metastatic CoMs, a clinical trial (ChiCTR2100045061) has been initiated to evaluate the efficacy of VEGFR blockade in combination with anti-PD1 therapy for patients with distant metastatic CoM, showing promising tumor-inhibitory effects. In conclusion, our study uncovered the landscape and heterogeneity of the TME during CoM tumorigenesis and progression, empowering clinical decisions in the management of distal metastatic CoM. To our knowledge, this is the initial exploration to translate scRNA-seq analysis to a clinical trial dealing with cancer, providing a novel concept by accommodating scRNA-seq data in cancer therapy.

结膜黑色素瘤(CoM)是一种潜在的破坏性肿瘤,可导致远处转移。尽管针对远处转移的结膜黑色素瘤有多种治疗策略,但临床结果仍然不容乐观。在此,我们对从正常结膜样本(3 个)和结膜黑色素瘤(7 个)中获得的 47,017 个细胞进行了单细胞 RNA 测序(scRNA-seq)。值得注意的是,我们注意到肿瘤微环境(TME)中癌症相关成纤维细胞(CAFs)的丰度更高,这与远端转移性结膜黑色素瘤血管生成能力增强和血管内皮生长因子受体(VEGFR)表达增加有关。此外,我们还观察到总 CD8+ T 细胞的比例显著下降,而幼稚 CD8+ T 细胞的比例上升,从而导致远端转移性 CoM 的免疫环境相对静止。由于远端转移性CoM中VEGFR介导的血管生成增加,T细胞环境不活跃,一项临床试验(ChiCTR2100045061)已经启动,以评估VEGFR阻断联合抗PD1疗法对远端转移性CoM患者的疗效,结果显示了良好的抑瘤效果。总之,我们的研究揭示了CoM肿瘤发生和发展过程中TME的格局和异质性,有助于在治疗远处转移性CoM时做出临床决策。据我们所知,这是将scRNA-seq分析应用于癌症临床试验的首次探索,为将scRNA-seq数据应用于癌症治疗提供了一个新的概念。
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引用次数: 0
Author Correction: A genetically encoded ratiometric indicator for tryptophan. 作者更正:基因编码的色氨酸比率指示器
IF 33.5 1区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-10 DOI: 10.1038/s41421-024-00695-8
Rongkun Tao, Kui Wang, Tian-Lun Chen, Xin-Xin Zhang, Jian-Bin Cao, Wen-Quan Zhao, Jiu-Lin Du, Yu Mu
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引用次数: 0
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