Molecular Cell最新文献

英文中文

The many faces of RNA 核糖核酸的多面性

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.09.017

Bryan T. Harada

No Abstract

无摘要

引用次数: 0

An RNA-centric view of transcription and genome organization 以 RNA 为中心的转录和基因组组织视角

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.08.021

Jonathan E. Henninger, Richard A. Young

Foundational models of transcriptional regulation involve the assembly of protein complexes at DNA elements associated with specific genes. These assemblies, which can include transcription factors, cofactors, RNA polymerase, and various chromatin regulators, form dynamic spatial compartments that contribute to both gene regulation and local genome architecture. This DNA-protein-centric view has been modified with recent evidence that RNA molecules have important roles to play in gene regulation and genome structure. Here, we discuss evidence that gene regulation by RNA occurs at multiple levels that include assembly of transcriptional complexes and genome compartments, feedback regulation of active genes, silencing of genes, and control of protein kinases. We thus provide an RNA-centric view of transcriptional regulation that must reside alongside the more traditional DNA-protein-centric perspectives on gene regulation and genome architecture.

转录调控的基本模式涉及在与特定基因相关的 DNA 元件上组装蛋白质复合物。这些集合体可能包括转录因子、辅助因子、RNA 聚合酶和各种染色质调节因子，它们形成了动态的空间分区，有助于基因调控和局部基因组结构。最近有证据表明，RNA 分子在基因调控和基因组结构中发挥着重要作用，从而改变了这种以 DNA 蛋白为中心的观点。在这里，我们讨论了 RNA 在多个水平上进行基因调控的证据，这些水平包括转录复合物和基因组分区的组装、活性基因的反馈调控、基因沉默以及蛋白激酶的控制。因此，我们提供了一种以 RNA 为中心的转录调控观点，它必须与更传统的以 DNA 蛋白为中心的基因调控和基因组结构观点并存。

引用次数: 0

Dynamic conformation: Marching toward circular RNA function and application 动态构象：向环形 RNA 的功能和应用迈进

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.08.020

Chu-Xiao Liu, Li Yang, Ling-Ling Chen

Circular RNA is a group of covalently closed, single-stranded transcripts with unique biogenesis, stability, and conformation that play distinct roles in modulating cellular functions and also possess a great potential for developing circular RNA-based therapies. Importantly, due to its circular conformation, circular RNA generates distinct intramolecular base pairing that is different from the linear transcript. In this perspective, we review how circular RNA conformation can affect its turnover and modes of action, as well as what factors can modulate circular RNA conformation. We also discuss how understanding circular RNA conformation can facilitate learning about their functions as well as the remaining technological issues to further address their conformation. These efforts will ultimately inform the design of circular RNA-based platforms for biomedical applications.

环状 RNA 是一组共价封闭的单链转录本，具有独特的生物发生、稳定性和构象，在调节细胞功能方面发挥着不同的作用，在开发基于环状 RNA 的疗法方面也具有巨大潜力。重要的是，由于其环状构象，环状 RNA 会产生不同于线性转录本的分子内碱基配对。在这一视角中，我们回顾了环状 RNA 构象如何影响其周转和作用模式，以及哪些因素可以调节环状 RNA 构象。我们还讨论了了解环状 RNA 构象如何促进对其功能的了解，以及进一步解决其构象问题的剩余技术问题。这些努力最终将为设计基于环状 RNA 的生物医学应用平台提供信息。

引用次数: 0

Filament formation activates protease and ring nuclease activities of CRISPR Lon-SAVED 丝状体的形成激活了 CRISPR Lon-SAVED 的蛋白酶和环状核酸酶活性

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2024-10-02 DOI: 10.1016/j.molcel.2024.09.002

Dalia Smalakyte, Audrone Ruksenaite, Giedrius Sasnauskas, Giedre Tamulaitiene, Gintautas Tamulaitis

To combat phage infection, type III CRISPR-Cas systems utilize cyclic oligoadenylates (cA_n) signaling to activate various auxiliary effectors, including the CRISPR-associated Lon-SAVED protease CalpL, which forms a tripartite effector system together with an anti-σ factor, CalpT, and an ECF-like σ factor, CalpS. Here, we report the characterization of the Candidatus Cloacimonas acidaminovorans CalpL-CalpT-CalpS. We demonstrate that cA₄ binding triggers CalpL filament formation and activates it to cleave CalpT within the CalpT-CalpS dimer. This cleavage exposes the CalpT C-degron, which targets it for further degradation by cellular proteases. Consequently, CalpS is released to bind to RNA polymerase, causing growth arrest in E. coli. Furthermore, the CalpL-CalpT-CalpS system is regulated by the SAVED domain of CalpL, which is a ring nuclease that cleaves cA₄ in a sequential three-step mechanism. These findings provide key mechanistic details for the activation, proteolytic events, and regulation of the signaling cascade in the type III CRISPR-Cas immunity.

为了对抗噬菌体感染，III型CRISPR-Cas系统利用环状寡腺苷酸（cAn）信号来激活各种辅助效应器，包括CRISPR相关的Lon-SAVED蛋白酶CalpL，它与抗σ因子CalpT和类ECFσ因子CalpS一起构成了一个三方效应器系统。在这里，我们报告了 Cloacimonas acidaminovorans 杆菌 CalpL-CalpT-CalpS 的特征。我们证明，cA4 的结合会触发 CalpL 长丝的形成，并激活它裂解 CalpT-CalpS 二聚体中的 CalpT。这种裂解暴露了 CalpT 的 C-半导，使其成为细胞蛋白酶进一步降解的目标。因此，CalpS 被释放出来与 RNA 聚合酶结合，导致大肠杆菌生长停滞。此外，CalpL-CalpT-CalpS 系统还受 CalpL 的 SAVED 结构域调控，SAVED 结构域是一种环状核酸酶，能以三步顺序机制裂解 cA4。这些发现为III型CRISPR-Cas免疫中信号级联的激活、蛋白水解事件和调控提供了关键的机制细节。

{"title":"Filament formation activates protease and ring nuclease activities of CRISPR Lon-SAVED","authors":"Dalia Smalakyte, Audrone Ruksenaite, Giedrius Sasnauskas, Giedre Tamulaitiene, Gintautas Tamulaitis","doi":"10.1016/j.molcel.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.002","url":null,"abstract":"To combat phage infection, type III CRISPR-Cas systems utilize cyclic oligoadenylates (cAn) signaling to activate various auxiliary effectors, including the CRISPR-associated Lon-SAVED protease CalpL, which forms a tripartite effector system together with an anti-σ factor, CalpT, and an ECF-like σ factor, CalpS. Here, we report the characterization of the Candidatus Cloacimonas acidaminovorans CalpL-CalpT-CalpS. We demonstrate that cA4 binding triggers CalpL filament formation and activates it to cleave CalpT within the CalpT-CalpS dimer. This cleavage exposes the CalpT C-degron, which targets it for further degradation by cellular proteases. Consequently, CalpS is released to bind to RNA polymerase, causing growth arrest in E. coli. Furthermore, the CalpL-CalpT-CalpS system is regulated by the SAVED domain of CalpL, which is a ring nuclease that cleaves cA4 in a sequential three-step mechanism. These findings provide key mechanistic details for the activation, proteolytic events, and regulation of the signaling cascade in the type III CRISPR-Cas immunity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"4 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363100","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

Modulation of fungal phosphate homeostasis by the plant hormone strigolactone 植物激素绞股蓝内酯对真菌磷酸盐平衡的调节作用

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2024-10-01 DOI: 10.1016/j.molcel.2024.09.004

James M. Bradley, Michael Bunsick, George Ly, Bruno Aquino, Flora Zhiqi Wang, Duncan Holbrook-Smith, Shingo Suginoo, Dylan Bradizza, Naoki Kato, Omar As’sadiq, Nina Marsh, Hiroyuki Osada, François-Didier Boyer, Christopher S.P. McErlean, Yuichiro Tsuchiya, Rajagopal Subramaniam, Dario Bonetta, Peter McCourt, Shelley Lumba

Inter-kingdom communication through small molecules is essential to the coexistence of organisms in an ecosystem. In soil communities, the plant root is a nexus of interactions for a remarkable number of fungi and is a source of small-molecule plant hormones that shape fungal compositions. Although hormone signaling pathways are established in plants, how fungi perceive and respond to molecules is unclear because many plant-associated fungi are recalcitrant to experimentation. Here, we develop an approach using the model fungus, Saccharomyces cerevisiae, to elucidate mechanisms of fungal response to plant hormones. Two plant hormones, strigolactone and methyl jasmonate, produce unique transcript profiles in yeast, affecting phosphate and sugar metabolism, respectively. Genetic analysis in combination with structural studies suggests that SLs require the high-affinity transporter Pho84 to modulate phosphate homeostasis. The ability to study small-molecule plant hormones in a tractable genetic system should have utility in understanding fungal-plant interactions.

通过小分子进行王国间交流对生态系统中生物的共存至关重要。在土壤群落中，植物根部是大量真菌相互作用的纽带，也是影响真菌组成的小分子植物激素的来源。虽然植物中已经建立了激素信号通路，但真菌如何感知和响应这些分子尚不清楚，因为许多与植物相关的真菌不愿意接受实验。在这里，我们利用模式真菌酿酒酵母（Saccharomyces cerevisiae）来阐明真菌对植物激素的反应机制。绞股蓝内酯和茉莉酸甲酯这两种植物激素会在酵母中产生独特的转录谱，分别影响磷酸盐和糖的代谢。遗传分析结合结构研究表明，SLs 需要高亲和性转运体 Pho84 来调节磷酸盐的平衡。在可控的遗传系统中研究小分子植物激素的能力应有助于了解真菌与植物之间的相互作用。

{"title":"Modulation of fungal phosphate homeostasis by the plant hormone strigolactone","authors":"James M. Bradley, Michael Bunsick, George Ly, Bruno Aquino, Flora Zhiqi Wang, Duncan Holbrook-Smith, Shingo Suginoo, Dylan Bradizza, Naoki Kato, Omar As’sadiq, Nina Marsh, Hiroyuki Osada, François-Didier Boyer, Christopher S.P. McErlean, Yuichiro Tsuchiya, Rajagopal Subramaniam, Dario Bonetta, Peter McCourt, Shelley Lumba","doi":"10.1016/j.molcel.2024.09.004","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.004","url":null,"abstract":"Inter-kingdom communication through small molecules is essential to the coexistence of organisms in an ecosystem. In soil communities, the plant root is a nexus of interactions for a remarkable number of fungi and is a source of small-molecule plant hormones that shape fungal compositions. Although hormone signaling pathways are established in plants, how fungi perceive and respond to molecules is unclear because many plant-associated fungi are recalcitrant to experimentation. Here, we develop an approach using the model fungus, Saccharomyces cerevisiae, to elucidate mechanisms of fungal response to plant hormones. Two plant hormones, strigolactone and methyl jasmonate, produce unique transcript profiles in yeast, affecting phosphate and sugar metabolism, respectively. Genetic analysis in combination with structural studies suggests that SLs require the high-affinity transporter Pho84 to modulate phosphate homeostasis. The ability to study small-molecule plant hormones in a tractable genetic system should have utility in understanding fungal-plant interactions.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"58 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360654","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

Hydrogen sulfide-mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small cell lung cancer 硫化氢介导的过硫化作用可调控非小细胞肺癌中的同型半胱氨酸代谢并增强其铁蛋白沉积能力

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2024-09-24 DOI: 10.1016/j.molcel.2024.08.035

Hualei Zheng, Huidi Chen, Yunjie Cai, Min Shen, Xilin Li, Yi Han, Xusheng Deng, Hongjie Cao, Junjia Liu, Hao Li, Benchao Liu, Ganlin Li, Xindong Wang, Hui Chen, Jingjing Hou, Shu-Hai Lin, Lili Zong, Yongyou Zhang

Hydrogen sulfide (H₂S), a metabolite of the transsulfuration pathway, has been implicated in ferroptosis, a unique form of cell death caused by lipid peroxidation. While the exact mechanisms controlling ferroptosis remain unclear, our study reveals that H₂S sensitizes human non-small cell lung cancer (NSCLC) cells to this process, particularly when cysteine levels are low. Combining H₂S with cystine depletion significantly enhances the effectiveness of ferroptosis-based cancer therapy. Mechanistically, H₂S persulfidates the 195^th cysteine on S-adenosyl homocysteine hydrolase (SAHH), reducing its enzymatic activity. This leads to decreased homocysteine levels, subsequently lowering cysteine and glutathione concentrations under cystine depletion conditions. These changes ultimately increase the vulnerability of NSCLC cells to ferroptosis. Our findings establish H₂S as a key regulator of homocysteine metabolism and a critical factor in determining NSCLC cell susceptibility to ferroptosis. These results highlight the potential of H₂S-based therapies to improve the efficacy of ferroptosis-targeted cancer treatments for NSCLC.

硫化氢（H₂S）是反式硫化途径的一种代谢产物，它与铁蜕变（一种由脂质过氧化引起的独特的细胞死亡形式）有关。虽然控制铁中毒的确切机制仍不清楚，但我们的研究发现，H₂S 会使人类非小细胞肺癌（NSCLC）细胞对这一过程敏感，尤其是当半胱氨酸水平较低时。将H₂S与胱氨酸耗竭相结合，可显著提高基于铁突变的癌症治疗效果。从机理上讲，H₂S 可使 S-腺苷同型半胱氨酸水解酶（SAHH）上的第 195 个半胱氨酸过硫化，从而降低其酶活性。这导致同型半胱氨酸水平下降，进而在胱氨酸耗竭条件下降低半胱氨酸和谷胱甘肽的浓度。这些变化最终增加了 NSCLC 细胞对铁变态反应的脆弱性。我们的研究结果表明，H₂S 是同型半胱氨酸代谢的关键调节因子，也是决定 NSCLC 细胞对铁中毒易感性的关键因素。这些结果凸显了基于 H₂S 的疗法在提高 NSCLC 癌症铁突变靶向疗法疗效方面的潜力。

{"title":"Hydrogen sulfide-mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small cell lung cancer","authors":"Hualei Zheng, Huidi Chen, Yunjie Cai, Min Shen, Xilin Li, Yi Han, Xusheng Deng, Hongjie Cao, Junjia Liu, Hao Li, Benchao Liu, Ganlin Li, Xindong Wang, Hui Chen, Jingjing Hou, Shu-Hai Lin, Lili Zong, Yongyou Zhang","doi":"10.1016/j.molcel.2024.08.035","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.035","url":null,"abstract":"Hydrogen sulfide (H₂S), a metabolite of the transsulfuration pathway, has been implicated in ferroptosis, a unique form of cell death caused by lipid peroxidation. While the exact mechanisms controlling ferroptosis remain unclear, our study reveals that H₂S sensitizes human non-small cell lung cancer (NSCLC) cells to this process, particularly when cysteine levels are low. Combining H₂S with cystine depletion significantly enhances the effectiveness of ferroptosis-based cancer therapy. Mechanistically, H₂S persulfidates the 195th cysteine on S-adenosyl homocysteine hydrolase (SAHH), reducing its enzymatic activity. This leads to decreased homocysteine levels, subsequently lowering cysteine and glutathione concentrations under cystine depletion conditions. These changes ultimately increase the vulnerability of NSCLC cells to ferroptosis. Our findings establish H₂S as a key regulator of homocysteine metabolism and a critical factor in determining NSCLC cell susceptibility to ferroptosis. These results highlight the potential of H₂S-based therapies to improve the efficacy of ferroptosis-targeted cancer treatments for NSCLC.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"42 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313557","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

Structural basis of the human transcriptional Mediator regulated by its dissociable kinase module 由可分离激酶模块调控的人类转录媒介的结构基础

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2024-09-24 DOI: 10.1016/j.molcel.2024.09.001

Ti-Chun Chao, Shin-Fu Chen, Hee Jong Kim, Hui-Chi Tang, Hsiang-Ching Tseng, An Xu, Leon Palao, Subash Khadka, Tao Li, Mo-Fan Huang, Dung-Fang Lee, Kenji Murakami, Thomas G. Boyer, Kuang-Lei Tsai

The eukaryotic transcriptional Mediator comprises a large core (cMED) and a dissociable CDK8 kinase module (CKM). cMED recruits RNA polymerase II (RNA Pol II) and promotes pre-initiation complex formation in a manner repressed by the CKM through mechanisms presently unknown. Herein, we report cryoelectron microscopy structures of the complete human Mediator and its CKM. The CKM binds to multiple regions on cMED through both MED12 and MED13, including a large intrinsically disordered region (IDR) in the latter. MED12 and MED13 together anchor the CKM to the cMED hook, positioning CDK8 downstream and proximal to the transcription start site. Notably, the MED13 IDR obstructs the recruitment of RNA Pol II/MED26 onto cMED by direct occlusion of their respective binding sites, leading to functional repression of cMED-dependent transcription. Combined with biochemical and functional analyses, these structures provide a conserved mechanistic framework to explain the basis for CKM-mediated repression of cMED function.

真核生物转录介导子由一个大核心（cMED）和一个可分离的 CDK8 激酶模块（CKM）组成。cMED 通过目前尚不清楚的机制招募 RNA 聚合酶 II（RNA Pol II），并以被 CKM 抑制的方式促进预启动复合物的形成。在此，我们报告了完整的人类 Mediator 及其 CKM 的冷冻电镜结构。CKM 通过 MED12 和 MED13 与 cMED 上的多个区域结合，包括后者的一个大的内在无序区 (IDR)。MED12 和 MED13 共同将 CKM 固定在 cMED 钩子上，使 CDK8 位于转录起始位点的下游和近端。值得注意的是，MED13 IDR 通过直接阻塞 RNA Pol II/MED26 与 cMED 的结合位点，阻碍了它们在 cMED 上的招募，从而导致 cMED 依赖性转录的功能抑制。结合生化和功能分析，这些结构为解释 CKM 介导的 cMED 功能抑制提供了一个保守的机制框架。

{"title":"Structural basis of the human transcriptional Mediator regulated by its dissociable kinase module","authors":"Ti-Chun Chao, Shin-Fu Chen, Hee Jong Kim, Hui-Chi Tang, Hsiang-Ching Tseng, An Xu, Leon Palao, Subash Khadka, Tao Li, Mo-Fan Huang, Dung-Fang Lee, Kenji Murakami, Thomas G. Boyer, Kuang-Lei Tsai","doi":"10.1016/j.molcel.2024.09.001","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.001","url":null,"abstract":"The eukaryotic transcriptional Mediator comprises a large core (cMED) and a dissociable CDK8 kinase module (CKM). cMED recruits RNA polymerase II (RNA Pol II) and promotes pre-initiation complex formation in a manner repressed by the CKM through mechanisms presently unknown. Herein, we report cryoelectron microscopy structures of the complete human Mediator and its CKM. The CKM binds to multiple regions on cMED through both MED12 and MED13, including a large intrinsically disordered region (IDR) in the latter. MED12 and MED13 together anchor the CKM to the cMED hook, positioning CDK8 downstream and proximal to the transcription start site. Notably, the MED13 IDR obstructs the recruitment of RNA Pol II/MED26 onto cMED by direct occlusion of their respective binding sites, leading to functional repression of cMED-dependent transcription. Combined with biochemical and functional analyses, these structures provide a conserved mechanistic framework to explain the basis for CKM-mediated repression of cMED function.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"22 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317258","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

Alternative translation initiation produces synaptic organizer proteoforms with distinct localization and functions 交替翻译起始产生的突触组织者蛋白形式具有不同的定位和功能

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2024-09-23 DOI: 10.1016/j.molcel.2024.08.032

Paul Jongseo Lee, Yu Sun, Alexa R. Soares, Caroline Fai, Marina R. Picciotto, Junjie U. Guo

While many mRNAs contain more than one translation initiation site (TIS), the functions of most alternative TISs and their corresponding protein isoforms (proteoforms) remain undetermined. Here, we showed that alternative usage of CUG and AUG TISs in neuronal pentraxin receptor (NPR) mRNA produced two proteoforms, of which the ratio was regulated by RNA secondary structure and neuronal activity. Downstream AUG initiation truncated the N-terminal transmembrane domain and produced a secreted NPR proteoform sufficient in promoting synaptic clustering of AMPA-type glutamate receptors. Mutations that altered the ratio of NPR proteoforms reduced AMPA receptors in parvalbumin-positive interneurons and affected learning behaviors in mice. In addition to NPR, upstream AUU-initiated N-terminal extension of C1q-like synaptic organizers anchored these otherwise secreted factors to the membrane. Together, these results uncovered the plasticity of N-terminal signal sequences regulated by alternative TIS usage as a potentially widespread mechanism in diversifying protein localization and functions.

虽然许多 mRNA 都含有一个以上的翻译起始位点（TIS），但大多数替代性 TIS 的功能及其相应的蛋白质异构体（蛋白型）仍未确定。在这里，我们发现神经元五肽受体（NPR）mRNA 中 CUG 和 AUG TIS 的交替使用产生了两种蛋白形式，其比例受 RNA 二级结构和神经元活性的调节。下游 AUG 起始位点截断了 N 端跨膜结构域，产生的分泌型 NPR 蛋白形式足以促进 AMPA 型谷氨酸受体的突触集聚。改变 NPR 蛋白形式比例的突变会减少副发光体阳性中间神经元中的 AMPA 受体，并影响小鼠的学习行为。除 NPR 外，上游 AUU 引发的 C1q 样突触组织者的 N 端延伸也将这些原本分泌的因子固定在膜上。总之，这些结果揭示了受TIS替代用法调控的N端信号序列的可塑性，它可能是蛋白质定位和功能多样化的一种广泛机制。

{"title":"Alternative translation initiation produces synaptic organizer proteoforms with distinct localization and functions","authors":"Paul Jongseo Lee, Yu Sun, Alexa R. Soares, Caroline Fai, Marina R. Picciotto, Junjie U. Guo","doi":"10.1016/j.molcel.2024.08.032","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.032","url":null,"abstract":"While many mRNAs contain more than one translation initiation site (TIS), the functions of most alternative TISs and their corresponding protein isoforms (proteoforms) remain undetermined. Here, we showed that alternative usage of CUG and AUG TISs in neuronal pentraxin receptor (NPR) mRNA produced two proteoforms, of which the ratio was regulated by RNA secondary structure and neuronal activity. Downstream AUG initiation truncated the N-terminal transmembrane domain and produced a secreted NPR proteoform sufficient in promoting synaptic clustering of AMPA-type glutamate receptors. Mutations that altered the ratio of NPR proteoforms reduced AMPA receptors in parvalbumin-positive interneurons and affected learning behaviors in mice. In addition to NPR, upstream AUU-initiated N-terminal extension of C1q-like synaptic organizers anchored these otherwise secreted factors to the membrane. Together, these results uncovered the plasticity of N-terminal signal sequences regulated by alternative TIS usage as a potentially widespread mechanism in diversifying protein localization and functions.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"21 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276838","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

Large-scale map of RNA-binding protein interactomes across the mRNA life cycle 横跨 mRNA 生命周期的大规模 RNA 结合蛋白相互作用组图谱

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.030

Lena A. Street, Katherine L. Rothamel, Kristopher W. Brannan, Wenhao Jin, Benjamin J. Bokor, Kevin Dong, Kevin Rhine, Assael Madrigal, Norah Al-Azzam, Jenny Kim Kim, Yanzhe Ma, Darvesh Gorhe, Ahmed Abdou, Erica Wolin, Orel Mizrahi, Joshua Ahdout, Mayuresh Mujumdar, Ella Doron-Mandel, Marko Jovanovic, Gene W. Yeo

mRNAs interact with RNA-binding proteins (RBPs) throughout their processing and maturation. While efforts have assigned RBPs to RNA substrates, less exploration has leveraged protein-protein interactions (PPIs) to study proteins in mRNA life-cycle stages. We generated an RNA-aware, RBP-centric PPI map across the mRNA life cycle in human cells by immunopurification-mass spectrometry (IP-MS) of ∼100 endogenous RBPs with and without RNase, augmented by size exclusion chromatography-mass spectrometry (SEC-MS). We identify 8,742 known and 20,802 unreported interactions between 1,125 proteins and determine that 73% of the IP-MS-identified interactions are RNA regulated. Our interactome links many proteins, some with unknown functions, to specific mRNA life-cycle stages, with nearly half associated with multiple stages. We demonstrate the value of this resource by characterizing the splicing and export functions of enhancer of rudimentary homolog (ERH), and by showing that small nuclear ribonucleoprotein U5 subunit 200 (SNRNP200) interacts with stress granule proteins and binds cytoplasmic RNA differently during stress.

mRNA 在整个加工和成熟过程中都会与 RNA 结合蛋白（RBPs）发生相互作用。虽然人们已努力将 RBPs 与 RNA 底物结合，但利用蛋白质-蛋白质相互作用（PPI）来研究 mRNA 生命周期各阶段蛋白质的探索却较少。我们通过免疫纯化-质谱分析法（IP-MS）对含有或不含 RNase 的 100 ∼ 100 种内源 RBPs 进行分析，并辅以尺寸排阻色谱-质谱分析法（SEC-MS），生成了一张以 RNA 为中心、贯穿人体细胞 mRNA 生命周期的 PPI 图谱。我们确定了 1,125 个蛋白质之间的 8,742 种已知和 20,802 种未报道的相互作用，并确定 IP-MS 确定的相互作用中有 73% 受 RNA 调节。我们的相互作用组将许多蛋白质（其中一些功能未知）与特定的 mRNA 生命周期阶段联系起来，其中近一半与多个阶段相关。我们通过鉴定原始同源增强子（ERH）的剪接和输出功能，并通过证明核小核糖核蛋白 U5 亚基 200（SNRNP200）与应激颗粒蛋白的相互作用以及在应激过程中与细胞质 RNA 的不同结合，证明了这一资源的价值。

{"title":"Large-scale map of RNA-binding protein interactomes across the mRNA life cycle","authors":"Lena A. Street, Katherine L. Rothamel, Kristopher W. Brannan, Wenhao Jin, Benjamin J. Bokor, Kevin Dong, Kevin Rhine, Assael Madrigal, Norah Al-Azzam, Jenny Kim Kim, Yanzhe Ma, Darvesh Gorhe, Ahmed Abdou, Erica Wolin, Orel Mizrahi, Joshua Ahdout, Mayuresh Mujumdar, Ella Doron-Mandel, Marko Jovanovic, Gene W. Yeo","doi":"10.1016/j.molcel.2024.08.030","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.030","url":null,"abstract":"mRNAs interact with RNA-binding proteins (RBPs) throughout their processing and maturation. While efforts have assigned RBPs to RNA substrates, less exploration has leveraged protein-protein interactions (PPIs) to study proteins in mRNA life-cycle stages. We generated an RNA-aware, RBP-centric PPI map across the mRNA life cycle in human cells by immunopurification-mass spectrometry (IP-MS) of ∼100 endogenous RBPs with and without RNase, augmented by size exclusion chromatography-mass spectrometry (SEC-MS). We identify 8,742 known and 20,802 unreported interactions between 1,125 proteins and determine that 73% of the IP-MS-identified interactions are RNA regulated. Our interactome links many proteins, some with unknown functions, to specific mRNA life-cycle stages, with nearly half associated with multiple stages. We demonstrate the value of this resource by characterizing the splicing and export functions of enhancer of rudimentary homolog (ERH), and by showing that small nuclear ribonucleoprotein U5 subunit 200 (SNRNP200) interacts with stress granule proteins and binds cytoplasmic RNA differently during stress.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"46 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246050","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

Activation of automethylated PRC2 by dimerization on chromatin 通过染色质上的二聚化激活自动甲基化的 PRC2

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.025

Paul V. Sauer, Egor Pavlenko, Trinity Cookis, Linda C. Zirden, Juliane Renn, Ankush Singhal, Pascal Hunold, Michaela N. Hoehne-Wiechmann, Olivia van Ray, Farnusch Kaschani, Markus Kaiser, Robert Hänsel-Hertsch, Karissa Y. Sanbonmatsu, Eva Nogales, Simon Poepsel

Polycomb repressive complex 2 (PRC2) is an epigenetic regulator that trimethylates lysine 27 of histone 3 (H3K27me3) and is essential for embryonic development and cellular differentiation. H3K27me3 is associated with transcriptionally repressed chromatin and is established when PRC2 is allosterically activated upon methyl-lysine binding by the regulatory subunit EED. Automethylation of the catalytic subunit enhancer of zeste homolog 2 (EZH2) stimulates its activity by an unknown mechanism. Here, we show that human PRC2 forms a dimer on chromatin in which an inactive, automethylated PRC2 protomer is the allosteric activator of a second PRC2 that is poised to methylate H3 of a substrate nucleosome. Functional assays support our model of allosteric trans-autoactivation via EED, suggesting a previously unknown mechanism mediating context-dependent activation of PRC2. Our work showcases the molecular mechanism of auto-modification-coupled dimerization in the regulation of chromatin-modifying complexes.

多聚胞抑制复合体 2（PRC2）是一种表观遗传调控因子，可对组蛋白 3 的 27 号赖氨酸（H3K27me3）进行三甲基化，对胚胎发育和细胞分化至关重要。H3K27me3 与转录抑制染色质有关，当 PRC2 被调节亚基 EED 结合甲基赖氨酸后异源激活时，H3K27me3 就会形成。催化亚基泽斯特同源增强子 2（EZH2）的自甲基化通过一种未知的机制刺激其活性。在这里，我们展示了人类 PRC2 在染色质上形成的二聚体，其中一个非活性、自甲基化的 PRC2 原体是第二个 PRC2 的异位激活剂，后者准备甲基化底物核小体的 H3。功能测试支持了我们通过 EED 进行异生反式自激活的模型，这表明了一种以前未知的介导 PRC2 上下文依赖性激活的机制。我们的工作展示了自动修饰耦合二聚化在调控染色质修饰复合物中的分子机制。

{"title":"Activation of automethylated PRC2 by dimerization on chromatin","authors":"Paul V. Sauer, Egor Pavlenko, Trinity Cookis, Linda C. Zirden, Juliane Renn, Ankush Singhal, Pascal Hunold, Michaela N. Hoehne-Wiechmann, Olivia van Ray, Farnusch Kaschani, Markus Kaiser, Robert Hänsel-Hertsch, Karissa Y. Sanbonmatsu, Eva Nogales, Simon Poepsel","doi":"10.1016/j.molcel.2024.08.025","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.025","url":null,"abstract":"Polycomb repressive complex 2 (PRC2) is an epigenetic regulator that trimethylates lysine 27 of histone 3 (H3K27me3) and is essential for embryonic development and cellular differentiation. H3K27me3 is associated with transcriptionally repressed chromatin and is established when PRC2 is allosterically activated upon methyl-lysine binding by the regulatory subunit EED. Automethylation of the catalytic subunit enhancer of zeste homolog 2 (EZH2) stimulates its activity by an unknown mechanism. Here, we show that human PRC2 forms a dimer on chromatin in which an inactive, automethylated PRC2 protomer is the allosteric activator of a second PRC2 that is poised to methylate H3 of a substrate nucleosome. Functional assays support our model of allosteric trans-autoactivation via EED, suggesting a previously unknown mechanism mediating context-dependent activation of PRC2. Our work showcases the molecular mechanism of auto-modification-coupled dimerization in the regulation of chromatin-modifying complexes.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"64 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246066","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

首页上一页

下一页尾页

类型

全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

数据库

全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley

期刊

Molecular Cell

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.

﹀