首页 > 最新文献

Molecular Cell最新文献

英文 中文
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 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":null,"pages":null},"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
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 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":"<p>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 <em>trans</em>-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.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"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
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 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":"<p>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.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"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
C2H2-zinc-finger transcription factors bind RNA and function in diverse post-transcriptional regulatory processes C2H2-锌指转录因子与 RNA 结合并在多种转录后调控过程中发挥作用
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.037
Syed Nabeel-Shah, Shuye Pu, James D. Burns, Ulrich Braunschweig, Nujhat Ahmed, Giovanni L. Burke, Hyunmin Lee, Ernest Radovani, Guoqing Zhong, Hua Tang, Edyta Marcon, Zhaolei Zhang, Timothy R. Hughes, Benjamin J. Blencowe, Jack F. Greenblatt

Cys2-His2 zinc-finger proteins (C2H2-ZNFs) constitute the largest class of DNA-binding transcription factors (TFs) yet remain largely uncharacterized. Although certain family members, e.g., GTF3A, have been shown to bind both DNA and RNA, the extent to which C2H2-ZNFs interact with—and regulate—RNA-associated processes is not known. Using UV crosslinking and immunoprecipitation (CLIP), we observe that 148 of 150 analyzed C2H2-ZNFs bind directly to RNA in human cells. By integrating CLIP sequencing (CLIP-seq) RNA-binding maps for 50 of these C2H2-ZNFs with data from chromatin immunoprecipitation sequencing (ChIP-seq), protein-protein interaction assays, and transcriptome profiling experiments, we observe that the RNA-binding profiles of C2H2-ZNFs are generally distinct from their DNA-binding preferences and that they regulate a variety of post-transcriptional processes, including pre-mRNA splicing, cleavage and polyadenylation, and m6A modification of mRNA. Our results thus define a substantially expanded repertoire of C2H2-ZNFs that bind RNA and provide an important resource for elucidating post-transcriptional regulatory programs.

Cys2-His2锌指蛋白(C2H2-ZNFs)构成了 DNA 结合转录因子(TFs)中最大的一类,但大部分尚未定性。虽然某些家族成员(如 GTF3A)已被证明能同时结合 DNA 和 RNA,但 C2H2-ZNFs 与 RNA 相关过程的相互作用和调控程度尚不清楚。利用紫外交联和免疫沉淀(CLIP)技术,我们观察到 150 个被分析的 C2H2-ZNFs 中有 148 个直接与人体细胞中的 RNA 结合。通过将其中 50 个 C2H2-ZNFs 的 CLIP 测序(CLIP-seq)RNA 结合图谱与染色质免疫沉淀测序(ChIP-seq)、蛋白质-蛋白质相互作用测定和转录组图谱分析实验的数据进行整合、我们观察到,C2H2-ZNFs 的 RNA 结合特征通常不同于它们的 DNA 结合偏好,而且它们能调控多种转录后过程,包括 mRNA 的前剪接、裂解和多聚腺苷酸化,以及 mRNA 的 m6A 修饰。因此,我们的研究结果确定了可与 RNA 结合的 C2H2-ZNFs 种类,为阐明转录后调控程序提供了重要资源。
{"title":"C2H2-zinc-finger transcription factors bind RNA and function in diverse post-transcriptional regulatory processes","authors":"Syed Nabeel-Shah, Shuye Pu, James D. Burns, Ulrich Braunschweig, Nujhat Ahmed, Giovanni L. Burke, Hyunmin Lee, Ernest Radovani, Guoqing Zhong, Hua Tang, Edyta Marcon, Zhaolei Zhang, Timothy R. Hughes, Benjamin J. Blencowe, Jack F. Greenblatt","doi":"10.1016/j.molcel.2024.08.037","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.037","url":null,"abstract":"<p>Cys2-His2 zinc-finger proteins (C2H2-ZNFs) constitute the largest class of DNA-binding transcription factors (TFs) yet remain largely uncharacterized. Although certain family members, e.g., GTF3A, have been shown to bind both DNA and RNA, the extent to which C2H2-ZNFs interact with—and regulate—RNA-associated processes is not known. Using UV crosslinking and immunoprecipitation (CLIP), we observe that 148 of 150 analyzed C2H2-ZNFs bind directly to RNA in human cells. By integrating CLIP sequencing (CLIP-seq) RNA-binding maps for 50 of these C2H2-ZNFs with data from chromatin immunoprecipitation sequencing (ChIP-seq), protein-protein interaction assays, and transcriptome profiling experiments, we observe that the RNA-binding profiles of C2H2-ZNFs are generally distinct from their DNA-binding preferences and that they regulate a variety of post-transcriptional processes, including pre-mRNA splicing, cleavage and polyadenylation, and m<sup>6</sup>A modification of mRNA. Our results thus define a substantially expanded repertoire of C2H2-ZNFs that bind RNA and provide an important resource for elucidating post-transcriptional regulatory programs.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246010","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
Transcription regulation through selective partitioning: Weak interactions with a strong foundation 通过选择性分区进行转录调控:基础牢固的弱相互作用
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.029
Megan Palacio, Dylan J. Taatjes

In this issue of Molecular Cell, De La Cruz, Pradhan, Veettil et al.1 examine how selective partitioning of proteins via low-affinity IDR-dependent interactions may help regulate RNA polymerase II (RNA Pol II) function and identify sequence features that drive partitioning in cells.

在本期《分子细胞》(Molecular Cell)杂志上,De La Cruz、Pradhan、Veettil 等人1 研究了蛋白质通过低亲和性 IDR 依赖性相互作用进行选择性分区如何有助于调节 RNA 聚合酶 II(RNA Pol II)的功能,并确定了细胞中驱动分区的序列特征。
{"title":"Transcription regulation through selective partitioning: Weak interactions with a strong foundation","authors":"Megan Palacio, Dylan J. Taatjes","doi":"10.1016/j.molcel.2024.08.029","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.029","url":null,"abstract":"<p>In this issue of <em>Molecular Cell</em>, De La Cruz, Pradhan, Veettil et al.<span><span><sup>1</sup></span></span> examine how selective partitioning of proteins via low-affinity IDR-dependent interactions may help regulate RNA polymerase II (RNA Pol II) function and identify sequence features that drive partitioning in cells.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246011","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
Integrated multi-omics analysis of zinc-finger proteins uncovers roles in RNA regulation 锌指蛋白的多组学综合分析揭示其在 RNA 调控中的作用
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.010
Maya L. Gosztyla, Lijun Zhan, Sara Olson, Xintao Wei, Jack Naritomi, Grady Nguyen, Lena Street, Grant A. Goda, Francisco F. Cavazos, Jonathan C. Schmok, Manya Jain, Easin Uddin Syed, Eunjeong Kwon, Wenhao Jin, Eric Kofman, Alexandra T. Tankka, Allison Li, Valerie Gonzalez, Eric Lécuyer, Daniel Dominguez, Gene W. Yeo

RNA interactome studies have revealed that hundreds of zinc-finger proteins (ZFPs) are candidate RNA-binding proteins (RBPs), yet their RNA substrates and functional significance remain largely uncharacterized. Here, we present a systematic multi-omics analysis of the DNA- and RNA-binding targets and regulatory roles of more than 100 ZFPs representing 37 zinc-finger families. We show that multiple ZFPs are previously unknown regulators of RNA splicing, alternative polyadenylation, stability, or translation. The examined ZFPs show widespread sequence-specific RNA binding and preferentially bind proximal to transcription start sites. Additionally, several ZFPs associate with their targets at both the DNA and RNA levels. We highlight ZNF277, a C2H2 ZFP that binds thousands of RNA targets and acts as a multi-functional RBP. We also show that ZNF473 is a DNA/RNA-associated protein that regulates the expression and splicing of cell cycle genes. Our results reveal diverse roles for ZFPs in transcriptional and post-transcriptional gene regulation.

RNA相互作用组研究发现,数百种锌指蛋白(ZFPs)是候选的 RNA 结合蛋白(RBPs),但它们的 RNA 底物和功能意义在很大程度上仍未得到表征。在这里,我们对代表 37 个锌指家族的 100 多个 ZFPs 的 DNA 和 RNA 结合靶标及调控作用进行了系统的多组学分析。我们发现多个 ZFPs 是以前未知的 RNA 剪接、替代多腺苷酸化、稳定性或翻译的调控因子。所研究的 ZFPs 显示出广泛的序列特异性 RNA 结合,并优先结合到转录起始位点附近。此外,有几种 ZFP 在 DNA 和 RNA 水平上与它们的靶标结合。我们重点介绍了 ZNF277,它是一种 C2H2 ZFP,能与数千个 RNA 靶标结合,是一种多功能 RBP。我们还发现 ZNF473 是一种 DNA/RNA 相关蛋白,可调节细胞周期基因的表达和剪接。我们的研究结果揭示了 ZFP 在转录和转录后基因调控中的多种作用。
{"title":"Integrated multi-omics analysis of zinc-finger proteins uncovers roles in RNA regulation","authors":"Maya L. Gosztyla, Lijun Zhan, Sara Olson, Xintao Wei, Jack Naritomi, Grady Nguyen, Lena Street, Grant A. Goda, Francisco F. Cavazos, Jonathan C. Schmok, Manya Jain, Easin Uddin Syed, Eunjeong Kwon, Wenhao Jin, Eric Kofman, Alexandra T. Tankka, Allison Li, Valerie Gonzalez, Eric Lécuyer, Daniel Dominguez, Gene W. Yeo","doi":"10.1016/j.molcel.2024.08.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.010","url":null,"abstract":"<p>RNA interactome studies have revealed that hundreds of zinc-finger proteins (ZFPs) are candidate RNA-binding proteins (RBPs), yet their RNA substrates and functional significance remain largely uncharacterized. Here, we present a systematic multi-omics analysis of the DNA- and RNA-binding targets and regulatory roles of more than 100 ZFPs representing 37 zinc-finger families. We show that multiple ZFPs are previously unknown regulators of RNA splicing, alternative polyadenylation, stability, or translation. The examined ZFPs show widespread sequence-specific RNA binding and preferentially bind proximal to transcription start sites. Additionally, several ZFPs associate with their targets at both the DNA and RNA levels. We highlight ZNF277, a C2H2 ZFP that binds thousands of RNA targets and acts as a multi-functional RBP. We also show that ZNF473 is a DNA/RNA-associated protein that regulates the expression and splicing of cell cycle genes. Our results reveal diverse roles for ZFPs in transcriptional and post-transcriptional gene regulation.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246241","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
Ubiquitylation: Sword and shield in the bacterial arsenal 泛素化:细菌武库中的剑与盾
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.034
Jonathan N. Pruneda, Felix Randow

In two recent studies in Nature, Hör et al.1 and Chambers et al.2 report that ubiquitin-like conjugation in bacteria antagonizes phage replication.

最近在《自然》杂志上发表的两项研究中,Hör 等人1 和 Chambers 等人2 报告说,细菌中的泛素类连接能拮抗噬菌体的复制。
{"title":"Ubiquitylation: Sword and shield in the bacterial arsenal","authors":"Jonathan N. Pruneda, Felix Randow","doi":"10.1016/j.molcel.2024.08.034","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.034","url":null,"abstract":"<p>In two recent studies in <em>Nature</em>, Hör et al.<span><span><sup>1</sup></span></span> and Chambers et al.<span><span><sup>2</sup></span></span> report that ubiquitin-like conjugation in bacteria antagonizes phage replication.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246057","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
Finish the unfinished: Chd1 resolving hexasome-nucleosome complex with FACT 完成未完成的工作Chd1 与 FACT 一起解析六聚体-核小体复合物
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.031
Hongxin Yin, Yang Liu

In this issue of Molecular Cell, Engeholm et al.1 present cryo-EM structures of the chromatin remodeler Chd1 bound to a hexasome-nucleosome complex, an intermediate state during transcription either with or without FACT to restore the missing H2A-H2B dimer. These two binding modes reveal how Chd1 and FACT cooperate in nucleosome re-establishment during transcription.

在本期的《分子细胞》(Molecular Cell)杂志上,Engeholm 等人1 展示了染色质重塑者 Chd1 与六聚体-核小体复合物结合的冷冻电镜结构,六聚体-核小体复合物是转录过程中的中间状态,可与 FACT 结合或不与 FACT 结合,以恢复缺失的 H2A-H2B 二聚体。这两种结合模式揭示了 Chd1 和 FACT 如何在转录过程中合作重建核小体。
{"title":"Finish the unfinished: Chd1 resolving hexasome-nucleosome complex with FACT","authors":"Hongxin Yin, Yang Liu","doi":"10.1016/j.molcel.2024.08.031","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.031","url":null,"abstract":"<p>In this issue of <em>Molecular Cell</em>, Engeholm et al.<span><span><sup>1</sup></span></span> present cryo-EM structures of the chromatin remodeler Chd1 bound to a hexasome-nucleosome complex, an intermediate state during transcription either with or without FACT to restore the missing H2A-H2B dimer. These two binding modes reveal how Chd1 and FACT cooperate in nucleosome re-establishment during transcription.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246067","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 TBK1-independent primordial function of STING in lysosomal biogenesis STING 在溶酶体生物发生过程中的原始功能与 TBK1 无关
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.026
Bo Lv, William A. Dion, Haoxiang Yang, Jinrui Xun, Do-Hyung Kim, Bokai Zhu, Jay Xiaojun Tan

Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING. Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.

干扰素基因刺激器(STING)在许多病理生理条件下被激活,导致高等生物产生依赖于 TBK1 的干扰素。然而,人们对 STING 独立于 TBK1 的原始功能知之甚少。在这里,通过蛋白质组学和生物信息学方法,我们发现溶酶体生物生成是 STING 的一项意想不到的功能。转录因子 EB(TFEB)是溶酶体生物生成和宿主防御的进化保守调节因子,它被包括人类、小鼠和青蛙在内的多个物种的 STING 激活。STING 介导的 TFEB 激活与 TBK1 无关,但需要 STING 的贩运及其保守的质子通道。由 STING 通道刺激的 GABARAP 脂化是 STING 依赖性 TFEB 激活的关键。STING 可刺激 TFEB 靶基因的全面上调,介导溶酶体的生物生成和自噬。在慢性无菌 STING 激活过程中,TFEB 支持细胞存活,这是衰老和与年龄相关疾病的常见情况。这些结果揭示了 STING 在溶酶体生物发生过程中的基本功能,而溶酶体是免疫和细胞抗应激的重要细胞器。
{"title":"A TBK1-independent primordial function of STING in lysosomal biogenesis","authors":"Bo Lv, William A. Dion, Haoxiang Yang, Jinrui Xun, Do-Hyung Kim, Bokai Zhu, Jay Xiaojun Tan","doi":"10.1016/j.molcel.2024.08.026","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.026","url":null,"abstract":"<p>Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING. Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246009","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
Coming in out of the cold: Rho-dependent termination contributes to adaptation to cold shock 从寒冷中走来依赖 Rho 的终止有助于适应冷休克
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.033
Teppei Morita, Susan Gottesman

During cold shock, bacteria shut down translation of all but a set of cold-shock proteins critical for recovery; in this issue of Molecular Cell, Delaleau et al.1 show that Rho-dependent transcription termination plays an important role in cold adaptation, via temperature-regulated termination of the cold-shock protein mRNAs.

在本期《分子细胞》杂志上,Delaleau 等人1 通过温度调节冷休克蛋白 mRNA 的终止,证明 Rho 依赖性转录终止在冷适应中发挥着重要作用。
{"title":"Coming in out of the cold: Rho-dependent termination contributes to adaptation to cold shock","authors":"Teppei Morita, Susan Gottesman","doi":"10.1016/j.molcel.2024.08.033","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.033","url":null,"abstract":"<p>During cold shock, bacteria shut down translation of all but a set of cold-shock proteins critical for recovery; in this issue of <em>Molecular Cell</em>, Delaleau et al.<span><span><sup>1</sup></span></span> show that Rho-dependent transcription termination plays an important role in cold adaptation, via temperature-regulated termination of the cold-shock protein mRNAs.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246126","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
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.
×
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