Pub Date : 2024-11-07DOI: 10.1016/j.molcel.2024.10.019
Khadija Shahed Khan, Billy Wai-Lung Ng
In this issue, Won et al.1 report a covalent ligand binding the pioneer transcription factor FOXA1, altering its function and remodeling chromatin. This important finding highlights the potential of small molecules to modulate transcription factor activity and demonstrates the promise of chemical proteomics in discovering first-in-class ligands.
{"title":"A small molecule that reshapes the chromatin dynamics of FOXA1","authors":"Khadija Shahed Khan, Billy Wai-Lung Ng","doi":"10.1016/j.molcel.2024.10.019","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.019","url":null,"abstract":"In this issue, Won et al.<span><span><sup>1</sup></span></span> report a covalent ligand binding the pioneer transcription factor FOXA1, altering its function and remodeling chromatin. This important finding highlights the potential of small molecules to modulate transcription factor activity and demonstrates the promise of chemical proteomics in discovering first-in-class ligands.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"5 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594590","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}
Pub Date : 2024-11-07DOI: 10.1016/j.molcel.2024.10.013
Zhifu Han, Yu Cao, Jijie Chai
In this issue of Molecular Cell, Luo et al.1 identify a signaling pathway, OSM1-COLD6, that induces cold tolerance in rice by promoting production of the non-canonical cyclic nucleotide 2′,3′-cAMP. The study opens new avenues for enhancing cold tolerance in rice breeding.
{"title":"Inducing rice chilling tolerance by the second messenger 2′,3′-cAMP","authors":"Zhifu Han, Yu Cao, Jijie Chai","doi":"10.1016/j.molcel.2024.10.013","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.013","url":null,"abstract":"In this issue of <em>Molecular Cell</em>, Luo et al.<span><span><sup>1</sup></span></span> identify a signaling pathway, OSM1-COLD6, that induces cold tolerance in rice by promoting production of the non-canonical cyclic nucleotide 2′,3′-cAMP. The study opens new avenues for enhancing cold tolerance in rice breeding.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"15 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594588","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}
Pub Date : 2024-11-07DOI: 10.1016/j.molcel.2024.10.014
Shinichiro Akichika, Tsutomu Suzuki
In this issue of Molecular Cell, An et al.1 reports a novel function of cap-specific m6Am modification acting as an anti-terminator for premature RNA polymerase II transcription by sequestering a transcriptional terminator PCF11. This study provides new insights into RNA modifications in transcriptional control and cancer treatment.
{"title":"Cap-specific m6Am modification: A transcriptional anti-terminator by sequestering PCF11 with implications for neuroblastoma therapy","authors":"Shinichiro Akichika, Tsutomu Suzuki","doi":"10.1016/j.molcel.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.014","url":null,"abstract":"In this issue of <em>Molecular Cell</em>, An et al.<span><span><sup>1</sup></span></span> reports a novel function of cap-specific m<sup>6</sup>Am modification acting as an anti-terminator for premature RNA polymerase II transcription by sequestering a transcriptional terminator PCF11. This study provides new insights into RNA modifications in transcriptional control and cancer treatment.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"243 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594589","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}
Pub Date : 2024-11-07DOI: 10.1016/j.molcel.2024.10.015
Katsutoshi Imamura, William Garland, Manfred Schmid, Lis Jakobsen, Kengo Sato, Jérôme O. Rouvière, Kristoffer Pors Jakobsen, Elena Burlacu, Marta Loureiro Lopez, Søren Lykke-Andersen, Jens S. Andersen, Torben Heick Jensen
In mammalian cells, primary miRNAs are cleaved at their hairpin structures by the Microprocessor complex, whose core is composed of DROSHA and DGCR8. Here, we show that 5′ flanking regions, resulting from Microprocessor cleavage, are targeted by the RNA exosome in mouse embryonic stem cells (mESCs). This is facilitated by a physical link between DGCR8 and the nuclear exosome targeting (NEXT) component ZCCHC8. Surprisingly, however, both biochemical and mutagenesis studies demonstrate that a variant NEXT complex, containing the RNA helicase MTR4 but devoid of the RNA-binding protein RBM7, is the active entity. This Microprocessor-NEXT variant also targets stem-loop-containing RNAs expressed from other genomic regions, such as enhancers. By contrast, Microprocessor does not contribute to the turnover of less structured NEXT substrates. Our results therefore demonstrate that MTR4-ZCCHC8 can link to either RBM7 or DGCR8/DROSHA to target different RNA substrates depending on their structural context.
{"title":"A functional connection between the Microprocessor and a variant NEXT complex","authors":"Katsutoshi Imamura, William Garland, Manfred Schmid, Lis Jakobsen, Kengo Sato, Jérôme O. Rouvière, Kristoffer Pors Jakobsen, Elena Burlacu, Marta Loureiro Lopez, Søren Lykke-Andersen, Jens S. Andersen, Torben Heick Jensen","doi":"10.1016/j.molcel.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.015","url":null,"abstract":"In mammalian cells, primary miRNAs are cleaved at their hairpin structures by the Microprocessor complex, whose core is composed of DROSHA and DGCR8. Here, we show that 5′ flanking regions, resulting from Microprocessor cleavage, are targeted by the RNA exosome in mouse embryonic stem cells (mESCs). This is facilitated by a physical link between DGCR8 and the nuclear exosome targeting (NEXT) component ZCCHC8. Surprisingly, however, both biochemical and mutagenesis studies demonstrate that a variant NEXT complex, containing the RNA helicase MTR4 but devoid of the RNA-binding protein RBM7, is the active entity. This Microprocessor-NEXT variant also targets stem-loop-containing RNAs expressed from other genomic regions, such as enhancers. By contrast, Microprocessor does not contribute to the turnover of less structured NEXT substrates. Our results therefore demonstrate that MTR4-ZCCHC8 can link to either RBM7 or DGCR8/DROSHA to target different RNA substrates depending on their structural context.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"167 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594591","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}
Pub Date : 2024-11-07DOI: 10.1016/j.molcel.2024.10.018
Shane M. Harding
In two recent studies in Science, Martin et al. and Di Bona et al.1,2 showed that mitochondrial-derived reactive oxygen species (ROS) drive mechanisms responsible for micronuclei membrane rupture, with important implications for cancer.
{"title":"A road to rupture: New insights into the loss of micronuclear membrane integrity","authors":"Shane M. Harding","doi":"10.1016/j.molcel.2024.10.018","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.018","url":null,"abstract":"In two recent studies in <em>Science</em>, Martin et al. and Di Bona et al.<span><span><sup>1</sup></span></span><sup>,</sup><span><span><sup>2</sup></span></span> showed that mitochondrial-derived reactive oxygen species (ROS) drive mechanisms responsible for micronuclei membrane rupture, with important implications for cancer.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"8 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594514","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}
Pub Date : 2024-11-06DOI: 10.1016/j.molcel.2024.10.017
Gabriele Cerutti, Ronald Arias, Fabiana Bahna, Seetha Mannepalli, Phinikoula S. Katsamba, Goran Ahlsen, Brian Kloss, Renato Bruni, Andrew Tomlinson, Lawrence Shapiro
Sevenless (Sev) is a Drosophila receptor tyrosine kinase (RTK) required for the specification of the R7 photoreceptor. It is cleaved into α and β subunits and binds the ectodomain of the G-protein-coupled receptor bride of sevenless (Boss). Previous work showed that the Boss ectodomain could bind but not activate Sev; rather, the whole seven-pass transmembrane Boss was required. Here, we show that Sev does not need to be cleaved to function and that a single-pass transmembrane form of Boss activates Sev. We use cryo-electron microscopy and biophysical methods to determine the structural basis of ligand binding and pH-dependent dimerization of Sev, and we discuss the implications in the process of Sev activation. The Sev human homolog, receptor oncogene from sarcoma 1 (ROS1), is associated with oncogenic transformations, and we discuss their structural similarities.
七无（Sev）是果蝇受体酪氨酸激酶（RTK），R7感光器的规格化需要它。它被裂解成 α 和 β 亚基，并与七无 G 蛋白偶联受体新娘（Boss）的外显子结合。以前的研究表明，Boss 外结构域能与 Sev 结合，但不能激活 Sev；相反，需要整个七孔跨膜 Boss。在这里，我们证明 Sev 不需要被裂解就能发挥作用，而且单通跨膜形式的 Boss 能激活 Sev。我们使用冷冻电镜和生物物理方法确定了配体结合和 Sev 的 pH 依赖性二聚化的结构基础，并讨论了 Sev 激活过程中的影响。Sev 的人类同源物肉瘤受体癌基因 1（ROS1）与致癌转化有关，我们讨论了它们在结构上的相似性。
{"title":"Structures and pH-dependent dimerization of the sevenless receptor tyrosine kinase","authors":"Gabriele Cerutti, Ronald Arias, Fabiana Bahna, Seetha Mannepalli, Phinikoula S. Katsamba, Goran Ahlsen, Brian Kloss, Renato Bruni, Andrew Tomlinson, Lawrence Shapiro","doi":"10.1016/j.molcel.2024.10.017","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.017","url":null,"abstract":"Sevenless (Sev) is a <em>Drosophila</em> receptor tyrosine kinase (RTK) required for the specification of the R7 photoreceptor. It is cleaved into α and β subunits and binds the ectodomain of the G-protein-coupled receptor bride of sevenless (Boss). Previous work showed that the Boss ectodomain could bind but not activate Sev; rather, the whole seven-pass transmembrane Boss was required. Here, we show that Sev does not need to be cleaved to function and that a single-pass transmembrane form of Boss activates Sev. We use cryo-electron microscopy and biophysical methods to determine the structural basis of ligand binding and pH-dependent dimerization of Sev, and we discuss the implications in the process of Sev activation. The Sev human homolog, receptor oncogene from sarcoma 1 (ROS1), is associated with oncogenic transformations, and we discuss their structural similarities.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"244 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589074","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}
Pub Date : 2024-11-06DOI: 10.1016/j.molcel.2024.10.016
Sumin Feng, Kaiwen Liu, Jinfeng Shang, Lisa Hoeg, Graziana Pastore, William Yang, Sabrina Roy, Guillermo Sastre-Moreno, Jordan T.F. Young, Wei Wu, Dongyi Xu, Daniel Durocher
DNA replication stress is a threat to genome integrity. The large SNF2-family of ATPases participates in preventing and mitigating DNA replication stress by employing their ATP-driven motor to remodel DNA or DNA-bound proteins. To understand the contribution of these ATPases in genome maintenance, we undertook CRISPR-based synthetic lethality screens in human cells with three SNF2-type ATPases: SMARCAL1, ZRANB3, and HLTF. Here, we show that SMARCAL1 displays a profound synthetic-lethal interaction with FANCM, another ATP-dependent translocase involved in DNA replication and genome stability. Their combined loss causes severe genome instability that we link to chromosome breakage at loci enriched in simple repeats, which are known to challenge replication fork progression. Our findings illuminate a critical genetic buffering mechanism that provides an essential function for maintaining genome integrity.
DNA 复制压力是对基因组完整性的一种威胁。大型 SNF2 ATP 酶家族利用 ATP 驱动的马达重塑 DNA 或 DNA 结合蛋白，从而参与预防和减轻 DNA 复制压力。为了了解这些 ATP 酶在基因组维护中的贡献，我们在人体细胞中利用三种 SNF2 型 ATP 酶进行了基于 CRISPR 的合成致死筛选：SMARCAL1、ZRANB3 和 HLTF。在这里，我们发现 SMARCAL1 与 FANCM（另一种参与 DNA 复制和基因组稳定性的 ATP 依赖性转运酶）之间存在深远的合成致死相互作用。它们的共同缺失会导致严重的基因组不稳定性，我们将这种不稳定性与染色体在富含简单重复序列的位点上的断裂联系起来，众所周知，简单重复序列会挑战复制叉的进展。我们的发现揭示了一种关键的遗传缓冲机制，它为维持基因组完整性提供了重要功能。
{"title":"Profound synthetic lethality between SMARCAL1 and FANCM","authors":"Sumin Feng, Kaiwen Liu, Jinfeng Shang, Lisa Hoeg, Graziana Pastore, William Yang, Sabrina Roy, Guillermo Sastre-Moreno, Jordan T.F. Young, Wei Wu, Dongyi Xu, Daniel Durocher","doi":"10.1016/j.molcel.2024.10.016","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.016","url":null,"abstract":"DNA replication stress is a threat to genome integrity. The large SNF2-family of ATPases participates in preventing and mitigating DNA replication stress by employing their ATP-driven motor to remodel DNA or DNA-bound proteins. To understand the contribution of these ATPases in genome maintenance, we undertook CRISPR-based synthetic lethality screens in human cells with three SNF2-type ATPases: SMARCAL1, ZRANB3, and HLTF. Here, we show that <em>SMARCAL1</em> displays a profound synthetic-lethal interaction with <em>FANCM</em>, another ATP-dependent translocase involved in DNA replication and genome stability. Their combined loss causes severe genome instability that we link to chromosome breakage at loci enriched in simple repeats, which are known to challenge replication fork progression. Our findings illuminate a critical genetic buffering mechanism that provides an essential function for maintaining genome integrity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"36 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589072","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}
Pub Date : 2024-11-05DOI: 10.1016/j.molcel.2024.10.012
Daniel Blears, Jiangman Lou, Nova Fong, Richard Mitter, Ryan M. Sheridan, Dandan He, A. Barbara Dirac-Svejstrup, David Bentley, Jesper Q. Svejstrup
The biological purpose of Integrator and RNA polymerase II (RNAPII) promoter-proximal pausing remains uncertain. Here, we show that loss of INTS6 in human cells results in increased interaction of RNAPII with proteins that can mediate its dissociation from the DNA template, including the CRL3ARMC5 E3 ligase, which ubiquitylates CTD serine5-phosphorylated RPB1 for degradation. ARMC5-dependent RNAPII ubiquitylation is activated by defects in factors acting at the promoter-proximal pause, including Integrator, DSIF, and capping enzyme. This ARMC5 checkpoint normally curtails a sizeable fraction of RNAPII transcription, and ARMC5 knockout cells produce more uncapped transcripts. When both the Integrator and CRL3ARMC5 turnover mechanisms are compromised, cell growth ceases and RNAPII with high pausing propensity disperses from the promoter-proximal pause site into the gene body. These data support a model in which CRL3ARMC5 functions alongside Integrator in a checkpoint mechanism that removes faulty RNAPII complexes at promoter-proximal pause sites to safeguard transcription integrity.
{"title":"Redundant pathways for removal of defective RNA polymerase II complexes at a promoter-proximal pause checkpoint","authors":"Daniel Blears, Jiangman Lou, Nova Fong, Richard Mitter, Ryan M. Sheridan, Dandan He, A. Barbara Dirac-Svejstrup, David Bentley, Jesper Q. Svejstrup","doi":"10.1016/j.molcel.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.012","url":null,"abstract":"The biological purpose of Integrator and RNA polymerase II (RNAPII) promoter-proximal pausing remains uncertain. Here, we show that loss of INTS6 in human cells results in increased interaction of RNAPII with proteins that can mediate its dissociation from the DNA template, including the CRL3<sup>ARMC5</sup> E3 ligase, which ubiquitylates CTD serine<sub>5</sub>-phosphorylated RPB1 for degradation. ARMC5-dependent RNAPII ubiquitylation is activated by defects in factors acting at the promoter-proximal pause, including Integrator, DSIF, and capping enzyme. This ARMC5 checkpoint normally curtails a sizeable fraction of RNAPII transcription, and <em>ARMC5</em> knockout cells produce more uncapped transcripts. When both the Integrator and CRL3<sup>ARMC5</sup> turnover mechanisms are compromised, cell growth ceases and RNAPII with high pausing propensity disperses from the promoter-proximal pause site into the gene body. These data support a model in which CRL3<sup>ARMC5</sup> functions alongside Integrator in a checkpoint mechanism that removes faulty RNAPII complexes at promoter-proximal pause sites to safeguard transcription integrity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"13 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580406","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}
Ribosomes translating damaged mRNAs may stall and prematurely split into their large and small subunits. The split large ribosome subunits can continue elongating stalled polypeptides. In yeast, this mRNA-independent translation appends the C-terminal alanine/threonine tail (CAT tail) to stalled polypeptides. If not degraded by the ribosome-associated quality control (RQC), CAT-tailed stalled polypeptides form aggregates. How the CAT tail, a low-complexity region composed of alanine and threonine, drives protein aggregation remains unknown. In this study, we demonstrate that C-terminal polythreonine or threonine-enriched tails form detergent-resistant aggregates. These aggregates exhibit a robust seeding effect on shorter tails with lower threonine content, elucidating how heterogeneous CAT tails co-aggregate. Polythreonine aggregates sequester molecular chaperones, disturbing proteostasis and provoking the heat shock response. Furthermore, polythreonine cross-seeds detergent-resistant polyserine aggregation, indicating structural similarity between the two aggregates. This study identifies polythreonine and polyserine as a distinct group of aggregation-prone protein motifs.
翻译受损 mRNA 的核糖体可能会停滞，并过早地分裂成大亚基和小亚基。分裂后的大核糖体亚基可以继续延长停滞的多肽。在酵母中，这种不依赖于 mRNA 的翻译会将 C 端丙氨酸/苏氨酸尾（CAT 尾）附加到停滞的多肽上。如果不被核糖体相关质量控制（RQC）降解，CAT 尾的滞留多肽就会形成聚集体。CAT 尾部是一个由丙氨酸和苏氨酸组成的低复杂性区域，它是如何驱动蛋白质聚集的仍是未知数。在这项研究中，我们证明了 C 端富含多苏氨酸或苏氨酸的尾部会形成抗清洁剂的聚集体。这些聚集体对苏氨酸含量较低的较短尾部表现出强大的播种效应，从而阐明了异质 CAT 尾部是如何共同聚集的。多苏氨酸聚集体会封闭分子伴侣，扰乱蛋白稳态并引发热休克反应。此外，聚苏氨酸还能交叉融合抗清洁剂的聚丝氨酸聚集体，这表明这两种聚集体在结构上具有相似性。这项研究确定了聚苏氨酸和聚丝氨酸是一组不同的易聚集蛋白质基团。
{"title":"Threonine-rich carboxyl-terminal extension drives aggregation of stalled polypeptides","authors":"Weili Denyse Chang, Mi-Jeong Yoon, Kian Hua Yeo, Young-Jun Choe","doi":"10.1016/j.molcel.2024.10.011","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.011","url":null,"abstract":"Ribosomes translating damaged mRNAs may stall and prematurely split into their large and small subunits. The split large ribosome subunits can continue elongating stalled polypeptides. In yeast, this mRNA-independent translation appends the C-terminal alanine/threonine tail (CAT tail) to stalled polypeptides. If not degraded by the ribosome-associated quality control (RQC), CAT-tailed stalled polypeptides form aggregates. How the CAT tail, a low-complexity region composed of alanine and threonine, drives protein aggregation remains unknown. In this study, we demonstrate that C-terminal polythreonine or threonine-enriched tails form detergent-resistant aggregates. These aggregates exhibit a robust seeding effect on shorter tails with lower threonine content, elucidating how heterogeneous CAT tails co-aggregate. Polythreonine aggregates sequester molecular chaperones, disturbing proteostasis and provoking the heat shock response. Furthermore, polythreonine cross-seeds detergent-resistant polyserine aggregation, indicating structural similarity between the two aggregates. This study identifies polythreonine and polyserine as a distinct group of aggregation-prone protein motifs.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"32 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562140","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}
Pub Date : 2024-11-01DOI: 10.1016/j.molcel.2024.10.010
Jing Wang, Zhengyang An, Zhongsheng Wu, Wei Zhou, Pengyu Sun, Piyu Wu, Song Dang, Rui Xue, Xue Bai, Yongtao Du, Rongmei Chen, Wenxu Wang, Pei Huang, Sin Man Lam, Youwei Ai, Suling Liu, Guanghou Shui, Zhe Zhang, Zheng Liu, Jianyong Huang, Kangmin He
The class I phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is a key regulator of cell survival, growth, and proliferation and is among the most frequently mutated pathways in cancer. However, where and how PI3K-AKT signaling is spatially activated and organized in mammalian cells remains poorly understood. Here, we identify focal adhesions (FAs) as subcellular signaling hubs organizing the activation of PI3K-PI(3,4,5)P3-AKT signaling in human cancer cells containing p110α mutations under basal conditions. We find that class IA PI3Ks are preferentially recruited to FAs for activation, resulting in localized production of PI(3,4,5)P3 around FAs. As the effector protein of PI(3,4,5)P3, AKT1 molecules are dynamically recruited around FAs for activation. The spatial recruitment/activation of the PI3K-PI(3,4,5)P3-AKT cascade is regulated by activated FA kinase (FAK). Furthermore, combined inhibition of p110α and FAK results in a more potent inhibitory effect on cancer cells. Thus, our results unveil a growth-factor independent, compartmentalized organization mechanism for PI3K-PI(3,4,5)P3-AKT signaling.
{"title":"Spatial organization of PI3K-PI(3,4,5)P3-AKT signaling by focal adhesions","authors":"Jing Wang, Zhengyang An, Zhongsheng Wu, Wei Zhou, Pengyu Sun, Piyu Wu, Song Dang, Rui Xue, Xue Bai, Yongtao Du, Rongmei Chen, Wenxu Wang, Pei Huang, Sin Man Lam, Youwei Ai, Suling Liu, Guanghou Shui, Zhe Zhang, Zheng Liu, Jianyong Huang, Kangmin He","doi":"10.1016/j.molcel.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.010","url":null,"abstract":"The class I phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is a key regulator of cell survival, growth, and proliferation and is among the most frequently mutated pathways in cancer. However, where and how PI3K-AKT signaling is spatially activated and organized in mammalian cells remains poorly understood. Here, we identify focal adhesions (FAs) as subcellular signaling hubs organizing the activation of PI3K-PI(3,4,5)P<sub>3</sub>-AKT signaling in human cancer cells containing p110α mutations under basal conditions. We find that class IA PI3Ks are preferentially recruited to FAs for activation, resulting in localized production of PI(3,4,5)P<sub>3</sub> around FAs. As the effector protein of PI(3,4,5)P<sub>3</sub>, AKT1 molecules are dynamically recruited around FAs for activation. The spatial recruitment/activation of the PI3K-PI(3,4,5)P<sub>3</sub>-AKT cascade is regulated by activated FA kinase (FAK). Furthermore, combined inhibition of p110α and FAK results in a more potent inhibitory effect on cancer cells. Thus, our results unveil a growth-factor independent, compartmentalized organization mechanism for PI3K-PI(3,4,5)P<sub>3</sub>-AKT signaling.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"31 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562139","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}
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