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A fatty acid switch drives ferroptosis in EMT 脂肪酸开关驱动 EMT 中的铁变态反应
IF 17.3 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-13 DOI: 10.1038/s41556-024-01483-y
Alina M. Winkelkotte, Almut Schulze
Ferroptosis is mediated by toxic accumulation of lipid peroxides. A new study reports that the transcription factor ZEB1 drives ferroptosis sensitivity by regulating the synthesis of highly oxidizable poly-unsaturated fatty acids. This creates a selective vulnerability that can be exploited to eliminate aggressive mesenchymal cancer cells.
铁中毒是由脂质过氧化物的毒性积累介导的。一项新的研究报告指出,转录因子ZEB1通过调节高度可氧化的多不饱和脂肪酸的合成来驱动铁中毒敏感性。这就产生了一种选择性的脆弱性,可以利用这种脆弱性消灭侵袭性间质癌细胞。
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引用次数: 0
Spermidine is essential for fasting-mediated autophagy and longevity 精胺对空腹介导的自噬和长寿至关重要
IF 17.3 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-08 DOI: 10.1038/s41556-024-01468-x
Sebastian J. Hofer, Ioanna Daskalaki, Martina Bergmann, Jasna Friščić, Andreas Zimmermann, Melanie I. Mueller, Mahmoud Abdellatif, Raffaele Nicastro, Sarah Masser, Sylvère Durand, Alexander Nartey, Mara Waltenstorfer, Sarah Enzenhofer, Isabella Faimann, Verena Gschiel, Thomas Bajaj, Christine Niemeyer, Ilias Gkikas, Lukas Pein, Giulia Cerrato, Hui Pan, YongTian Liang, Jelena Tadic, Andrea Jerkovic, Fanny Aprahamian, Christine E. Robbins, Nitharsshini Nirmalathasan, Hansjörg Habisch, Elisabeth Annerer, Frederik Dethloff, Michael Stumpe, Franziska Grundler, Françoise Wilhelmi de Toledo, Daniel E. Heinz, Daniela A. Koppold, Anika Rajput Khokhar, Andreas Michalsen, Norbert J. Tripolt, Harald Sourij, Thomas R. Pieber, Rafael de Cabo, Mark A. McCormick, Christoph Magnes, Oliver Kepp, Joern Dengjel, Stephan J. Sigrist, Nils C. Gassen, Simon Sedej, Tobias Madl, Claudio De Virgilio, Ulrich Stelzl, Markus H. Hoffmann, Tobias Eisenberg, Nektarios Tavernarakis, Guido Kroemer, Frank Madeo
Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine–hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity. Hofer et al. show that fasting promotes the synthesis of spermidine, which stimulates eIF5A hypusination to induce autophagy and increase lifespan in various species in a conserved manner.
限制热量摄入和间歇性禁食可以延长模式生物的寿命和健康期限,改善人类健康。天然多胺亚精胺同样与自噬增强、老年保护以及降低心血管和神经退行性疾病的发病率有关。在这里,我们想知道热量限制和禁食对细胞和生理的影响是否取决于多胺代谢。我们发现,在酵母、苍蝇、小鼠和人类志愿者体内,不同的禁食或热量限制方案会导致亚精胺水平升高。通过基因或药物阻断内源性亚精胺的合成可减少酵母、线虫和人类细胞中禁食诱导的自噬。此外,在体内扰乱多胺通路会减弱禁食对延长寿命和健康寿命的影响,以及对心脏和抗关节炎的保护作用。从机理上讲,亚精胺通过诱导自噬和降低翻译调节因子eIF5A的作用来介导这些效应。总之,多胺-羟化轴是一个系统发育保守的代谢控制中枢,可用于禁食介导的自噬增强和长寿。
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引用次数: 0
TorsinA is essential for neuronal nuclear pore complex localization and maturation TorsinA 对神经元核孔复合体的定位和成熟至关重要
IF 17.3 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-08 DOI: 10.1038/s41556-024-01480-1
Sumin Kim, Sébastien Phan, Hung Tri Tran, Thomas R. Shaw, Sarah H. Shahmoradian, Mark H. Ellisman, Sarah L. Veatch, Sami J. Barmada, Samuel S. Pappas, William T. Dauer
As lifelong interphase cells, neurons face an array of unique challenges. A key challenge is regulating nuclear pore complex (NPC) biogenesis and localization, the mechanisms of which are largely unknown. Here we identify neuronal maturation as a period of strongly upregulated NPC biogenesis. We demonstrate that the AAA+ protein torsinA, whose dysfunction causes the neurodevelopmental movement disorder DYT-TOR1A dystonia and co-ordinates NPC spatial organization without impacting total NPC density. We generated an endogenous Nup107-HaloTag mouse line to directly visualize NPC organization in developing neurons and find that torsinA is essential for proper NPC localization. In the absence of torsinA, the inner nuclear membrane buds excessively at sites of mislocalized nascent NPCs, and the formation of complete NPCs is delayed. Our work demonstrates that NPC spatial organization and number are independently determined and identifies NPC biogenesis as a process vulnerable to neurodevelopmental disease insults. Kim et al. show that nuclear pore complex (NPC) formation is strongly upregulated during a specific neurodevelopmental window. In neurons, torsinA is required for the maturation and normal localization of nascent NPCs, but not their density.
作为终生的间期细胞,神经元面临着一系列独特的挑战。其中一个关键挑战是调控核孔复合体(NPC)的生物生成和定位,其机制在很大程度上还不清楚。在这里,我们发现神经元的成熟期是 NPC 生物发生强烈上调的时期。我们证明,AAA+蛋白torsinA的功能障碍会导致神经发育运动障碍DYT-TOR1A肌张力障碍,并在不影响NPC总密度的情况下协调NPC的空间组织。我们生成了内源性 Nup107-HaloTag 小鼠品系,以直接观察发育中神经元中的 NPC 组织,结果发现 torsinA 对 NPC 的正确定位至关重要。在缺乏 torsinA 的情况下,核内膜会在新生 NPC 错误定位的位置过度萌发,完整 NPC 的形成也会延迟。我们的研究表明,NPC的空间组织和数量是独立决定的,并确定了NPC的生物发生是一个易受神经发育疾病损伤的过程。
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引用次数: 0
Spindle architecture constrains karyotype evolution 纺锤体结构制约核型进化
IF 17.3 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-08 DOI: 10.1038/s41556-024-01485-w
Jana Helsen, Md Hashim Reza, Ricardo Carvalho, Gavin Sherlock, Gautam Dey
The eukaryotic cell division machinery must rapidly and reproducibly duplicate and partition the cell’s chromosomes in a carefully coordinated process. However, chromosome numbers vary dramatically between genomes, even on short evolutionary timescales. We sought to understand how the mitotic machinery senses and responds to karyotypic changes by using a series of budding yeast strains in which the native chromosomes have been successively fused. Using a combination of cell biological profiling, genetic engineering and experimental evolution, we show that chromosome fusions are well tolerated up until a critical point. Cells with fewer than five centromeres lack the necessary number of kinetochore-microtubule attachments needed to counter outward forces in the metaphase spindle, triggering the spindle assembly checkpoint and prolonging metaphase. Our findings demonstrate that spindle architecture is a constraining factor for karyotype evolution. Helsen et al. use experimental evolution and chromosome engineering to probe the link between karyotype changes and the cell division machinery. They conclude that spindle organization dictates the available trajectories for karyotype evolution.
真核细胞的分裂机制必须在一个精心协调的过程中快速、可重复地复制和分割细胞的染色体。然而,即使在短进化时间尺度上,不同基因组之间的染色体数目也会发生巨大变化。我们试图利用一系列原生染色体连续融合的萌发酵母菌株,了解有丝分裂机制如何感知核型变化并做出反应。我们综合运用细胞生物学分析、基因工程和实验进化等方法,证明染色体融合在临界点之前都能很好地容忍。中心粒少于五个的细胞缺乏必要数量的动点核-微管连接,无法抵消分裂期纺锤体的外力,从而触发纺锤体组装检查点并延长分裂期。我们的研究结果表明,纺锤体结构是核型进化的一个制约因素。
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引用次数: 0
p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells p16 依赖性 PD-L1 稳定性的增加可调节衰老细胞的免疫监视。
IF 17.3 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-05 DOI: 10.1038/s41556-024-01465-0
Julia Majewska, Amit Agrawal, Avi Mayo, Lior Roitman, Rishita Chatterjee, Jarmila Sekeresova Kralova, Tomer Landsberger, Yonatan Katzenelenbogen, Tomer Meir-Salame, Efrat Hagai, Ilanit Sopher, Juan-Felipe Perez-Correa, Wolfgang Wagner, Avi Maimon, Ido Amit, Uri Alon, Valery Krizhanovsky
The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation. Majewska et al. show that p16-expressing senescent cells enhance the stability of the immune checkpoint PD-L1 by downregulating its proteasome-mediated ubiquitin-dependent degradation, leading to their accumulation in ageing and chronic inflammation.
衰老细胞的积累会促进衰老和与年龄有关的疾病,但衰老细胞逃避免疫清除并在组织中积累的分子机制仍有待阐明。在这里,我们报告了 p16 阳性衰老细胞上调免疫检查点蛋白程序性死亡配体 1(PD-L1),从而在衰老和慢性炎症中积聚。我们发现,p16 介导的细胞周期激酶 CDK4/6 抑制通过下调泛素依赖性降解诱导 PD-L1 在衰老细胞中的稳定性。激活效应细胞上 Fcγ 受体的抗 PD-L1 抗体可清除 PD-L1 和 p16 阳性细胞。我们的研究揭示了衰老细胞中 p16 依赖性调控 PD-L1 蛋白稳定性的分子机制,并揭示了靶向 PD-L1 改善衰老细胞免疫监视和改善衰老相关炎症的潜力。
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引用次数: 0
Systematic loss-of-function screens identify pathway-specific functional circular RNAs 系统性功能缺失筛选确定特异性通路功能环状 RNA
IF 17.3 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-02 DOI: 10.1038/s41556-024-01467-y
Ling Liu, Matthew Neve, Laura Perlaza-Jimenez, Xinqi Xi, Jacob Purcell, Azelle Hawdon, Simon J. Conn, Jennifer Zenker, Pablo Tamayo, Gregory J. Goodall, Joseph Rosenbluh
Circular RNA (circRNA) is covalently closed, single-stranded RNA produced by back-splicing. A few circRNAs have been implicated as functional; however, we lack understanding of pathways that are regulated by circRNAs. Here we generated a pooled short-hairpin RNA library targeting the back-splice junction of 3,354 human circRNAs that are expressed at different levels (ranging from low to high) in humans. We used this library for loss-of-function proliferation screens in a panel of 18 cancer cell lines from four tissue types harbouring mutations leading to constitutive activity of defined pathways. Both context-specific and non-specific circRNAs were identified. Some circRNAs were found to directly regulate their precursor, whereas some have a function unrelated to their precursor. We validated these observations with a secondary screen and uncovered a role for circRERE(4–10) and circHUWE1(22,23), two cell-essential circRNAs, circSMAD2(2–6), a WNT pathway regulator, and circMTO1(2,RI,3), a regulator of MAPK signalling. Our work sheds light on pathways regulated by circRNAs and provides a catalogue of circRNAs with a measurable function. Liu, Neve et al. use large-scale loss-of-function RNA-interference screens to identify circular RNAs that are direct regulators of important signalling pathways and also common essential and tissue-specific circRNAs.
环状 RNA(circRNA)是通过反向剪接产生的共价封闭的单链 RNA。一些 circRNA 被认为具有功能,但我们对 circRNA 的调控途径还缺乏了解。在这里,我们生成了一个以 3,354 个人类 circRNAs 的反向剪接交界处为靶点的短发夹 RNA 文库,这些 circRNAs 在人体内以不同水平(从低到高)表达。我们利用该文库对来自四种组织类型的 18 种癌症细胞系进行了功能缺失增殖筛选,这些细胞系均携带导致特定通路组成性活性的突变。结果发现了特异性和非特异性 circRNA。发现一些 circRNA 可直接调节其前体,而另一些则具有与其前体无关的功能。我们通过二次筛选验证了这些观察结果,并发现了 circRERE(4-10) 和 circHUWE1(22,23)(两种细胞必需的 circRNA)、circSMAD2(2-6)(一种 WNT 通路调控因子)和 circMTO1(2,RI,3)(一种 MAPK 信号调控因子)的作用。我们的工作揭示了受 circRNAs 调节的途径,并提供了具有可测量功能的 circRNAs 目录。
{"title":"Systematic loss-of-function screens identify pathway-specific functional circular RNAs","authors":"Ling Liu, Matthew Neve, Laura Perlaza-Jimenez, Xinqi Xi, Jacob Purcell, Azelle Hawdon, Simon J. Conn, Jennifer Zenker, Pablo Tamayo, Gregory J. Goodall, Joseph Rosenbluh","doi":"10.1038/s41556-024-01467-y","DOIUrl":"10.1038/s41556-024-01467-y","url":null,"abstract":"Circular RNA (circRNA) is covalently closed, single-stranded RNA produced by back-splicing. A few circRNAs have been implicated as functional; however, we lack understanding of pathways that are regulated by circRNAs. Here we generated a pooled short-hairpin RNA library targeting the back-splice junction of 3,354 human circRNAs that are expressed at different levels (ranging from low to high) in humans. We used this library for loss-of-function proliferation screens in a panel of 18 cancer cell lines from four tissue types harbouring mutations leading to constitutive activity of defined pathways. Both context-specific and non-specific circRNAs were identified. Some circRNAs were found to directly regulate their precursor, whereas some have a function unrelated to their precursor. We validated these observations with a secondary screen and uncovered a role for circRERE(4–10) and circHUWE1(22,23), two cell-essential circRNAs, circSMAD2(2–6), a WNT pathway regulator, and circMTO1(2,RI,3), a regulator of MAPK signalling. Our work sheds light on pathways regulated by circRNAs and provides a catalogue of circRNAs with a measurable function. Liu, Neve et al. use large-scale loss-of-function RNA-interference screens to identify circular RNAs that are direct regulators of important signalling pathways and also common essential and tissue-specific circRNAs.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 8","pages":"1359-1372"},"PeriodicalIF":17.3,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877604","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
Cleavage-independent GSDME activation by UVC 不依赖于裂解的紫外线激活 GSDME
IF 17.3 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-31 DOI: 10.1038/s41556-024-01470-3
Ellie Zhang, Liam Healy, Gang Du, Hao Wu
Gasdermins (GSDMs) are mediators of cell death that trigger membrane lysis. A study shows that full-length GSDME induces pyroptosis after ultraviolet irradiation, involving GSDME PARylation that releases autoinhibition and lipid reactive oxygen species that promote pore formation. This study adds insights on how GSDMs can be activated non-canonically.
气敏素(GSDMs)是细胞死亡的介质,可引发膜裂解。一项研究表明,紫外线照射后,全长 GSDME 会诱导热昏迷,其中涉及 GSDME PARylation,它能释放促进孔形成的自抑制和脂质活性氧。这项研究进一步揭示了 GSDM 如何被非规范激活。
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引用次数: 0
Distinct dynamics of parental 5-hydroxymethylcytosine during human preimplantation development regulate early lineage gene expression 人类胚胎植入前发育过程中亲本 5-羟甲基胞嘧啶的不同动态调节早期血统基因的表达
IF 17.3 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-30 DOI: 10.1038/s41556-024-01475-y
Dan Liang, Rui Yan, Xin Long, Dongmei Ji, Bing Song, Mengyao Wang, Fan Zhang, Xin Cheng, Fengyuan Sun, Ran Zhu, Xinling Hou, Tianjuan Wang, Weiwei Zou, Ying Zhang, Zhixin Pu, Jing Zhang, Zhiguo Zhang, Yajing Liu, Yuqiong Hu, Xiaojin He, Yunxia Cao, Fan Guo
The conversion of DNA 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by TET enzymes represents a significant epigenetic modification, yet its role in early human embryos remains largely unknown. Here we showed that the early human embryo inherited a significant amount of 5hmCs from an oocyte, which unexpectedly underwent de novo hydroxymethylation during its growth. Furthermore, the generation of 5hmC in the paternal genome after fertilization roughly followed the maternal pattern, which was linked to DNA methylation dynamics and regions of sustained methylation. The 5hmCs persisted until the eight-cell stage and exhibited high enrichment at OTX2 binding sites, whereas knockdown of OTX2 in human embryos compromised the expression of early lineage genes. Specifically, the depletion of 5hmC affected the activation of embryonic genes, which was further evaluated by ectopically expressing mouse Tet3 in human early embryos. These findings revealed distinct dynamics of 5hmC and unravelled its multifaceted functions in early human embryonic development. Liang, Yan, Long, Ji et al. find that the origin and dynamics of 5-hydroxymethylcytosine (5hmC) during early development are not conserved between humans and mice and that 5hmC contributes to the activation of human embryonic genes.
DNA 5-甲基胞嘧啶(5mC)通过 TET 酶转化为 5-羟甲基胞嘧啶(5hmC)是一种重要的表观遗传修饰,但它在人类早期胚胎中的作用在很大程度上仍不为人所知。在这里,我们发现人类早期胚胎从卵母细胞中继承了大量的 5hmC,而这些卵母细胞在生长过程中意外地发生了新的羟甲基化。此外,受精后父系基因组中 5hmC 的生成大致遵循母系模式,这与 DNA 甲基化动态和持续甲基化区域有关。5hmC一直持续到八细胞阶段,并在OTX2结合位点表现出高度富集,而在人类胚胎中敲除OTX2会影响早期系基因的表达。具体来说,5hmC的耗竭影响了胚胎基因的激活,这一点通过在人类早期胚胎中异位表达小鼠Tet3得到了进一步评估。这些发现揭示了 5hmC 的独特动态,并揭示了它在人类早期胚胎发育中的多方面功能。
{"title":"Distinct dynamics of parental 5-hydroxymethylcytosine during human preimplantation development regulate early lineage gene expression","authors":"Dan Liang, Rui Yan, Xin Long, Dongmei Ji, Bing Song, Mengyao Wang, Fan Zhang, Xin Cheng, Fengyuan Sun, Ran Zhu, Xinling Hou, Tianjuan Wang, Weiwei Zou, Ying Zhang, Zhixin Pu, Jing Zhang, Zhiguo Zhang, Yajing Liu, Yuqiong Hu, Xiaojin He, Yunxia Cao, Fan Guo","doi":"10.1038/s41556-024-01475-y","DOIUrl":"10.1038/s41556-024-01475-y","url":null,"abstract":"The conversion of DNA 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by TET enzymes represents a significant epigenetic modification, yet its role in early human embryos remains largely unknown. Here we showed that the early human embryo inherited a significant amount of 5hmCs from an oocyte, which unexpectedly underwent de novo hydroxymethylation during its growth. Furthermore, the generation of 5hmC in the paternal genome after fertilization roughly followed the maternal pattern, which was linked to DNA methylation dynamics and regions of sustained methylation. The 5hmCs persisted until the eight-cell stage and exhibited high enrichment at OTX2 binding sites, whereas knockdown of OTX2 in human embryos compromised the expression of early lineage genes. Specifically, the depletion of 5hmC affected the activation of embryonic genes, which was further evaluated by ectopically expressing mouse Tet3 in human early embryos. These findings revealed distinct dynamics of 5hmC and unravelled its multifaceted functions in early human embryonic development. Liang, Yan, Long, Ji et al. find that the origin and dynamics of 5-hydroxymethylcytosine (5hmC) during early development are not conserved between humans and mice and that 5hmC contributes to the activation of human embryonic genes.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1458-1469"},"PeriodicalIF":17.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01475-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
mTORC2-driven chromatin cGAS mediates chemoresistance through epigenetic reprogramming in colorectal cancer mTORC2 驱动的染色质 cGAS 通过表观遗传重编程介导结直肠癌的化疗抗药性
IF 17.3 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-30 DOI: 10.1038/s41556-024-01473-0
Guoqing Lv, Qian Wang, Lin Lin, Qiao Ye, Xi Li, Qian Zhou, Xiangzhen Kong, Hongxia Deng, Fuping You, Hebing Chen, Song Wu, Lin Yuan
Cyclic GMP–AMP synthase (cGAS), a cytosolic DNA sensor that initiates a STING-dependent innate immune response, binds tightly to chromatin, where its catalytic activity is inhibited; however, mechanisms underlying cGAS recruitment to chromatin and functions of chromatin-bound cGAS (ccGAS) remain unclear. Here we show that mTORC2-mediated phosphorylation of human cGAS serine 37 promotes its chromatin localization in colorectal cancer cells, regulating cell growth and drug resistance independently of STING. We discovered that ccGAS recruits the SWI/SNF complex at specific chromatin regions, modifying expression of genes linked to glutaminolysis and DNA replication. Although ccGAS depletion inhibited cell growth, it induced chemoresistance to fluorouracil treatment in vitro and in vivo. Moreover, blocking kidney-type glutaminase, a downstream ccGAS target, overcame chemoresistance caused by ccGAS loss. Thus, ccGAS coordinates colorectal cancer plasticity and acquired chemoresistance through epigenetic patterning. Targeting both mTORC2–ccGAS and glutaminase provides a promising strategy to eliminate quiescent resistant cancer cells. Lv, Wang, Lin, Ye et al. report that mTORC2 phosphorylates cGAS to promote its chromatin localization and SWI/SNF recruitment to regulate target gene expression, thereby mediating plasticity and chemoresistance in colorectal cancer.
环状 GMP-AMP 合酶(cGAS)是一种细胞膜 DNA 传感器,可启动 STING 依赖性先天免疫反应,它可与染色质紧密结合,其催化活性在染色质中受到抑制;然而,cGAS 招募到染色质的机制以及与染色质结合的 cGAS(ccGAS)的功能仍不清楚。在这里,我们发现 mTORC2 介导的人 cGAS 丝氨酸 37 磷酸化促进了其在结直肠癌细胞中的染色质定位,从而独立于 STING 调节细胞生长和耐药性。我们发现 ccGAS 在特定染色质区域招募 SWI/SNF 复合物,从而改变与谷氨酰胺溶解和 DNA 复制相关的基因的表达。虽然 ccGAS 的缺失抑制了细胞的生长,但它在体外和体内诱导了对氟尿嘧啶治疗的化疗抗性。此外,阻断肾型谷氨酰胺酶(ccGAS的下游靶标)可克服ccGAS缺失导致的化疗抗性。因此,ccGAS通过表观遗传模式协调结直肠癌的可塑性和获得性化疗耐药性。同时以mTORC2-ccGAS和谷氨酰胺酶为靶点,为消除静止抗药性癌细胞提供了一种前景广阔的策略。
{"title":"mTORC2-driven chromatin cGAS mediates chemoresistance through epigenetic reprogramming in colorectal cancer","authors":"Guoqing Lv, Qian Wang, Lin Lin, Qiao Ye, Xi Li, Qian Zhou, Xiangzhen Kong, Hongxia Deng, Fuping You, Hebing Chen, Song Wu, Lin Yuan","doi":"10.1038/s41556-024-01473-0","DOIUrl":"10.1038/s41556-024-01473-0","url":null,"abstract":"Cyclic GMP–AMP synthase (cGAS), a cytosolic DNA sensor that initiates a STING-dependent innate immune response, binds tightly to chromatin, where its catalytic activity is inhibited; however, mechanisms underlying cGAS recruitment to chromatin and functions of chromatin-bound cGAS (ccGAS) remain unclear. Here we show that mTORC2-mediated phosphorylation of human cGAS serine 37 promotes its chromatin localization in colorectal cancer cells, regulating cell growth and drug resistance independently of STING. We discovered that ccGAS recruits the SWI/SNF complex at specific chromatin regions, modifying expression of genes linked to glutaminolysis and DNA replication. Although ccGAS depletion inhibited cell growth, it induced chemoresistance to fluorouracil treatment in vitro and in vivo. Moreover, blocking kidney-type glutaminase, a downstream ccGAS target, overcame chemoresistance caused by ccGAS loss. Thus, ccGAS coordinates colorectal cancer plasticity and acquired chemoresistance through epigenetic patterning. Targeting both mTORC2–ccGAS and glutaminase provides a promising strategy to eliminate quiescent resistant cancer cells. Lv, Wang, Lin, Ye et al. report that mTORC2 phosphorylates cGAS to promote its chromatin localization and SWI/SNF recruitment to regulate target gene expression, thereby mediating plasticity and chemoresistance in colorectal cancer.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1585-1596"},"PeriodicalIF":17.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01473-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Publisher Correction: A dual role of ERGIC-localized Rabs in TMED10-mediated unconventional protein secretion 出版商更正:ERGIC定位的Rabs在TMED10介导的非常规蛋白质分泌中的双重作用。
IF 17.3 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-24 DOI: 10.1038/s41556-024-01471-2
Yuxin Sun, Xuan Tao, Yaping Han, Xubo Lin, Rui Tian, Haodong Wang, Pei Chang, Qiming Sun, Liang Ge, Min Zhang
{"title":"Publisher Correction: A dual role of ERGIC-localized Rabs in TMED10-mediated unconventional protein secretion","authors":"Yuxin Sun, Xuan Tao, Yaping Han, Xubo Lin, Rui Tian, Haodong Wang, Pei Chang, Qiming Sun, Liang Ge, Min Zhang","doi":"10.1038/s41556-024-01471-2","DOIUrl":"10.1038/s41556-024-01471-2","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1623-1623"},"PeriodicalIF":17.3,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01471-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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