EMBO Journal最新文献_第9页

Human genomic DNA is widely interspersed with i-motif structures. 人类基因组 DNA 中广泛存在 i-motif 结构。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-10-01 Epub Date: 2024-08-29 DOI: 10.1038/s44318-024-00210-5

Cristian David Peña Martinez, Mahdi Zeraati, Romain Rouet, Ohan Mazigi, Jake Y Henry, Brian Gloss, Jessica A Kretzmann, Cameron W Evans, Emanuela Ruggiero, Irene Zanin, Maja Marušič, Janez Plavec, Sara N Richter, Tracy M Bryan, Nicole M Smith, Marcel E Dinger, Sarah Kummerfeld, Daniel Christ

{"title":"Human genomic DNA is widely interspersed with i-motif structures.","authors":"Cristian David Peña Martinez, Mahdi Zeraati, Romain Rouet, Ohan Mazigi, Jake Y Henry, Brian Gloss, Jessica A Kretzmann, Cameron W Evans, Emanuela Ruggiero, Irene Zanin, Maja Marušič, Janez Plavec, Sara N Richter, Tracy M Bryan, Nicole M Smith, Marcel E Dinger, Sarah Kummerfeld, Daniel Christ","doi":"10.1038/s44318-024-00210-5","DOIUrl":"10.1038/s44318-024-00210-5","url":null,"abstract":"DNA i-motif structures are formed in the nuclei of human cells and are believed to provide critical genomic regulation. While the existence, abundance, and distribution of i-motif structures in human cells has been demonstrated and studied by immunofluorescent staining, and more recently NMR and CUT&Tag, the abundance and distribution of such structures in human genomic DNA have remained unclear. Here we utilise high-affinity i-motif immunoprecipitation followed by sequencing to map i-motifs in the purified genomic DNA of human MCF7, U2OS and HEK293T cells. Validated by biolayer interferometry and circular dichroism spectroscopy, our approach aimed to identify DNA sequences capable of i-motif formation on a genome-wide scale, revealing that such sequences are widely distributed throughout the human genome and are common in genes upregulated in G0/G1 cell cycle phases. Our findings provide experimental evidence for the widespread formation of i-motif structures in human genomic DNA and a foundational resource for future studies of their genomic, structural, and molecular roles.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4786-4804"},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114396","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

PUFFFIN: an ultra-bright, customisable, single-plasmid system for labelling cell neighbourhoods. PUFFFIN：用于标记细胞邻域的超亮、可定制的单质粒系统。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-07-12 DOI: 10.1038/s44318-024-00154-w

Tamina Lebek, Mattias Malaguti, Giulia Lm Boezio, Lida Zoupi, James Briscoe, Alistair Elfick, Sally Lowell

{"title":"PUFFFIN: an ultra-bright, customisable, single-plasmid system for labelling cell neighbourhoods.","authors":"Tamina Lebek, Mattias Malaguti, Giulia Lm Boezio, Lida Zoupi, James Briscoe, Alistair Elfick, Sally Lowell","doi":"10.1038/s44318-024-00154-w","DOIUrl":"10.1038/s44318-024-00154-w","url":null,"abstract":"Cell communication coordinates developmental processes, maintains homeostasis, and contributes to disease. Therefore, understanding the relationship between cells in a shared environment is crucial. Here we introduce Positive Ultra-bright Fluorescent Fusion For Identifying Neighbours (PUFFFIN), a cell neighbour-labelling system based upon secretion and uptake of positively supercharged fluorescent protein s36GFP. We fused s36GFP to mNeonGreen or to a HaloTag, facilitating ultra-bright, sensitive, colour-of-choice labelling. Secretor cells transfer PUFFFIN to neighbours while retaining nuclear mCherry, making identification, isolation, and investigation of live neighbours straightforward. PUFFFIN can be delivered to cells, tissues, or embryos on a customisable single-plasmid construct composed of interchangeable components with the option to incorporate any transgene. This versatility enables the manipulation of cell properties, while simultaneously labelling surrounding cells, in cell culture or in vivo. We use PUFFFIN to ask whether pluripotent cells adjust the pace of differentiation to synchronise with their neighbours during exit from naïve pluripotency. PUFFFIN offers a simple, sensitive, customisable approach to profile non-cell-autonomous responses to natural or induced changes in cell identity or behaviour.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4110-4135"},"PeriodicalIF":9.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11405414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602077","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

Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23. 抗蠕虫药莫奈潘特尔和甜菜碱对优雅尾线虫乙酰胆碱受体 ACR-23 分子影响的结构性启示。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-07-15 DOI: 10.1038/s44318-024-00165-7

Fenglian Liu, Tianyu Li, Huihui Gong, Fei Tian, Yan Bai, Haowei Wang, Chonglin Yang, Yang Li, Fei Guo, Sheng Liu, Qingfeng Chen

{"title":"Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23.","authors":"Fenglian Liu, Tianyu Li, Huihui Gong, Fei Tian, Yan Bai, Haowei Wang, Chonglin Yang, Yang Li, Fei Guo, Sheng Liu, Qingfeng Chen","doi":"10.1038/s44318-024-00165-7","DOIUrl":"10.1038/s44318-024-00165-7","url":null,"abstract":"Anthelmintics are drugs used for controlling pathogenic helminths in animals and plants. The natural compound betaine and the recently developed synthetic compound monepantel are both anthelmintics that target the acetylcholine receptor ACR-23 and its homologs in nematodes. Here, we present cryo-electron microscopy structures of ACR-23 in apo, betaine-bound, and betaine- and monepantel-bound states. We show that ACR-23 forms a homo-pentameric channel, similar to some other pentameric ligand-gated ion channels (pLGICs). While betaine molecules are bound to the classical neurotransmitter sites in the inter-subunit interfaces in the extracellular domain, monepantel molecules are bound to allosteric sites formed in the inter-subunit interfaces in the transmembrane domain of the receptor. Although the pore remains closed in betaine-bound state, monepantel binding results in an open channel by wedging into the cleft between the transmembrane domains of two neighboring subunits, which causes dilation of the ion conduction pore. By combining structural analyses with site-directed mutagenesis, electrophysiology and in vivo locomotion assays, we provide insights into the mechanism of action of the anthelmintics monepantel and betaine.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"3787-3806"},"PeriodicalIF":9.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621656","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

Modular control of vertebrate axis segmentation in time and space. 脊椎动物轴分节在时间和空间上的模块化控制

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-08-09 DOI: 10.1038/s44318-024-00186-2

Ali Seleit, Ian Brettell, Tomas Fitzgerald, Carina Vibe, Felix Loosli, Joachim Wittbrodt, Kiyoshi Naruse, Ewan Birney, Alexander Aulehla

{"title":"Modular control of vertebrate axis segmentation in time and space.","authors":"Ali Seleit, Ian Brettell, Tomas Fitzgerald, Carina Vibe, Felix Loosli, Joachim Wittbrodt, Kiyoshi Naruse, Ewan Birney, Alexander Aulehla","doi":"10.1038/s44318-024-00186-2","DOIUrl":"10.1038/s44318-024-00186-2","url":null,"abstract":"How the timing of development is linked to organismal size is a longstanding question. Although numerous studies have reported a correlation of temporal and spatial traits, the developmental or selective constraints underlying this link remain largely unexplored. We address this question by studying the periodic process of embryonic axis segmentation in-vivo in Oryzias fish. Interspecies comparisons reveal that the timing of segmentation correlates to segment, tissue and organismal size. Segment size in turn scales according to tissue and organism size. To probe for underlying causes, we genetically hybridised two closely related species. Quantitative analysis in ~600 phenotypically diverse F2 embryos reveals a decoupling of timing from size control, while spatial scaling is preserved. Using developmental quantitative trait loci (devQTL) mapping we identify distinct genetic loci linked to either the control of segmentation timing or tissue size. This study demonstrates that a developmental constraint mechanism underlies spatial scaling of axis segmentation, while its spatial and temporal control are dissociable modules.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4068-4091"},"PeriodicalIF":9.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11405765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914443","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

Identification of BiP as a temperature sensor mediating temperature-induced germline sex reversal in C. elegans. 鉴定 BiP 作为温度传感器介导温度诱导的秀丽隐杆线虫种系性别逆转。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-08-12 DOI: 10.1038/s44318-024-00197-z

Jing Shi, Danli Sheng, Jie Guo, Fangyuan Zhou, Shaofeng Wu, Hongyun Tang

{"title":"Identification of BiP as a temperature sensor mediating temperature-induced germline sex reversal in C. elegans.","authors":"Jing Shi, Danli Sheng, Jie Guo, Fangyuan Zhou, Shaofeng Wu, Hongyun Tang","doi":"10.1038/s44318-024-00197-z","DOIUrl":"10.1038/s44318-024-00197-z","url":null,"abstract":"Sex determination in animals is not only determined by karyotype but can also be modulated by environmental cues like temperature via unclear transduction mechanisms. Moreover, in contrast to earlier views that sex may exclusively be determined by either karyotype or temperature, recent observations suggest that these factors rather co-regulate sex, posing another mechanistic mystery. Here, we discovered that certain wild-isolated and mutant C. elegans strains displayed genotypic germline sex determination (GGSD), but with a temperature-override mechanism. Further, we found that BiP, an ER chaperone, transduces temperature information into a germline sex-governing signal, thereby enabling the coexistence of GGSD and temperature-dependent germline sex determination (TGSD). At the molecular level, increased ER protein-folding requirements upon increased temperatures lead to BiP sequestration, resulting in ERAD-dependent degradation of the oocyte fate-driving factor, TRA-2, thus promoting male germline fate. Remarkably, experimentally manipulating BiP or TRA-2 expression allows to switch between GGSD and TGSD. Physiologically, TGSD allows C. elegans hermaphrodites to maintain brood size at warmer temperatures. Moreover, BiP can also influence germline sex determination in a different, non-hermaphroditic nematode species. Collectively, our findings identify thermosensitive BiP as a conserved temperature sensor in TGSD, and provide mechanistic insights into the transition between GGSD and TGSD.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4020-4048"},"PeriodicalIF":9.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11405683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141972260","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

Loss of Elp3 blocks intestinal tuft cell differentiation via an mTORC1-Atf4 axis. Elp3的缺失会通过mTORC1-Atf4轴阻碍肠簇细胞的分化。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-07-31 DOI: 10.1038/s44318-024-00184-4

Caroline Wathieu, Arnaud Lavergne, Xinyi Xu, Marion Rolot, Ivan Nemazanyy, Kateryna Shostak, Najla El Hachem, Chloé Maurizy, Charlotte Leemans, Pierre Close, Laurent Nguyen, Christophe Desmet, Sylvia Tielens, Benjamin G Dewals, Alain Chariot

{"title":"Loss of Elp3 blocks intestinal tuft cell differentiation via an mTORC1-Atf4 axis.","authors":"Caroline Wathieu, Arnaud Lavergne, Xinyi Xu, Marion Rolot, Ivan Nemazanyy, Kateryna Shostak, Najla El Hachem, Chloé Maurizy, Charlotte Leemans, Pierre Close, Laurent Nguyen, Christophe Desmet, Sylvia Tielens, Benjamin G Dewals, Alain Chariot","doi":"10.1038/s44318-024-00184-4","DOIUrl":"10.1038/s44318-024-00184-4","url":null,"abstract":"Intestinal tuft cells are critical for anti-helminth parasite immunity because they produce IL-25, which triggers IL-13 secretion by activated group 2 innate lymphoid cells (ILC2s) to expand both goblet and tuft cells. We show that epithelial Elp3, a tRNA-modifying enzyme, promotes tuft cell differentiation and is consequently critical for IL-25 production, ILC2 activation, goblet cell expansion and control of Nippostrongylus brasiliensis helminth infection in mice. Elp3 is essential for the generation of intestinal immature tuft cells and for the IL-13-dependent induction of glycolytic enzymes such as Hexokinase 1 and Aldolase A. Importantly, loss of epithelial Elp3 in the intestine blocks the codon-dependent translation of the Gator1 subunit Nprl2, an mTORC1 inhibitor, which consequently enhances mTORC1 activation and stabilizes Atf4 in progenitor cells. Likewise, Atf4 overexpression in mouse intestinal epithelium blocks tuft cell differentiation in response to intestinal helminth infection. Collectively, our data define Atf4 as a negative regulator of tuft cells and provide insights into promotion of intestinal type 2 immune response to parasites through tRNA modifications.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"3916-3947"},"PeriodicalIF":9.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11405396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861531","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

Reactive oxygen species activate the Drosophila TNF receptor Wengen for damage-induced regeneration. 活性氧激活果蝇 TNF 受体 Wengen，促进损伤诱导的再生。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-07-17 DOI: 10.1038/s44318-024-00155-9

José Esteban-Collado, Mar Fernández-Mañas, Manuel Fernández-Moreno, Ignacio Maeso, Montserrat Corominas, Florenci Serras

{"title":"Reactive oxygen species activate the Drosophila TNF receptor Wengen for damage-induced regeneration.","authors":"José Esteban-Collado, Mar Fernández-Mañas, Manuel Fernández-Moreno, Ignacio Maeso, Montserrat Corominas, Florenci Serras","doi":"10.1038/s44318-024-00155-9","DOIUrl":"10.1038/s44318-024-00155-9","url":null,"abstract":"Tumor necrosis factor receptors (TNFRs) control pleiotropic pro-inflammatory functions that range from apoptosis to cell survival. The ability to trigger a particular function will depend on the upstream cues, association with regulatory complexes, and downstream pathways. In Drosophila melanogaster, two TNFRs have been identified, Wengen (Wgn) and Grindelwald (Grnd). Although several reports associate these receptors with JNK-dependent apoptosis, it has recently been found that Wgn activates a variety of other functions. We demonstrate that Wgn is required for survival by protecting cells from apoptosis. This is mediated by dTRAF1 and results in the activation of p38 MAP kinase. Remarkably, Wgn is required for apoptosis-induced regeneration and is activated by the reactive oxygen species (ROS) produced following apoptosis. This ROS activation is exclusive for Wgn, but not for Grnd, and can occur after knocking down Eiger/TNFα. The extracellular cysteine-rich domain of Grnd is much more divergent than that of Wgn, which is more similar to TNFRs from other animals, including humans. Our results show a novel TNFR function that responds to stressors by ensuring p38-dependent regeneration.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"3604-3626"},"PeriodicalIF":9.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141635648","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

Wengen's hidden powers: ROS triggers a TNFR-dependent tissue regenerative pathway in Drosophila. 翁根的隐藏力量：ROS 触发果蝇体内依赖 TNFR 的组织再生途径

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-07-17 DOI: 10.1038/s44318-024-00170-w

Ditte S Andersen, Julien Colombani

引用次数: 0

CMG helicase disassembly is essential and driven by two pathways in budding yeast. 在芽殖酵母中，CMG 螺旋酶的分解是必不可少的，并由两种途径驱动。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-07-22 DOI: 10.1038/s44318-024-00161-x

Cristian Polo Rivera, Tom D Deegan, Karim P M Labib

{"title":"CMG helicase disassembly is essential and driven by two pathways in budding yeast.","authors":"Cristian Polo Rivera, Tom D Deegan, Karim P M Labib","doi":"10.1038/s44318-024-00161-x","DOIUrl":"10.1038/s44318-024-00161-x","url":null,"abstract":"The CMG helicase is the stable core of the eukaryotic replisome and is ubiquitylated and disassembled during DNA replication termination. Fungi and animals use different enzymes to ubiquitylate the Mcm7 subunit of CMG, suggesting that CMG ubiquitylation arose repeatedly during eukaryotic evolution. Until now, it was unclear whether cells also have ubiquitin-independent pathways for helicase disassembly and whether CMG disassembly is essential for cell viability. Using reconstituted assays with budding yeast CMG, we generated the mcm7-10R allele that compromises ubiquitylation by SCFDia2. mcm7-10R delays helicase disassembly in vivo, driving genome instability in the next cell cycle. These data indicate that defective CMG ubiquitylation explains the major phenotypes of cells lacking Dia2. Notably, the viability of mcm7-10R and dia2∆ is dependent upon the related Rrm3 and Pif1 DNA helicases that have orthologues in all eukaryotes. We show that Rrm3 acts during S-phase to disassemble old CMG complexes from the previous cell cycle. These findings indicate that CMG disassembly is essential in yeast cells and suggest that Pif1-family helicases might have mediated CMG disassembly in ancestral eukaryotes.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"3818-3845"},"PeriodicalIF":9.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11405719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749563","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

Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition. 溶酶体 TBK1 对氨基酸的可用性做出反应，以缓解 Rab7 依赖性 mTORC1 的抑制作用。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI: 10.1038/s44318-024-00180-8

Gabriel Talaia, Amanda Bentley-DeSousa, Shawn M Ferguson

{"title":"Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition.","authors":"Gabriel Talaia, Amanda Bentley-DeSousa, Shawn M Ferguson","doi":"10.1038/s44318-024-00180-8","DOIUrl":"10.1038/s44318-024-00180-8","url":null,"abstract":"Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. This lysosomal TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"3948-3967"},"PeriodicalIF":9.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11405869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894802","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