EMBO Journal最新文献_第3页

Calcium signaling from damaged lysosomes induces cytoprotective stress granules. 来自受损溶酶体的钙信号诱导细胞保护应激颗粒。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-12 DOI: 10.1038/s44318-024-00292-1

Jacob Duran, Jay E Salinas, Rui Ping Wheaton, Suttinee Poolsup, Lee Allers, Monica Rosas-Lemus, Li Chen, Qiuying Cheng, Jing Pu, Michelle Salemi, Brett Phinney, Pavel Ivanov, Alf Håkon Lystad, Kiran Bhaskar, Jaya Rajaiya, Douglas J Perkins, Jingyue Jia

{"title":"Calcium signaling from damaged lysosomes induces cytoprotective stress granules.","authors":"Jacob Duran, Jay E Salinas, Rui Ping Wheaton, Suttinee Poolsup, Lee Allers, Monica Rosas-Lemus, Li Chen, Qiuying Cheng, Jing Pu, Michelle Salemi, Brett Phinney, Pavel Ivanov, Alf Håkon Lystad, Kiran Bhaskar, Jaya Rajaiya, Douglas J Perkins, Jingyue Jia","doi":"10.1038/s44318-024-00292-1","DOIUrl":"https://doi.org/10.1038/s44318-024-00292-1","url":null,"abstract":"Lysosomal damage induces stress granule (SG) formation. However, the importance of SGs in determining cell fate and the precise mechanisms that mediate SG formation in response to lysosomal damage remain unclear. Here, we describe a novel calcium-dependent pathway controlling SG formation, which promotes cell survival during lysosomal damage. Mechanistically, the calcium-activated protein ALIX transduces lysosomal damage signals to SG formation by controlling eIF2α phosphorylation after sensing calcium leakage. ALIX enhances eIF2α phosphorylation by promoting the association between PKR and its activator PACT, with galectin-3 inhibiting this interaction; these regulatory events occur on damaged lysosomes. We further find that SG formation plays a crucial role in promoting cell survival upon lysosomal damage caused by factors such as SARS-CoV-2ORF3a, adenovirus, malarial pigment, proteopathic tau, or environmental hazards. Collectively, these data provide insights into the mechanism of SG formation upon lysosomal damage and implicate it in diseases associated with damaged lysosomes and SGs.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631870","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

LARP1 binds ribosomes and TOP mRNAs in repressed complexes. LARP1 与核糖体和 TOP mRNA 结合，形成受抑制的复合物。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-12 DOI: 10.1038/s44318-024-00294-z

James A Saba, Zixuan Huang, Kate L Schole, Xianwen Ye, Shrey D Bhatt, Yi Li, Winston Timp, Jingdong Cheng, Rachel Green

{"title":"LARP1 binds ribosomes and TOP mRNAs in repressed complexes.","authors":"James A Saba, Zixuan Huang, Kate L Schole, Xianwen Ye, Shrey D Bhatt, Yi Li, Winston Timp, Jingdong Cheng, Rachel Green","doi":"10.1038/s44318-024-00294-z","DOIUrl":"https://doi.org/10.1038/s44318-024-00294-z","url":null,"abstract":"Terminal oligopyrimidine motif-containing mRNAs (TOPs) encode all ribosomal proteins in mammals and are regulated to tune ribosome synthesis to cell state. Previous studies have implicated LARP1 in 40S- or 80S-ribosome complexes that are thought to repress and stabilize TOPs. However, a molecular understanding of how LARP1 and TOPs interact with these ribosome complexes is lacking. Here, we show that LARP1 directly binds non-translating ribosomal subunits. Cryo-EM structures reveal a previously uncharacterized domain of LARP1 bound to and occluding the mRNA channel of the 40S subunit. Increased availability of free ribosomal subunits downstream of various stresses promote 60S joining at the same interface to form LARP1-80S complexes. Simultaneously, LARP1 engages the TOP via its previously characterized La/PAM2 and DM15 domains. Contrary to expectations, ribosome binding within these complexes is not required for LARP1-mediated TOP repression or stabilization, two canonical LARP1 functions. Together, this work provides molecular insight into how LARP1 directly binds ribosomal subunits and challenges existing models describing the function of repressed LARP1-40S/80S-TOP complexes.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631874","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

Determinants of chemoselectivity in ubiquitination by the J2 family of ubiquitin-conjugating enzymes. 泛素结合酶 J2 家族泛素化过程中化学选择性的决定因素。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-12 DOI: 10.1038/s44318-024-00301-3

Anuruti Swarnkar, Florian Leidner, Ashok K Rout, Sofia Ainatzi, Claudia C Schmidt, Stefan Becker, Henning Urlaub, Christian Griesinger, Helmut Grubmüller, Alexander Stein

{"title":"Determinants of chemoselectivity in ubiquitination by the J2 family of ubiquitin-conjugating enzymes.","authors":"Anuruti Swarnkar, Florian Leidner, Ashok K Rout, Sofia Ainatzi, Claudia C Schmidt, Stefan Becker, Henning Urlaub, Christian Griesinger, Helmut Grubmüller, Alexander Stein","doi":"10.1038/s44318-024-00301-3","DOIUrl":"https://doi.org/10.1038/s44318-024-00301-3","url":null,"abstract":"Ubiquitin-conjugating enzymes (E2) play a crucial role in the attachment of ubiquitin to proteins. Together with ubiquitin ligases (E3), they catalyze the transfer of ubiquitin (Ub) onto lysines with high chemoselectivity. A subfamily of E2s, including yeast Ubc6 and human Ube2J2, also mediates noncanonical modification of serines, but the structural determinants for this chemical versatility remain unknown. Using a combination of X-ray crystallography, molecular dynamics (MD) simulations, and reconstitution approaches, we have uncovered a two-layered mechanism that underlies this unique reactivity. A rearrangement of the Ubc6/Ube2J2 active site enhances the reactivity of the E2-Ub thioester, facilitating attack by weaker nucleophiles. Moreover, a conserved histidine in Ubc6/Ube2J2 activates a substrate serine by general base catalysis. Binding of RING-type E3 ligases further increases the serine selectivity inherent to Ubc6/Ube2J2, via an allosteric mechanism that requires specific positioning of the ubiquitin tail at the E2 active site. Our results elucidate how subtle structural modifications to the highly conserved E2 fold yield distinct enzymatic activity.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631872","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

METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma. METTL3/MYCN合作推动神经嵴分化，并为神经母细胞瘤的治疗提供脆弱性。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-11 DOI: 10.1038/s44318-024-00299-8

Ketan Thombare, Roshan Vaid, Perla Pucci, Kristina Ihrmark Lundberg, Ritish Ayyalusamy, Mohammad Hassan Baig, Akram Mendez, Rebeca Burgos-Panadero, Stefanie Höppner, Christoph Bartenhagen, Daniel Sjövall, Aqsa Ali Rehan, Sagar Dattatraya Nale, Anna Djos, Tommy Martinsson, Pekka Jaako, Jae-June Dong, Per Kogner, John Inge Johnsen, Matthias Fischer, Suzanne D Turner, Tanmoy Mondal

{"title":"METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma.","authors":"Ketan Thombare, Roshan Vaid, Perla Pucci, Kristina Ihrmark Lundberg, Ritish Ayyalusamy, Mohammad Hassan Baig, Akram Mendez, Rebeca Burgos-Panadero, Stefanie Höppner, Christoph Bartenhagen, Daniel Sjövall, Aqsa Ali Rehan, Sagar Dattatraya Nale, Anna Djos, Tommy Martinsson, Pekka Jaako, Jae-June Dong, Per Kogner, John Inge Johnsen, Matthias Fischer, Suzanne D Turner, Tanmoy Mondal","doi":"10.1038/s44318-024-00299-8","DOIUrl":"https://doi.org/10.1038/s44318-024-00299-8","url":null,"abstract":"Neuroblastoma (NB) is the most common extracranial childhood cancer, caused by the improper differentiation of developing trunk neural crest cells (tNCC) in the sympathetic nervous system. The N6-methyladenosine (m6A) epitranscriptomic modification controls post-transcriptional gene expression but the mechanism by which the m6A methyltransferase complex METTL3/METTL14/WTAP is recruited to specific loci remains to be fully characterized. We explored whether the m6A epitranscriptome could fine-tune gene regulation in migrating/differentiating tNCC. We demonstrate that the m6A modification regulates the expression of HOX genes in tNCC, thereby contributing to their timely differentiation into sympathetic neurons. Furthermore, we show that posterior HOX genes are m6A modified in MYCN-amplified NB with reduced expression. In addition, we provide evidence that sustained overexpression of the MYCN oncogene in tNCC drives METTL3 recruitment to a specific subset of genes including posterior HOX genes creating an undifferentiated state. Moreover, METTL3 depletion/inhibition induces DNA damage and differentiation of MYCN overexpressing cells and increases vulnerability to chemotherapeutic drugs in MYCN-amplified patient-derived xenografts (PDX) in vivo, suggesting METTL3 inhibition could be a potential therapeutic approach for NB.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631876","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

Glutamylation imbalance impairs the molecular architecture of the photoreceptor cilium. 谷氨酰化失衡会损害感光细胞纤毛的分子结构。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-11 DOI: 10.1038/s44318-024-00284-1

Olivier Mercey, Sudarshan Gadadhar, Maria M Magiera, Laura Lebrun, Corinne Kostic, Alexandre Moulin, Yvan Arsenijevic, Carsten Janke, Paul Guichard, Virginie Hamel

{"title":"Glutamylation imbalance impairs the molecular architecture of the photoreceptor cilium.","authors":"Olivier Mercey, Sudarshan Gadadhar, Maria M Magiera, Laura Lebrun, Corinne Kostic, Alexandre Moulin, Yvan Arsenijevic, Carsten Janke, Paul Guichard, Virginie Hamel","doi":"10.1038/s44318-024-00284-1","DOIUrl":"https://doi.org/10.1038/s44318-024-00284-1","url":null,"abstract":"Microtubules, composed of conserved α/β-tubulin dimers, undergo complex post-translational modifications (PTMs) that fine-tune their properties and interactions with other proteins. Cilia exhibit several tubulin PTMs, such as polyglutamylation, polyglycylation, detyrosination, and acetylation, with functions that are not fully understood. Mutations in AGBL5, which encodes the deglutamylating enzyme CCP5, have been linked to retinitis pigmentosa, suggesting that altered polyglutamylation may cause photoreceptor cell degeneration, though the underlying mechanisms are unclear. Using super-resolution ultrastructure expansion microscopy (U-ExM) in mouse and human photoreceptor cells, we observed that most tubulin PTMs accumulate at the connecting cilium that links outer and inner photoreceptor segments. Mouse models with increased glutamylation (Ccp5-/- and Ccp1-/-) or loss of tubulin acetylation (Atat1-/-) showed that aberrant glutamylation, but not acetylation loss, disrupts outer segment architecture. This disruption includes exacerbation of the connecting cilium, loss of the bulge region, and destabilization of the distal axoneme. Additionally, we found significant impairment in tubulin glycylation, as well as reduced levels of intraflagellar transport proteins and of retinitis pigmentosa-associated protein RPGR. Our findings indicate that proper glutamylation levels are crucial for maintaining the molecular architecture of the photoreceptor cilium.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631873","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

Nuclear receptor E75/NR1D2 promotes tumor malignant transformation by integrating Hippo and Notch pathways. 核受体E75/NR1D2通过整合Hippo和Notch通路促进肿瘤恶性转化

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-08 DOI: 10.1038/s44318-024-00290-3

Xianping Wang, Yifan Guo, Peng Lin, Min Yu, Sha Song, Wenyan Xu, Du Kong, Yin Wang, Yanxiao Zhang, Fei Lu, Qi Xie, Xianjue Ma

{"title":"Nuclear receptor E75/NR1D2 promotes tumor malignant transformation by integrating Hippo and Notch pathways.","authors":"Xianping Wang, Yifan Guo, Peng Lin, Min Yu, Sha Song, Wenyan Xu, Du Kong, Yin Wang, Yanxiao Zhang, Fei Lu, Qi Xie, Xianjue Ma","doi":"10.1038/s44318-024-00290-3","DOIUrl":"https://doi.org/10.1038/s44318-024-00290-3","url":null,"abstract":"Hormone therapy resistance and the ensuing aggressive tumor progression present a significant clinical challenge. However, the mechanisms underlying the induction of tumor malignancy upon inhibition of steroid hormone signaling remain poorly understood. Here, we demonstrate that Drosophila malignant epithelial tumors show a similar reduction in ecdysone signaling, the main steroid hormone pathway. Our analysis of ecdysone-induced downstream targets reveals that overexpression of the nuclear receptor E75, particularly facilitates the malignant transformation of benign tumors. Genome-wide DNA binding profiles and biochemistry data reveal that E75 not only binds to the transcription factors of both Hippo and Notch pathways, but also exhibits widespread co-binding to their target genes, thus contributing to tumor malignancy. We further validated these findings by demonstrating that depletion of NR1D2, the mammalian homolog of E75, inhibits the activation of Hippo and Notch target genes, impeding glioblastoma progression. Together, our study unveils a novel mechanism by which hormone inhibition promotes tumor malignancy, and describes an evolutionarily conserved role of the oncogene E75/NR1D2 in integration of Hippo and Notch pathway activity during tumor progression.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural basis of 3'-tRNA maturation by the human mitochondrial RNase Z complex. 人类线粒体 RNase Z 复合物 3'-tRNA 成熟的结构基础。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-08 DOI: 10.1038/s44318-024-00297-w

Genís Valentín Gesé, B Martin Hällberg

引用次数: 0

Rab2A-mediated Golgi-lipid droplet interactions support very-low-density lipoprotein secretion in hepatocytes. Rab2A 介导的高尔基体-脂滴相互作用支持肝细胞分泌极低密度脂蛋白。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-04 DOI: 10.1038/s44318-024-00288-x

Min Xu, Zi-Yue Chen, Yang Li, Yue Li, Ge Guo, Rong-Zheng Dai, Na Ni, Jing Tao, Hong-Yu Wang, Qiao-Li Chen, Hua Wang, Hong Zhou, Yi-Ning Yang, Shuai Chen, Liang Chen

{"title":"Rab2A-mediated Golgi-lipid droplet interactions support very-low-density lipoprotein secretion in hepatocytes.","authors":"Min Xu, Zi-Yue Chen, Yang Li, Yue Li, Ge Guo, Rong-Zheng Dai, Na Ni, Jing Tao, Hong-Yu Wang, Qiao-Li Chen, Hua Wang, Hong Zhou, Yi-Ning Yang, Shuai Chen, Liang Chen","doi":"10.1038/s44318-024-00288-x","DOIUrl":"https://doi.org/10.1038/s44318-024-00288-x","url":null,"abstract":"Lipid droplets (LDs) serve as crucial hubs for lipid trafficking and metabolic regulation through their numerous interactions with various organelles. While the interplay between LDs and the Golgi apparatus has been recognized, their roles and underlying mechanisms remain poorly understood. Here, we reveal the role of Ras-related protein Rab-2A (Rab2A) in mediating LD-Golgi interactions, thereby contributing to very-low-density lipoprotein (VLDL) lipidation and secretion in hepatocytes. Mechanistically, our findings identify a selective interaction between Golgi-localized Rab2A and 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) protein residing on LDs. This complex facilitates dynamic organelle communication between the Golgi apparatus and LDs, thus contributing to lipid transfer from LDs to the Golgi apparatus for VLDL2 lipidation and secretion. Attenuation of Rab2A activity via AMP-activated protein kinase (AMPK) suppresses the Rab2A-HSD17B13 complex formation, impairing LD-Golgi interactions and subsequent VLDL secretion. Furthermore, genetic inhibition of Rab2A and HSD17B13 in the liver reduces the serum triglyceride and cholesterol levels. Collectively, this study provides a new perspective on the interactions between the Golgi apparatus and LDs.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577097","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

Bridging structural biology and clinical research through in-tissue cryo-electron tomography. 通过组织内低温电子断层扫描技术架起结构生物学与临床研究之间的桥梁。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-16 DOI: 10.1038/s44318-024-00216-z

Kathryn Kixmoeller, Benjamin C Creekmore, Edward B Lee, Yi-Wei Chang

引用次数: 0

TRPC5: a new entry to the chromaffin cell's palette of ion channels that control adrenal response to hypoglycemia. TRPC5：控制肾上腺对低血糖反应的绒毛膜细胞离子通道的新成员。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 DOI: 10.1038/s44318-024-00286-z

Emilio Carbone

引用次数: 0