EMBO Journal最新文献_第2页

Intestinal NUCB2/nesfatin-1 regulates hepatic glucose production via the MC4R-cAMP-GLP-1 pathway. 肠道 NUCB2/nesfatin-1 通过 MC4R-cAMP-GLP-1 途径调节肝脏葡萄糖的产生。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-19 DOI: 10.1038/s44318-024-00300-4

Shan Geng, Shan Yang, Xuejiao Tang, Shiyao Xue, Ke Li, Dongfang Liu, Chen Chen, Zhiming Zhu, Hongting Zheng, Yuanqiang Wang, Gangyi Yang, Ling Li, Mengliu Yang

{"title":"Intestinal NUCB2/nesfatin-1 regulates hepatic glucose production via the MC4R-cAMP-GLP-1 pathway.","authors":"Shan Geng, Shan Yang, Xuejiao Tang, Shiyao Xue, Ke Li, Dongfang Liu, Chen Chen, Zhiming Zhu, Hongting Zheng, Yuanqiang Wang, Gangyi Yang, Ling Li, Mengliu Yang","doi":"10.1038/s44318-024-00300-4","DOIUrl":"https://doi.org/10.1038/s44318-024-00300-4","url":null,"abstract":"Communication of gut hormones with the central nervous system is important to regulate systemic glucose homeostasis, but the precise underlying mechanism involved remain little understood. Nesfatin-1, encoded by nucleobindin-2 (NUCB2), a potent anorexigenic peptide hormone, was found to be released from the gastrointestinal tract, but its specific function in this context remains unclear. Herein, we found that gut nesfatin-1 can sense nutrients such as glucose and lipids and subsequently decreases hepatic glucose production. Nesfatin-1 infusion in the small intestine of NUCB2-knockout rats reduced hepatic glucose production via a gut - brain - liver circuit. Mechanistically, NUCB2/nesfatin-1 interacted directly with melanocortin 4 receptor (MC4R) through its H-F-R domain and increased cyclic adenosine monophosphate (cAMP) levels and glucagon-like peptide 1 (GLP-1) secretion in the intestinal epithelium, thus inhibiting hepatic glucose production. The intestinal nesfatin-1 -MC4R-cAMP-GLP-1 pathway and systemic gut-brain communication are required for nesfatin-1 - mediated regulation of liver energy metabolism. These findings reveal a novel mechanism of hepatic glucose production control by gut hormones through the central nervous system.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677405","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

Towards routine proteome profiling of FFPE tissue: insights from a 1,220-case pan-cancer study. 实现 FFPE 组织的常规蛋白质组分析：一项 1220 例泛癌症研究的启示。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-18 DOI: 10.1038/s44318-024-00289-w

Johanna Tüshaus, Stephan Eckert, Marius Schliemann, Yuxiang Zhou, Pauline Pfeiffer, Christiane Halves, Federico Fusco, Johannes Weigel, Lisa Hönikl, Vicki Butenschön, Rumyana Todorova, Hilka Rauert-Wunderlich, Matthew The, Andreas Rosenwald, Volker Heinemann, Julian Holch, Katja Steiger, Claire Delbridge, Bernhard Meyer, Wilko Weichert, Carolin Mogler, Peer-Hendrik Kuhn, Bernhard Kuster

{"title":"Towards routine proteome profiling of FFPE tissue: insights from a 1,220-case pan-cancer study.","authors":"Johanna Tüshaus, Stephan Eckert, Marius Schliemann, Yuxiang Zhou, Pauline Pfeiffer, Christiane Halves, Federico Fusco, Johannes Weigel, Lisa Hönikl, Vicki Butenschön, Rumyana Todorova, Hilka Rauert-Wunderlich, Matthew The, Andreas Rosenwald, Volker Heinemann, Julian Holch, Katja Steiger, Claire Delbridge, Bernhard Meyer, Wilko Weichert, Carolin Mogler, Peer-Hendrik Kuhn, Bernhard Kuster","doi":"10.1038/s44318-024-00289-w","DOIUrl":"10.1038/s44318-024-00289-w","url":null,"abstract":"Proteome profiling of formalin-fixed paraffin-embedded (FFPE) specimens has gained traction for the analysis of cancer tissue for the discovery of molecular biomarkers. However, reports so far focused on single cancer entities, comprised relatively few cases and did not assess the long-term performance of experimental workflows. In this study, we analyze 1220 tumors from six cancer entities processed over the course of three years. Key findings include the need for a new normalization method ensuring equal and reproducible sample loading for LC-MS/MS analysis across cohorts, showing that tumors can, on average, be profiled to a depth of >4000 proteins and discovering that current software fails to process such large ion mobility-based online fractionated datasets. We report the first comprehensive pan-cancer proteome expression resource for FFPE material comprising 11,000 proteins which is of immediate utility to the scientific community, and can be explored via a web resource. It enables a range of analyses including quantitative comparisons of proteins between patients and cohorts, the discovery of protein fingerprints representing the tissue of origin or proteins enriched in certain cancer entities.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669710","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

Layered entrenchment maintains essentiality in the evolution of Form I Rubisco complexes. 在形式 I Rubisco 复合物的进化过程中，层状堑壕保持了基本性。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-18 DOI: 10.1038/s44318-024-00311-1

Luca Schulz, Jan Zarzycki, Wieland Steinchen, Georg K A Hochberg, Tobias J Erb

{"title":"Layered entrenchment maintains essentiality in the evolution of Form I Rubisco complexes.","authors":"Luca Schulz, Jan Zarzycki, Wieland Steinchen, Georg K A Hochberg, Tobias J Erb","doi":"10.1038/s44318-024-00311-1","DOIUrl":"10.1038/s44318-024-00311-1","url":null,"abstract":"Protein complexes composed of strictly essential subunits are abundant in nature and often arise through the gradual complexification of ancestral precursor proteins. Essentiality can arise through the accumulation of changes that are tolerated in the complex state but would be deleterious for the standalone complex components. While this theoretical framework to explain how essentiality arises has been proposed long ago, it is unclear which factors cause essentiality to persist over evolutionary timescales. In this work we show that the central enzyme of photosynthesis, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), can easily start to depend on a newly recruited interaction partner through multiple, genetically distinct mechanisms that affect stability, solubility, and catalysis. We demonstrate that layering multiple mechanisms of essentiality can lead to its persistence, even if any given mechanism reverts. More broadly, our work highlights that new interaction partners can drastically re-shape which substitutions are tolerated in the proteins they are recruited into. This can lead to the evolution of multilayered essentiality through the exploration of areas of sequence space that are only accessible in the complex state.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669701","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

Deciphering the molecular logic of WOX5 function in the root stem cell organizer. 解密WOX5在根干细胞组织器中功能的分子逻辑

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-18 DOI: 10.1038/s44318-024-00302-2

Ning Zhang, Pamela Bitterli, Peter Oluoch, Marita Hermann, Ernst Aichinger, Edwin P Groot, Thomas Laux

{"title":"Deciphering the molecular logic of WOX5 function in the root stem cell organizer.","authors":"Ning Zhang, Pamela Bitterli, Peter Oluoch, Marita Hermann, Ernst Aichinger, Edwin P Groot, Thomas Laux","doi":"10.1038/s44318-024-00302-2","DOIUrl":"10.1038/s44318-024-00302-2","url":null,"abstract":"Plant and animal stem cells receive signals from their surrounding cells to stay undifferentiated. In the Arabidopsis root, the quiescent center (QC) acts as a stem cell organizer, signaling to the neighboring stem cells. WOX5 is a central transcription factor regulating QC function. However, due to the scarcity of QC cells, WOX5 functions in the QC are largely unexplored at a genomic scale. Here, we unveil the transcriptional and epigenetic landscapes of the QC and the role of WOX5 within them. We find that WOX5 functions both as a transcriptional repressor and activator, affecting histone modifications and chromatin accessibility. Our data expand on known WOX5 functions, such as the regulation of differentiation, cell division, and auxin biosynthesis. We also uncover unexpected WOX5-regulated pathways involved in nitrate transport and the regulation of basal expression levels of genes associated with mature root tissues. These data suggest a role for QC cells as reserve stem cells and primed cells for prospective progenitor fates. Taken together, these findings offer insights into the role of WOX5 at the QC and provide a basis for further analyses to advance our understanding of the nature of plant stem cell organizers.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669666","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

Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma. 分化信号通过 GRHL3 在鳞状上皮细胞和鳞状细胞癌中诱导 APOBEC3A 的表达。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-15 DOI: 10.1038/s44318-024-00298-9

Nicola J Smith, Ian Reddin, Paige Policelli, Sunwoo Oh, Nur Zainal, Emma Howes, Benjamin Jenkins, Ian Tracy, Mark Edmond, Benjamin Sharpe, Damian Amendra, Ke Zheng, Nagayasu Egawa, John Doorbar, Anjali Rao, Sangeetha Mahadevan, Michael A Carpenter, Reuben S Harris, Simak Ali, Christopher Hanley, Rémi Buisson, Emma King, Gareth J Thomas, Tim R Fenton

{"title":"Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma.","authors":"Nicola J Smith, Ian Reddin, Paige Policelli, Sunwoo Oh, Nur Zainal, Emma Howes, Benjamin Jenkins, Ian Tracy, Mark Edmond, Benjamin Sharpe, Damian Amendra, Ke Zheng, Nagayasu Egawa, John Doorbar, Anjali Rao, Sangeetha Mahadevan, Michael A Carpenter, Reuben S Harris, Simak Ali, Christopher Hanley, Rémi Buisson, Emma King, Gareth J Thomas, Tim R Fenton","doi":"10.1038/s44318-024-00298-9","DOIUrl":"10.1038/s44318-024-00298-9","url":null,"abstract":"Two APOBEC DNA cytosine deaminase enzymes, APOBEC3A and APOBEC3B, generate somatic mutations in cancer, thereby driving tumour development and drug resistance. Here, we used single-cell RNA sequencing to study APOBEC3A and APOBEC3B expression in healthy and malignant mucosal epithelia, validating key observations with immunohistochemistry, spatial transcriptomics and functional experiments. Whereas APOBEC3B is expressed in keratinocytes entering mitosis, we show that APOBEC3A expression is confined largely to terminally differentiating cells and requires grainyhead-like transcription factor 3 (GRHL3). Thus, in normal tissue, neither deaminase appears to be expressed at high levels during DNA replication, the cell-cycle stage associated with APOBEC-mediated mutagenesis. In contrast, in squamous cell carcinoma we find that, there is expansion of GRHL3expression and activity to a subset of cells undergoing DNA replication and concomitant extension of APOBEC3A expression to proliferating cells. These findings suggest that APOBEC3A may play a functional role during keratinocyte differentiation, and offer a mechanism for acquisition of APOBEC3A mutagenic activity in tumours.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640206","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

Redistribution of PU.1 partner transcription factor RUNX1 binding secures cell survival during leukemogenesis. PU.1伙伴转录因子RUNX1结合的再分布确保了白血病发生过程中细胞的存活。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-14 DOI: 10.1038/s44318-024-00295-y

Alexander Bender, Füsun Boydere, Ashok Kumar Jayavelu, Alessia Tibello, Thorsten König, Hanna Aleth, Gerd Meyer Zu Hörste, Thomas Vogl, Frank Rosenbauer

引用次数: 0

Virion morphology and on-virus spike protein structures of diverse SARS-CoV-2 variants. 多种 SARS-CoV-2 变体的病毒形态和病毒尖峰蛋白结构。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-14 DOI: 10.1038/s44318-024-00303-1

Zunlong Ke, Thomas P Peacock, Jonathan C Brown, Carol M Sheppard, Tristan I Croll, Abhay Kotecha, Daniel H Goldhill, Wendy S Barclay, John A G Briggs

{"title":"Virion morphology and on-virus spike protein structures of diverse SARS-CoV-2 variants.","authors":"Zunlong Ke, Thomas P Peacock, Jonathan C Brown, Carol M Sheppard, Tristan I Croll, Abhay Kotecha, Daniel H Goldhill, Wendy S Barclay, John A G Briggs","doi":"10.1038/s44318-024-00303-1","DOIUrl":"https://doi.org/10.1038/s44318-024-00303-1","url":null,"abstract":"The evolution of SARS-CoV-2 variants with increased fitness has been accompanied by structural changes in the spike (S) proteins, which are the major target for the adaptive immune response. Single-particle cryo-EM analysis of soluble S protein from SARS-CoV-2 variants has revealed this structural adaptation at high resolution. The analysis of S trimers in situ on intact virions has the potential to provide more functionally relevant insights into S structure and virion morphology. Here, we characterized B.1, Alpha, Beta, Gamma, Delta, Kappa, and Mu variants by cryo-electron microscopy and tomography, assessing S cleavage, virion morphology, S incorporation, \"in-situ\" high-resolution S structures, and the range of S conformational states. We found no evidence for adaptive changes in virion morphology, but describe multiple different positions in the S protein where amino acid changes alter local protein structure. Taken together, our data are consistent with a model where amino acid changes at multiple positions from the top to the base of the spike cause structural changes that can modulate the conformational dynamics of the S protein.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631883","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

The transcription factor Dof3.6/OBP3 regulates iron homeostasis in Arabidopsis. 转录因子Dof3.6/OBP3调节拟南芥的铁稳态。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-13 DOI: 10.1038/s44318-024-00304-0

Peipei Xu, Yilin Yang, Zhongtian Zhao, Jinbo Hu, Junyan Xie, Lihua Wang, Huiqiong Zheng, Weiming Cai

{"title":"The transcription factor Dof3.6/OBP3 regulates iron homeostasis in Arabidopsis.","authors":"Peipei Xu, Yilin Yang, Zhongtian Zhao, Jinbo Hu, Junyan Xie, Lihua Wang, Huiqiong Zheng, Weiming Cai","doi":"10.1038/s44318-024-00304-0","DOIUrl":"https://doi.org/10.1038/s44318-024-00304-0","url":null,"abstract":"Iron is an essential element for plants. Iron uptake by plants is highly regulated, but the underlying mechanism is poorly understood. Using a truncated fragment of the iron deficiency-responsive bHLH100 gene promoter, we screened the Arabidopsis transcription factor yeast one-hybrid (Y1H) library and identified the DOF family protein, OBP3, as a crucial component of the iron deficiency-signaling pathway. OBP3 is a transcriptional repressor with a C-terminal activation domain. Its expression is induced by iron deficiency. The transgenic lines that overexpress OBP3 exhibited iron overload and premature leaf necrosis, while the obp3 mutant was less tolerant of iron deficiency. It was discovered that OBP3 directly targets the Ib subgroup of bHLH gene promoters. OBP3 interacts with the bHLH transcription factor ILR3 (IAA-LEUCINE RESISTANT3), and their interaction enhances the DNA-binding ability and transcriptional promoting activity of OBP3, resulting in the positive regulation of iron deficiency-response genes. In addition, the E3 Ligase BRUTUS facilitates 26S proteasome-mediated degradation of OBP3 protein to prevent excessive iron uptake in plants. In conclusion, our research emphasizes the vital role of OBP3 in regulating plant iron homeostasis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631882","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

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