The EMBO Journal最新文献

SLC13A2 promotes hepatocyte metabolic remodeling and liver regeneration by enhancing de novo cholesterol biosynthesis. SLC13A2通过增强新生胆固醇生物合成促进肝细胞代谢重塑和肝脏再生。

The EMBO Journal Pub Date : 2025-01-17 DOI: 10.1038/s44318-025-00362-y

Li Shi,Hao Chen,Yuxin Zhang,Donghao An,Mengyao Qin,Wanting Yu,Bin Wen,Dandan He,Haiping Hao,Jing Xiong

{"title":"SLC13A2 promotes hepatocyte metabolic remodeling and liver regeneration by enhancing de novo cholesterol biosynthesis.","authors":"Li Shi,Hao Chen,Yuxin Zhang,Donghao An,Mengyao Qin,Wanting Yu,Bin Wen,Dandan He,Haiping Hao,Jing Xiong","doi":"10.1038/s44318-025-00362-y","DOIUrl":"https://doi.org/10.1038/s44318-025-00362-y","url":null,"abstract":"Metabolic requirements of dividing hepatocytes are prerequisite for liver regeneration after injury. In contrast to transcriptional dynamics during liver repair, its metabolic dependencies remain poorly defined. Here, we screened metabolic genes differentially regulated during liver regeneration, and report that SLC13A2, a transporter for TCA cycle intermediates, is decreased in rapid response to partial hepatectomy in mice and recovered along restoration of liver mass and function. Liver-specific overexpression or depletion of SLC13A2 promoted or attenuated liver regeneration, respectively. SLC13A2 increased cleavage of SREBP2, and expression of cholesterol metabolism genes, including LDLR and HMGCR. Mechanistically, SLC13A2 promotes import of citrate into hepatocytes, serving as building block for ACLY-dependent acetyl-CoA formation and de novo synthesis of cholesterol. In line, the pre-administration of the HMGCR inhibitor lovastatin abolished SLC13A2-mediated liver regeneration. Similarly, ACLY inhibition suppressed SLC13A2-promoted cholesterol synthesis for hepatocellular proliferation and liver regeneration in vivo. In sum, this study demonstrates that citrate transported by SLC13A2 acts as an intermediate metabolite to restore the metabolic homeostasis during liver regeneration, suggesting SLC13A2 as a potential drug target after liver damage.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The microcephaly-associated transcriptional regulator AUTS2 cooperates with Polycomb complex PRC2 to produce upper-layer neurons in mice. 小头症相关转录调节因子AUTS2与Polycomb复合体PRC2在小鼠中协同产生上层神经元。

The EMBO Journal Pub Date : 2025-01-15 DOI: 10.1038/s44318-024-00343-7

Kazumi Shimaoka,Kei Hori,Satoshi Miyashita,Yukiko U Inoue,Nao K N Tabe,Asami Sakamoto,Ikuko Hasegawa,Kayo Nishitani,Kunihiko Yamashiro,Saki F Egusa,Shoji Tatsumoto,Yasuhiro Go,Manabu Abe,Kenji Sakimura,Takayoshi Inoue,Takuya Imamura,Mikio Hoshino

{"title":"The microcephaly-associated transcriptional regulator AUTS2 cooperates with Polycomb complex PRC2 to produce upper-layer neurons in mice.","authors":"Kazumi Shimaoka,Kei Hori,Satoshi Miyashita,Yukiko U Inoue,Nao K N Tabe,Asami Sakamoto,Ikuko Hasegawa,Kayo Nishitani,Kunihiko Yamashiro,Saki F Egusa,Shoji Tatsumoto,Yasuhiro Go,Manabu Abe,Kenji Sakimura,Takayoshi Inoue,Takuya Imamura,Mikio Hoshino","doi":"10.1038/s44318-024-00343-7","DOIUrl":"https://doi.org/10.1038/s44318-024-00343-7","url":null,"abstract":"AUTS2 syndrome is characterized by intellectual disability and microcephaly, and is often associated with autism spectrum disorder, but the underlying mechanisms, particularly concerning microcephaly, remain incompletely understood. Here, we analyze mice mutated for the transcriptional regulator AUTS2, which recapitulate microcephaly. Their brains exhibit reduced division of intermediate progenitor cells (IPCs), leading to fewer neurons and decreased thickness in the upper-layer cortex. Increased expression of the AUTS2 transcriptional target Robo1 in the mutant animals suppresses IPC division, and transcriptomic and chromatin profiling shows that AUTS2 primarily represses transcription of genes like Robo1 in IPCs. Regions around the transcriptional start sites of AUTS2 target genes are enriched for the repressive histone modification H3K27me3, which is reduced in Auts2 mutants. Furthermore, we find that AUTS2 interacts with Polycomb complex PRC2, with which it cooperates to promote IPC division. These findings shed light on the microcephaly phenotype observed in the AUTS2 syndrome.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"119 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Recruitment of autophagy initiator TAX1BP1 advances aggrephagy from cargo collection to sequestration. 自噬启动子 TAX1BP1 的招募将凝集作用从货物收集推进到螯合。

The EMBO Journal Pub Date : 2024-10-24 DOI: 10.1038/s44318-024-00280-5

Bernd Bauer,Jonas Idinger,Martina Schuschnig,Luca Ferrari,Sascha Martens

{"title":"Recruitment of autophagy initiator TAX1BP1 advances aggrephagy from cargo collection to sequestration.","authors":"Bernd Bauer,Jonas Idinger,Martina Schuschnig,Luca Ferrari,Sascha Martens","doi":"10.1038/s44318-024-00280-5","DOIUrl":"https://doi.org/10.1038/s44318-024-00280-5","url":null,"abstract":"Autophagy mediates the degradation of harmful material within lysosomes. In aggrephagy, the pathway mediating the degradation of aggregated, ubiquitinated proteins, this cargo material is collected in larger condensates prior to its sequestration by autophagosomes. In this process, the autophagic cargo receptors SQSTM1/p62 and NBR1 drive cargo condensation, while TAX1BP1, which binds to NBR1, recruits the autophagy machinery to facilitate autophagosome biogenesis at the condensates. The mechanistic basis for the TAX1BP1-mediated switch from cargo collection to its sequestration is unclear. Here we show that TAX1BP1 is not a constitutive component of the condensates. Its recruitment correlates with the induction of autophagosome biogenesis. TAX1BP1 is sufficient to recruit the TBK1 kinase via the SINTBAD adapter. We define the NBR1-TAX1BP1-binding site, which is adjacent to the GABARAP/LC3 interaction site, and demonstrate that the recruitment of TAX1BP1 to cargo mimetics can be enhanced by an increased ubiquitin load. Our study suggests that autophagosome biogenesis is initiated once sufficient cargo is collected in the condensates.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cyclophilin D plays a critical role in the survival of senescent cells. 环纤蛋白 D 在衰老细胞的存活过程中发挥着关键作用。

The EMBO Journal Pub Date : 2024-10-24 DOI: 10.1038/s44318-024-00259-2

Margherita Protasoni,Vanessa López-Polo,Camille Stephan-Otto Attolini,Julian Brandariz,Nicolas Herranz,Joaquin Mateo,Sergio Ruiz,Oscar Fernandez-Capetillo,Marta Kovatcheva,Manuel Serrano

{"title":"Cyclophilin D plays a critical role in the survival of senescent cells.","authors":"Margherita Protasoni,Vanessa López-Polo,Camille Stephan-Otto Attolini,Julian Brandariz,Nicolas Herranz,Joaquin Mateo,Sergio Ruiz,Oscar Fernandez-Capetillo,Marta Kovatcheva,Manuel Serrano","doi":"10.1038/s44318-024-00259-2","DOIUrl":"https://doi.org/10.1038/s44318-024-00259-2","url":null,"abstract":"Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca2+ and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel LRR receptor-like kinase BRAK reciprocally phosphorylates PSKR1 to enhance growth and defense in tomato. 一种新型 LRR 受体样激酶 BRAK 相互磷酸化 PSKR1，以增强番茄的生长和防御能力。

The EMBO Journal Pub Date : 2024-10-24 DOI: 10.1038/s44318-024-00278-z

Shuting Ding,Shuxian Feng,Shibo Zhou,Zhengran Zhao,Xiao Liang,Jiao Wang,Ruishuang Fu,Rui Deng,Tao Zhang,Shujun Shao,Jingquan Yu,Christine H Foyer,Kai Shi

{"title":"A novel LRR receptor-like kinase BRAK reciprocally phosphorylates PSKR1 to enhance growth and defense in tomato.","authors":"Shuting Ding,Shuxian Feng,Shibo Zhou,Zhengran Zhao,Xiao Liang,Jiao Wang,Ruishuang Fu,Rui Deng,Tao Zhang,Shujun Shao,Jingquan Yu,Christine H Foyer,Kai Shi","doi":"10.1038/s44318-024-00278-z","DOIUrl":"https://doi.org/10.1038/s44318-024-00278-z","url":null,"abstract":"Plants face constant threats from pathogens, leading to growth retardation and crop failure. Cell-surface leucine-rich repeat receptor-like kinases (LRR-RLKs) are crucial for plant growth and defense, but their specific functions, especially to necrotrophic fungal pathogens, are largely unknown. Here, we identified an LRR-RLK (Solyc06g069650) in tomato (Solanum lycopersicum) induced by the economically important necrotrophic pathogen Botrytis cinerea. Knocking out this LRR-RLK reduced plant growth and increased sensitivity to B. cinerea, while its overexpression led to enhanced growth, yield, and resistance. We named this LRR-RLK as BRAK (B. cinerea resistance-associated kinase). Yeast two-hybrid screen revealed BRAK interacted with phytosulfokine (PSK) receptor PSKR1. PSK-induced growth and defense responses were impaired in pskr1, brak single and double mutants, as well as in PSKR1-overexpressing plants with silenced BRAK. Moreover, BRAK and PSKR1 phosphorylated each other, promoting their interaction as detected by microscale thermophoresis. This reciprocal phosphorylation was crucial for growth and resistance. In summary, we identified BRAK as a novel regulator of seedling growth, fruit yield and defense, offering new possibilities for developing fungal disease-tolerant plants without compromising yield.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tight junction protein LSR is a host defense factor against SARS-CoV-2 infection in the small intestine. 紧密连接蛋白 LSR 是小肠中抵抗 SARS-CoV-2 感染的宿主防御因子。

The EMBO Journal Pub Date : 2024-10-23 DOI: 10.1038/s44318-024-00281-4

Yanan An,Chao Wang,Ziqi Wang,Feng Kong,Hao Liu,Min Jiang,Ti Liu,Shu Zhang,Kaige Du,Liang Yin,Peng Jiao,Ying Li,Baozhen Fan,Chengjun Zhou,Mingxia Wang,Hui Sun,Jie Lei,Shengtian Zhao,Yongfeng Gong

{"title":"Tight junction protein LSR is a host defense factor against SARS-CoV-2 infection in the small intestine.","authors":"Yanan An,Chao Wang,Ziqi Wang,Feng Kong,Hao Liu,Min Jiang,Ti Liu,Shu Zhang,Kaige Du,Liang Yin,Peng Jiao,Ying Li,Baozhen Fan,Chengjun Zhou,Mingxia Wang,Hui Sun,Jie Lei,Shengtian Zhao,Yongfeng Gong","doi":"10.1038/s44318-024-00281-4","DOIUrl":"https://doi.org/10.1038/s44318-024-00281-4","url":null,"abstract":"The identification of host factors with antiviral potential is important for developing effective prevention and therapeutic strategies against SARS-CoV-2 infection. Here, by using immortalized cell lines, intestinal organoids, ex vivo intestinal tissues and humanized ACE2 mouse model as proof-of-principle systems, we have identified lipolysis-stimulated lipoprotein receptor (LSR) as a crucial host defense factor against SARS-CoV-2 infection in the small intestine. Loss of endogenous LSR enhances ACE2-dependent infection by SARS-CoV-2 Spike (S) protein-pseudotyped virus and authentic SARS-CoV-2 virus, and exogenous administration of LSR protects against viral infection. Mechanistically, LSR interacts with ACE2 both in cis and in trans, preventing its binding to S protein, and thus inhibiting viral entry and S protein-mediated cell-cell fusion. Finally, a small LSR-derived peptide blocks S protein binding to the ACE2 receptor in vitro. These results identify both a previously unknown function for LSR in antiviral host defense against SARS-CoV-2, with potential implications for peptide-based pan-variant therapeutic interventions.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease. 线粒体长非编码 RNA lncMtloop 可调控线粒体转录并抑制阿尔茨海默病。

The EMBO Journal Pub Date : 2024-10-18 DOI: 10.1038/s44318-024-00270-7

Wandi Xiong,Kaiyu Xu,Jacquelyne Ka-Li Sun,Siling Liu,Baizhen Zhao,Jie Shi,Karl Herrup,Hei-Man Chow,Lin Lu,Jiali Li

{"title":"The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease.","authors":"Wandi Xiong,Kaiyu Xu,Jacquelyne Ka-Li Sun,Siling Liu,Baizhen Zhao,Jie Shi,Karl Herrup,Hei-Man Chow,Lin Lu,Jiali Li","doi":"10.1038/s44318-024-00270-7","DOIUrl":"https://doi.org/10.1038/s44318-024-00270-7","url":null,"abstract":"Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer's disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3'UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer's pathogenesis.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"233 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural insights into the mechanism of DNA branch migration during homologous recombination in bacteria. 从结构上洞察细菌同源重组过程中 DNA 分支迁移的机制。

The EMBO Journal Pub Date : 2024-10-18 DOI: 10.1038/s44318-024-00264-5

Leonardo Talachia Rosa,Émeline Vernhes,Anne-Lise Soulet,Patrice Polard,Rémi Fronzes

引用次数: 0

An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease. Orai1功能获得性肾小管聚集性肌病小鼠模型表现出人类疾病的主要特征。

The EMBO Journal Pub Date : 2024-10-17 DOI: 10.1038/s44318-024-00273-4

Nan Zhao,Antonio Michelucci,Laura Pietrangelo,Sundeep Malik,Linda Groom,Jennifer Leigh,Thomas N O'Connor,Takahiro Takano,Paul D Kingsley,James Palis,Simona Boncompagni,Feliciano Protasi,Robert T Dirksen

{"title":"An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease.","authors":"Nan Zhao,Antonio Michelucci,Laura Pietrangelo,Sundeep Malik,Linda Groom,Jennifer Leigh,Thomas N O'Connor,Takahiro Takano,Paul D Kingsley,James Palis,Simona Boncompagni,Feliciano Protasi,Robert T Dirksen","doi":"10.1038/s44318-024-00273-4","DOIUrl":"https://doi.org/10.1038/s44318-024-00273-4","url":null,"abstract":"Tubular aggregate myopathy (TAM) is a heritable myopathy primarily characterized by progressive muscle weakness, elevated levels of creatine kinase (CK), hypocalcemia, exercise intolerance, and the presence of tubular aggregates (TAs). Here, we generated a knock-in mouse model based on a human gain-of-function mutation which results in a severe, early-onset form of TAM, by inducing a glycine-to-serine point mutation in the ORAI1 pore (Orai1G100S/+ or GS mice). By 8 months of age, GS mice exhibited significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust TA presence. Unexpectedly, constitutive Ca2+ entry in mutant mice was observed in muscle only during early development and was abolished in adult skeletal muscle, partly due to reduced ORAI1 expression. Consistent with proteomic results, significant mitochondrial damage and dysfunction was observed in skeletal muscle of GS mice. Thus, GS mice represent a powerful model for investigation of the pathophysiological mechanisms that underlie key TAM symptoms, as well as those compensatory responses that limit the damaging effects of uncontrolled ORAI1-mediated Ca2+ influx.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"106 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure of a step II catalytically activated spliceosome from Chlamydomonas reinhardtii. 莱茵衣藻第二步催化活化剪接体的结构。

The EMBO Journal Pub Date : 2024-10-16 DOI: 10.1038/s44318-024-00274-3

Yichen Lu,Ke Liang,Xiechao Zhan

引用次数: 0