EMBO Journal最新文献_第9页

NADH-bound AIF activates the mitochondrial CHCHD4/MIA40 chaperone by a substrate-mimicry mechanism. nadh结合的AIF通过底物模拟机制激活线粒体CHCHD4/MIA40伴侣。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-13 DOI: 10.1038/s44318-024-00360-6

Chris A Brosey, Runze Shen, John A Tainer

{"title":"NADH-bound AIF activates the mitochondrial CHCHD4/MIA40 chaperone by a substrate-mimicry mechanism.","authors":"Chris A Brosey, Runze Shen, John A Tainer","doi":"10.1038/s44318-024-00360-6","DOIUrl":"10.1038/s44318-024-00360-6","url":null,"abstract":"Mitochondrial metabolism requires the chaperoned import of disulfide-stabilized proteins via CHCHD4/MIA40 and its enigmatic interaction with oxidoreductase Apoptosis-inducing factor (AIF). By crystallizing human CHCHD4's AIF-interaction domain with an activated AIF dimer, we uncover how NADH allosterically configures AIF to anchor CHCHD4's β-hairpin and histidine-helix motifs to the inner mitochondrial membrane. The structure further reveals a similarity between the AIF-interaction domain and recognition sequences of CHCHD4 substrates. NMR and X-ray scattering (SAXS) solution measurements, mutational analyses, and biochemistry show that the substrate-mimicking AIF-interaction domain shields CHCHD4's redox-sensitive active site. Disrupting this shield critically activates CHCHD4 substrate affinity and chaperone activity. Regulatory-domain sequestration by NADH-activated AIF directly stimulates chaperone binding and folding, revealing how AIF mediates CHCHD4 mitochondrial import. These results establish AIF as an integral component of the metazoan disulfide relay and point to NADH-activated dimeric AIF as an organizational import center for CHCHD4 and its substrates. Importantly, AIF regulation of CHCHD4 directly links AIF's cellular NAD(H) sensing to CHCHD4 chaperone function, suggesting a mechanism to balance tissue-specific oxidative phosphorylation (OXPHOS) capacity with NADH availability.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1220-1248"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980583","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

E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A. E3泛素连接酶CHIP通过多泛素化PDE9A促进cAMP和cGMP信号串导。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-13 DOI: 10.1038/s44318-024-00351-7

Xiaoyan Hao, Zhengwei Hu, Mengjie Li, Shuo Zhang, Mibo Tang, Chenwei Hao, Shasha Qi, Yuanyuan Liang, Michael F Almeida, Kaitlan Smith, Chunyan Zuo, Yanmei Feng, Mengnan Guo, Dongrui Ma, Shuangjie Li, Zhiyun Wang, Yuemeng Sun, Zhifen Deng, Chengyuan Mao, Zongping Xia, Yong Jiang, Yanxia Gao, Yuming Xu, Jonathan C Schisler, Changhe Shi

{"title":"E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.","authors":"Xiaoyan Hao, Zhengwei Hu, Mengjie Li, Shuo Zhang, Mibo Tang, Chenwei Hao, Shasha Qi, Yuanyuan Liang, Michael F Almeida, Kaitlan Smith, Chunyan Zuo, Yanmei Feng, Mengnan Guo, Dongrui Ma, Shuangjie Li, Zhiyun Wang, Yuemeng Sun, Zhifen Deng, Chengyuan Mao, Zongping Xia, Yong Jiang, Yanxia Gao, Yuming Xu, Jonathan C Schisler, Changhe Shi","doi":"10.1038/s44318-024-00351-7","DOIUrl":"10.1038/s44318-024-00351-7","url":null,"abstract":"The carboxyl terminus of Hsc70-interacting protein (CHIP) is pivotal for managing misfolded and aggregated proteins via chaperone networks and degradation pathways. In a preclinical rodent model of CHIP-related ataxia, we observed that CHIP mutations lead to increased levels of phosphodiesterase 9A (PDE9A), whose role in this context remains poorly understood. Here, we investigated the molecular mechanisms underlying the role of PDE9A in CHIP-related ataxia and demonstrated that CHIP binds to PDE9A, facilitating its polyubiquitination and autophagic degradation. Conversely, dysfunctional CHIP disrupts this process, resulting in PDE9A accumulation, increased cGMP hydrolysis, and impaired PKG phosphorylation of CHIP at serine 19. This cascade further amplifies PDE9A accumulation, ultimately disrupting mitophagy and triggering neuronal apoptosis. Elevated PKA levels inhibit PDE9A degradation, further exacerbating this neuronal dysfunction. Notably, pharmacological inhibition of PDE9A via Bay 73-6691 or virus-mediated CHIP expression restored the balance of cGMP/cAMP signalling. These interventions protect against cerebellar neuropathologies, particularly Purkinje neuron mitophagy dysfunction. Thus, PDE9A upregulation considerably exacerbates ataxia associated with CHIP mutations, and targeting the interaction between PDE9A and CHIP is an innovative therapeutic strategy for CHIP-related ataxia.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1249-1273"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980578","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

Molecular mechanism of condensin I activation by KIF4A. KIF4A活化凝缩素I的分子机制。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2024-12-17 DOI: 10.1038/s44318-024-00340-w

Erin E Cutts, Damla Tetiker, Eugene Kim, Luis Aragon

引用次数: 0

The Asgard archaeal ESCRT-III system forms helical filaments and remodels eukaryotic-like membranes. 阿斯加德古菌ESCRT-III系统形成螺旋细丝并重塑真核样膜。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-03 DOI: 10.1038/s44318-024-00346-4

Nataly Melnikov, Benedikt Junglas, Gal Halbi, Dikla Nachmias, Erez Zerbib, Noam Gueta, Alexander Upcher, Ran Zalk, Carsten Sachse, Anne Bernheim-Groswasser, Natalie Elia

{"title":"The Asgard archaeal ESCRT-III system forms helical filaments and remodels eukaryotic-like membranes.","authors":"Nataly Melnikov, Benedikt Junglas, Gal Halbi, Dikla Nachmias, Erez Zerbib, Noam Gueta, Alexander Upcher, Ran Zalk, Carsten Sachse, Anne Bernheim-Groswasser, Natalie Elia","doi":"10.1038/s44318-024-00346-4","DOIUrl":"10.1038/s44318-024-00346-4","url":null,"abstract":"The ESCRT machinery mediates membrane remodeling in numerous processes in cells including cell division and nuclear membrane reformation. The identification of ESCRT homologs in Asgard archaea, currently considered the closest prokaryotic relative of eukaryotes, implies a role for ESCRTs in the membrane remodeling processes that occurred during eukaryogenesis. Yet, the function of these distant ESCRT homologs is mostly unresolved. Here we show that Asgard ESCRT-III proteins of the Lokiarcheota self-assemble into helical filaments, a hallmark of the ESCRT system. We determined the cryo-EM structure of the filaments at 3.6 Å resolution and found that they share features of bacterial and eukaryotic ESCRT-III assemblies. Markedly, Asgard ESCRT-III filaments bound and deformed eukaryotic-like membrane vesicles. Oligonucleotides facilitated the assembly of ESCRT-III filaments and tuned the extent of membrane remodeling. The ability of Asgard archaeal ESCRTs to remodel eukaryotic-like membranes, which are fundamentally different from archaeal membranes, and the structural properties of these proteins places them at the junction between prokaryotes and eukaryotes.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"665-681"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928590","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

Cohesin positions the epigenetic reader Phf2 within the genome. 内聚蛋白定位表观遗传解读器Phf2在基因组中的位置。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44318-024-00348-2

Wen Tang, Lorenzo Costantino, Roman Stocsits, Gordana Wutz, Rene Ladurner, Otto Hudecz, Karl Mechtler, Jan-Michael Peters

{"title":"Cohesin positions the epigenetic reader Phf2 within the genome.","authors":"Wen Tang, Lorenzo Costantino, Roman Stocsits, Gordana Wutz, Rene Ladurner, Otto Hudecz, Karl Mechtler, Jan-Michael Peters","doi":"10.1038/s44318-024-00348-2","DOIUrl":"10.1038/s44318-024-00348-2","url":null,"abstract":"Genomic DNA is assembled into chromatin by histones, and extruded into loops by cohesin. These mechanisms control important genomic functions, but whether histones and cohesin cooperate in genome regulation is poorly understood. Here we identify Phf2, a member of the Jumonji-C family of histone demethylases, as a cohesin-interacting protein. Phf2 binds to H3K4me3 nucleosomes at active transcription start sites (TSSs), but also co-localizes with cohesin. Cohesin depletion reduces Phf2 binding at sites lacking H3K4me3, and depletion of Wapl and CTCF re-positions Phf2 together with cohesin in the genome, resulting in the accumulation of both proteins in chromosomal regions called vermicelli and cohesin islands. Conversely, Phf2 depletion reduces cohesin binding at TSSs lacking CTCF and decreases the number of short cohesin loops, while increasing the length of heterochromatic B compartments. These results suggest that Phf2 is an 'epigenetic reader', which is translocated through the genome by cohesin-mediated DNA loop extrusion, and which recruits cohesin to active TSSs and limits the size of B compartments. These findings reveal an unexpected degree of cooperativity between epigenetic and architectural mechanisms of eukaryotic genome regulation.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"736-766"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923905","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

A bipartite bacterial virulence factor targets the complement system and neutrophil activation. 两部分细菌毒力因子的目标是补体系统和中性粒细胞活化。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-03 DOI: 10.1038/s44318-024-00342-8

Kurni Kurniyati, Nicholas D Clark, Hongxia Wang, Yijie Deng, Ching Wooen Sze, Michelle B Visser, Michael G Malkowski, Chunhao Li

{"title":"A bipartite bacterial virulence factor targets the complement system and neutrophil activation.","authors":"Kurni Kurniyati, Nicholas D Clark, Hongxia Wang, Yijie Deng, Ching Wooen Sze, Michelle B Visser, Michael G Malkowski, Chunhao Li","doi":"10.1038/s44318-024-00342-8","DOIUrl":"10.1038/s44318-024-00342-8","url":null,"abstract":"The complement system and neutrophils constitute the two main pillars of the host innate immune defense against infection by bacterial pathogens. Here, we identify T-Mac, a novel virulence factor of the periodontal pathogen Treponema denticola that allows bacteria to evade both defense systems. We show that T-Mac is expressed as a pre-protein that is cleaved into two functional units. The N-terminal fragment has two immunoglobulin-like domains and binds with high affinity to the major neutrophil chemokine receptors FPR1 and CXCR1, blocking N-formyl-Met-Leu-Phe- and IL-8-induced neutrophil chemotaxis and activation. The C-terminal fragment functions as a cysteine protease with a unique proteolytic activity and structure, which degrades several components of the complement system, such as C3 and C3b. Murine infection studies further reveal a critical T-Mac role in tissue damage and inflammation caused by bacterial infection. Collectively, these results disclose a novel innate immunity-evasion strategy, and open avenues for investigating the role of cysteine proteases and immunoglobulin-like domains of gram-positive and -negative bacterial pathogens.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1154-1184"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928579","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

An ultra-conserved poison exon in the Tra2b gene encoding a splicing activator is essential for male fertility and meiotic cell division. 编码剪接激活子的Tra2b基因中的一个超保守毒性外显子对男性生育和减数分裂细胞分裂至关重要。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44318-024-00344-6

Caroline Dalgliesh, Saad Aldalaqan, Christian Atallah, Andrew Best, Emma Scott, Ingrid Ehrmann, George Merces, Joel Mannion, Barbora Badurova, Raveen Sandher, Ylva Illing, Brunhilde Wirth, Sara Wells, Gemma Codner, Lydia Teboul, Graham R Smith, Ann Hedley, Mary Herbert, Dirk G de Rooij, Colin Miles, Louise N Reynard, David J Elliott

{"title":"An ultra-conserved poison exon in the Tra2b gene encoding a splicing activator is essential for male fertility and meiotic cell division.","authors":"Caroline Dalgliesh, Saad Aldalaqan, Christian Atallah, Andrew Best, Emma Scott, Ingrid Ehrmann, George Merces, Joel Mannion, Barbora Badurova, Raveen Sandher, Ylva Illing, Brunhilde Wirth, Sara Wells, Gemma Codner, Lydia Teboul, Graham R Smith, Ann Hedley, Mary Herbert, Dirk G de Rooij, Colin Miles, Louise N Reynard, David J Elliott","doi":"10.1038/s44318-024-00344-6","DOIUrl":"10.1038/s44318-024-00344-6","url":null,"abstract":"The cellular concentrations of splicing factors (SFs) are critical for controlling alternative splicing. Most serine and arginine-enriched (SR) protein SFs regulate their own concentration via a homeostatic feedback mechanism that involves regulation of inclusion of non-coding 'poison exons' (PEs) that target transcripts for nonsense-mediated decay. The importance of SR protein PE splicing during animal development is largely unknown despite PE ultra-conservation across animal genomes. To address this, we used mouse genetics to disrupt an ultra-conserved PE in the Tra2b gene encoding the SR protein Tra2β. Focussing on germ cell development, we found that Tra2b PE deletion causes azoospermia due to catastrophic cell death during meiotic prophase. Failure to proceed through meiosis was associated with increased Tra2b expression sufficient to drive aberrant Tra2β protein hyper-responsive splice patterns. Although critical for meiotic prophase, Tra2b PE deletion spared earlier mitotically active germ cells, even though these still required Tra2b gene function. Our data indicate that PE splicing control prevents the accumulation of toxic levels of Tra2β protein that are incompatible with meiotic prophase. This unexpected connection with male fertility helps explain Tra2b PE ultra-conservation and indicates the importance of evaluating PE function in animal models.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"877-902"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923904","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

A phosphorylation-regulated NPF transporter determines salt tolerance by mediating chloride uptake in soybean plants. 磷酸化调控的NPF转运体通过介导大豆植物的氯吸收来决定耐盐性。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-03 DOI: 10.1038/s44318-024-00357-1

Yunzhen Wu, Jingya Yuan, Like Shen, Qinxue Li, Zhuomeng Li, Hongwei Cao, Lin Zhu, Dan Liu, Yalu Sun, Qianru Jia, Huatao Chen, Wubin Wang, Jörg Kudla, Wenhua Zhang, Junyi Gai, Qun Zhang

{"title":"A phosphorylation-regulated NPF transporter determines salt tolerance by mediating chloride uptake in soybean plants.","authors":"Yunzhen Wu, Jingya Yuan, Like Shen, Qinxue Li, Zhuomeng Li, Hongwei Cao, Lin Zhu, Dan Liu, Yalu Sun, Qianru Jia, Huatao Chen, Wubin Wang, Jörg Kudla, Wenhua Zhang, Junyi Gai, Qun Zhang","doi":"10.1038/s44318-024-00357-1","DOIUrl":"10.1038/s44318-024-00357-1","url":null,"abstract":"Chloride (Cl-) ions cause major damage to crops in saline soils. Understanding the key factors that influence Cl- uptake and translocation will aid the breeding of more salt-tolerant crops. Here, using genome-wide association study and transcriptomic analysis, we identified a NITRATE TRANSPORTER 1 (NRT1)/PEPTIDE TRANSPORTER family (NPF) protein, GmNPF7.5, as the dominant gene locus influencing Cl- homeostasis in soybean (Glycine max). A natural SNP variation resulted in two haplotypes (GmNPF7.5HapA and GmNPF7.5HapB), which was associated with Cl- content. GmNPF7.5HapA mediated Cl- or nitrate (NO3-) uptake in a pH-dependent manner and exhibited higher permeability for Cl- over NO3-. The suppression of GmNPF7.5HapA expression decreased Cl- accumulation and salt damage in plants, whereas its overexpression showed the opposite effects. The elite haplotype GmNPF7.5HapB diminished Cl- transport activity independently from NO3- permeability, thus enhancing soybean salt tolerance. Furthermore, the protein kinase GmPI4Kγ4 could phosphorylate GmNPF7.5, which repressed Cl- uptake without affecting NO3- permeability. Our findings define a regulatory mechanism for Cl- control under NaCl stress, providing a strategy for the improvement of salt tolerance in soybean plants.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"923-946"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928583","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

A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease. 一个新的人类胎儿肺源性肺泡类器官模型揭示了与间质性肺病相关的表面活性剂蛋白C成熟机制。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-15 DOI: 10.1038/s44318-024-00328-6

Kyungtae Lim, Eimear N Rutherford, Livia Delpiano, Peng He, Weimin Lin, Dawei Sun, Dick J H Van den Boomen, James R Edgar, Jae Hak Bang, Alexander Predeus, Sarah A Teichmann, John C Marioni, Lydia E Matesic, Joo-Hyeon Lee, Paul J Lehner, Stefan J Marciniak, Emma L Rawlins, Jennifer A Dickens

{"title":"A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease.","authors":"Kyungtae Lim, Eimear N Rutherford, Livia Delpiano, Peng He, Weimin Lin, Dawei Sun, Dick J H Van den Boomen, James R Edgar, Jae Hak Bang, Alexander Predeus, Sarah A Teichmann, John C Marioni, Lydia E Matesic, Joo-Hyeon Lee, Paul J Lehner, Stefan J Marciniak, Emma L Rawlins, Jennifer A Dickens","doi":"10.1038/s44318-024-00328-6","DOIUrl":"10.1038/s44318-024-00328-6","url":null,"abstract":"Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary surfactant. AT2 dysfunction underlies many lung diseases, including interstitial lung disease (ILD), in which some inherited forms result from the mislocalization of surfactant protein C (SFTPC) variants. Lung disease modeling and dissection of the underlying mechanisms remain challenging due to complexities in deriving and maintaining human AT2 cells ex vivo. Here, we describe the development of mature, expandable AT2 organoids derived from human fetal lungs which are phenotypically stable, can differentiate into AT1-like cells, and are genetically manipulable. We use these organoids to test key effectors of SFTPC maturation identified in a forward genetic screen including the E3 ligase ITCH, demonstrating that their depletion phenocopies the pathological SFTPC redistribution seen for the SFTPC-I73T variant. In summary, we demonstrate the development of a novel alveolar organoid model and use it to identify effectors of SFTPC maturation necessary for AT2 health.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"639-664"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015689","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

RHEB neddylation by the UBE2F-SAG axis enhances mTORC1 activity and aggravates liver tumorigenesis. UBE2F-SAG轴介导的RHEB类泛素化增强了mTORC1活性，并加剧了肝脏肿瘤的发生。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-06 DOI: 10.1038/s44318-024-00353-5

Fengwu Zhang, Xiufang Xiong, Zhijian Li, Haibo Wang, Weilin Wang, Yongchao Zhao, Yi Sun

{"title":"RHEB neddylation by the UBE2F-SAG axis enhances mTORC1 activity and aggravates liver tumorigenesis.","authors":"Fengwu Zhang, Xiufang Xiong, Zhijian Li, Haibo Wang, Weilin Wang, Yongchao Zhao, Yi Sun","doi":"10.1038/s44318-024-00353-5","DOIUrl":"10.1038/s44318-024-00353-5","url":null,"abstract":"Small GTPase RHEB is a well-known mTORC1 activator, whereas neddylation modifies cullins and non-cullin substrates to regulate their activity, subcellular localization and stability. Whether and how RHEB is subjected to neddylation modification remains unknown. Here, we report that RHEB is a substrate of NEDD8-conjugating E2 enzyme UBE2F. In cell culture, UBE2F depletion inactivates mTORC1, inhibiting cell cycle progression, cell growth and inducing autophagy. Mechanistically, UBE2F cooperates with E3 ligase SAG in neddylation of RHEB at K169 to enhance its lysosome localization and GTP-binding affinity. Furthermore, liver-specific Ube2f knockout attenuates steatosis and tumorigenesis induced by Pten loss in an mTORC1-dependent manner, suggesting a causal role of UBE2F in liver tumorigenesis. Finally, UBE2F expression levels and mTORC1 activity correlate with patient survival in hepatocellular carcinoma. Collectively, our study identifies RHEB as neddylation substrate of the UBE2F-SAG axis, and highlights the UBE2F-SAG axis as a potential target for the treatment of non-alcoholic fatty liver disease and hepatocellular carcinoma.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":"44 4","pages":"1185-1219"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442567","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