Pub Date : 2024-10-31DOI: 10.1038/s44319-024-00301-8
Maria Paglione, Leonardo Restivo, Sarah Zakhia, Arnau Llobet Rosell, Marco Terenzio, Lukas J Neukomm
After injury, severed axons separated from their somas activate programmed axon degeneration, a conserved pathway to initiate their degeneration within a day. Conversely, severed projections deficient in programmed axon degeneration remain morphologically preserved with functional synapses for weeks to months after axotomy. How this synaptic function is sustained remains currently unknown. Here, we show that dNmnat overexpression attenuates programmed axon degeneration in distinct neuronal populations. Severed projections remain morphologically preserved for weeks. When evoked, they elicit a postsynaptic behavior, a readout for preserved synaptic function. We used ribosomal pulldown to isolate the translatome from these projections 1 week after axotomy. Translatome candidates of enriched biological classes identified by transcriptional profiling are validated in a screen using a novel automated system to detect evoked antennal grooming as a proxy for preserved synaptic function. RNAi-mediated knockdown reveals that transcripts of the mTORC1 pathway, a mediator of protein synthesis, and of candidate genes involved in protein ubiquitination and Ca2+ homeostasis are required for preserved synaptic function. Our translatome dataset also uncovers several uncharacterized Drosophila genes associated with human disease. It may offer insights into novel avenues for therapeutic treatments.
{"title":"Local translatome sustains synaptic function in impaired Wallerian degeneration.","authors":"Maria Paglione, Leonardo Restivo, Sarah Zakhia, Arnau Llobet Rosell, Marco Terenzio, Lukas J Neukomm","doi":"10.1038/s44319-024-00301-8","DOIUrl":"https://doi.org/10.1038/s44319-024-00301-8","url":null,"abstract":"<p><p>After injury, severed axons separated from their somas activate programmed axon degeneration, a conserved pathway to initiate their degeneration within a day. Conversely, severed projections deficient in programmed axon degeneration remain morphologically preserved with functional synapses for weeks to months after axotomy. How this synaptic function is sustained remains currently unknown. Here, we show that dNmnat overexpression attenuates programmed axon degeneration in distinct neuronal populations. Severed projections remain morphologically preserved for weeks. When evoked, they elicit a postsynaptic behavior, a readout for preserved synaptic function. We used ribosomal pulldown to isolate the translatome from these projections 1 week after axotomy. Translatome candidates of enriched biological classes identified by transcriptional profiling are validated in a screen using a novel automated system to detect evoked antennal grooming as a proxy for preserved synaptic function. RNAi-mediated knockdown reveals that transcripts of the mTORC1 pathway, a mediator of protein synthesis, and of candidate genes involved in protein ubiquitination and Ca<sup>2+</sup> homeostasis are required for preserved synaptic function. Our translatome dataset also uncovers several uncharacterized Drosophila genes associated with human disease. It may offer insights into novel avenues for therapeutic treatments.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557441","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}
Pub Date : 2024-10-31DOI: 10.1038/s44319-024-00296-2
Mariano Malamud, Gordon D Brown
The ability of myeloid cells to recognize and differentiate endogenous or exogenous ligands rely on the presence of different transmembrane protein receptors. C-type lectin receptors (CLRs), defined by the presence of a conserved structural motif called C-type lectin-like domain (CTLD), are a crucial family of receptors involved in this process, being able to recognize a diverse range of ligands from glycans to proteins or lipids and capable of initiating an immune response. The Dectin-1 and Dectin-2 clusters involve two groups of CLRs, with genes genomically linked within the natural killer cluster of genes in both humans and mice, and all characterized by the presence of a single extracellular CTLD. Fundamental immune cell functions such as antimicrobial effector mechanisms as well as internalization and presentation of antigens are induced and/or regulated through activatory, or inhibitory signalling pathways triggered by these receptors after ligand binding. In this review, we will discuss the most recent concepts regarding expression, ligands, signaling pathways and functions of each member of the Dectin clusters of CLRs, highlighting the importance and diversity of their functions.
{"title":"The Dectin-1 and Dectin-2 clusters: C-type lectin receptors with fundamental roles in immunity.","authors":"Mariano Malamud, Gordon D Brown","doi":"10.1038/s44319-024-00296-2","DOIUrl":"https://doi.org/10.1038/s44319-024-00296-2","url":null,"abstract":"<p><p>The ability of myeloid cells to recognize and differentiate endogenous or exogenous ligands rely on the presence of different transmembrane protein receptors. C-type lectin receptors (CLRs), defined by the presence of a conserved structural motif called C-type lectin-like domain (CTLD), are a crucial family of receptors involved in this process, being able to recognize a diverse range of ligands from glycans to proteins or lipids and capable of initiating an immune response. The Dectin-1 and Dectin-2 clusters involve two groups of CLRs, with genes genomically linked within the natural killer cluster of genes in both humans and mice, and all characterized by the presence of a single extracellular CTLD. Fundamental immune cell functions such as antimicrobial effector mechanisms as well as internalization and presentation of antigens are induced and/or regulated through activatory, or inhibitory signalling pathways triggered by these receptors after ligand binding. In this review, we will discuss the most recent concepts regarding expression, ligands, signaling pathways and functions of each member of the Dectin clusters of CLRs, highlighting the importance and diversity of their functions.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557443","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}
Pub Date : 2024-10-31DOI: 10.1038/s44319-024-00271-x
Jie Li, Wenshan Nan, Xiaoli Huang, Huali Meng, Shue Wang, Yan Zheng, Ying Li, Hui Li, Zhiyue Zhang, Lei Du, Xiao Yin, Hao Wu
Diabetic cardiomyopathy (DC) leads to heart failure, with few effective approaches for its intervention. Eicosapentaenoic acid (EPA) is an essential nutrient that benefits the cardiovascular system, but its effect on DC remains unknown. Here, we report that EPA protects against DC in streptozotocin and high-fat diet-induced diabetic mice, with an emphasis on the reduction of cardiac M1-polarized macrophages. In vitro, EPA abrogates cardiomyocyte injury induced by M1-polarized macrophages, switching macrophage phenotype from M1 to Mox, but not M2, polarization. Moreover, macrophage Mox polarization combats M1-polarized macrophage-induced cardiomyocyte injury. Further, heme oxygenase 1 (HO-1) was identified to maintain the Mox phenotype, mediating EPA suppression of macrophage M1 polarization and the consequential cardiomyocyte injury. Mechanistic studies reveal that G-protein-coupled receptor 120 mediates the upregulation of HO-1 by EPA. Notably, EPA promotes Mox polarization in monocyte-derived macrophages from diabetic patients. The current study provides EPA and macrophage Mox polarization as novel strategies for DC intervention.
糖尿病心肌病(DC)会导致心力衰竭,但几乎没有有效的干预方法。二十碳五烯酸(EPA)是一种有益于心血管系统的必需营养素,但它对糖尿病心肌病的影响仍然未知。在这里,我们报告了 EPA 对链佐菌素和高脂饮食诱导的糖尿病小鼠的直流电有保护作用,重点是减少心脏 M1 极化巨噬细胞。在体外,EPA 可减轻 M1 极化巨噬细胞诱导的心肌细胞损伤,使巨噬细胞表型从 M1 极化转为 Mox 极化,而不是 M2 极化。此外,巨噬细胞的 Mox 极化还能对抗 M1 极化巨噬细胞诱导的心肌细胞损伤。此外,研究还发现血红素加氧酶1(HO-1)能维持Mox表型,介导EPA抑制巨噬细胞M1极化和随之而来的心肌细胞损伤。机理研究显示,G 蛋白偶联受体 120 介导了 EPA 对 HO-1 的上调。值得注意的是,EPA 能促进糖尿病患者单核巨噬细胞的 Mox 极化。目前的研究提供了 EPA 和巨噬细胞 Mox 极化作为直流电干预的新策略。
{"title":"Eicosapentaenoic acid induces macrophage Mox polarization to prevent diabetic cardiomyopathy.","authors":"Jie Li, Wenshan Nan, Xiaoli Huang, Huali Meng, Shue Wang, Yan Zheng, Ying Li, Hui Li, Zhiyue Zhang, Lei Du, Xiao Yin, Hao Wu","doi":"10.1038/s44319-024-00271-x","DOIUrl":"https://doi.org/10.1038/s44319-024-00271-x","url":null,"abstract":"<p><p>Diabetic cardiomyopathy (DC) leads to heart failure, with few effective approaches for its intervention. Eicosapentaenoic acid (EPA) is an essential nutrient that benefits the cardiovascular system, but its effect on DC remains unknown. Here, we report that EPA protects against DC in streptozotocin and high-fat diet-induced diabetic mice, with an emphasis on the reduction of cardiac M1-polarized macrophages. In vitro, EPA abrogates cardiomyocyte injury induced by M1-polarized macrophages, switching macrophage phenotype from M1 to Mox, but not M2, polarization. Moreover, macrophage Mox polarization combats M1-polarized macrophage-induced cardiomyocyte injury. Further, heme oxygenase 1 (HO-1) was identified to maintain the Mox phenotype, mediating EPA suppression of macrophage M1 polarization and the consequential cardiomyocyte injury. Mechanistic studies reveal that G-protein-coupled receptor 120 mediates the upregulation of HO-1 by EPA. Notably, EPA promotes Mox polarization in monocyte-derived macrophages from diabetic patients. The current study provides EPA and macrophage Mox polarization as novel strategies for DC intervention.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557439","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}
Pub Date : 2024-10-28DOI: 10.1038/s44319-024-00297-1
Kamil Filipek, Sandra Blanchet, Eliza Molestak, Monika Zaciura, Colin Chih-Chien Wu, Patrycja Horbowicz-Drożdżal, Przemysław Grela, Mateusz Zalewski, Sebastian Kmiecik, Alan González-Ibarra, Dawid Krokowski, Przemysław Latoch, Agata L Starosta, Mateusz Mołoń, Yutian Shao, Lidia Borkiewicz, Barbara Michalec-Wawiórka, Leszek Wawiórka, Konrad Kubiński, Katarzyna Socała, Piotr Wlaź, Kyle W Cunningham, Rachel Green, Marina V Rodnina, Marek Tchórzewski
Ribosomal action is facilitated by the orchestrated work of trans-acting factors and ribosomal elements, which are subject to regulatory events, often involving phosphorylation. One such element is the ribosomal P-stalk, which plays a dual function: it activates translational GTPases, which support basic ribosomal functions, and interacts with the Gcn2 kinase, linking the ribosomes to the ISR pathway. We show that P-stalk proteins, which form a pentamer, exist in the cell exclusively in a phosphorylated state at five C-terminal domains (CTDs), ensuring optimal translation (speed and accuracy) and may play a role in the timely regulation of the Gcn2-dependent stress response. Phosphorylation of the CTD induces a structural transition from a collapsed to a coil-like structure, and the CTD gains conformational freedom, allowing specific but transient binding to various protein partners, optimizing the ribosome action. The report reveals a unique feature of the P-stalk proteins, indicating that, unlike most ribosomal proteins, which are regulated by phosphorylation in an on/off manner, the P-stalk proteins exist in a constantly phosphorylated state, which optimizes their interaction with auxiliary factors.
{"title":"Phosphorylation of P-stalk proteins defines the ribosomal state for interaction with auxiliary protein factors.","authors":"Kamil Filipek, Sandra Blanchet, Eliza Molestak, Monika Zaciura, Colin Chih-Chien Wu, Patrycja Horbowicz-Drożdżal, Przemysław Grela, Mateusz Zalewski, Sebastian Kmiecik, Alan González-Ibarra, Dawid Krokowski, Przemysław Latoch, Agata L Starosta, Mateusz Mołoń, Yutian Shao, Lidia Borkiewicz, Barbara Michalec-Wawiórka, Leszek Wawiórka, Konrad Kubiński, Katarzyna Socała, Piotr Wlaź, Kyle W Cunningham, Rachel Green, Marina V Rodnina, Marek Tchórzewski","doi":"10.1038/s44319-024-00297-1","DOIUrl":"10.1038/s44319-024-00297-1","url":null,"abstract":"<p><p>Ribosomal action is facilitated by the orchestrated work of trans-acting factors and ribosomal elements, which are subject to regulatory events, often involving phosphorylation. One such element is the ribosomal P-stalk, which plays a dual function: it activates translational GTPases, which support basic ribosomal functions, and interacts with the Gcn2 kinase, linking the ribosomes to the ISR pathway. We show that P-stalk proteins, which form a pentamer, exist in the cell exclusively in a phosphorylated state at five C-terminal domains (CTDs), ensuring optimal translation (speed and accuracy) and may play a role in the timely regulation of the Gcn2-dependent stress response. Phosphorylation of the CTD induces a structural transition from a collapsed to a coil-like structure, and the CTD gains conformational freedom, allowing specific but transient binding to various protein partners, optimizing the ribosome action. The report reveals a unique feature of the P-stalk proteins, indicating that, unlike most ribosomal proteins, which are regulated by phosphorylation in an on/off manner, the P-stalk proteins exist in a constantly phosphorylated state, which optimizes their interaction with auxiliary factors.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521373","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}
Pub Date : 2024-10-28DOI: 10.1038/s44319-024-00295-3
Sara Salgado, Patricia L Abreu, Beatriz Moleirinho, Daniela S Guedes, Lee Larcombe, Claus M Azzalin
Cancer cells with an activated Alternative Lengthening of Telomeres (ALT) mechanism elongate telomeres via homology-directed repair. Sustained telomeric replication stress is an essential trigger of ALT activity; however, it can lead to cell death if not properly restricted. By analyzing publicly available data from genome-wide CRISPR KO screenings, we have identified the multifunctional protein PC4 as a novel factor essential for ALT cell viability. Depletion of PC4 results in rapid ALT cell death, while telomerase-positive cells show minimal effects. PC4 depletion induces replication stress and telomere fragility primarily in ALT cells, and increases ALT activity. PC4 binds to telomeric DNA in cells, and its binding can be enhanced by telomeric replication stress. Finally, a mutant PC4 with partly impaired single stranded DNA binding activity is capable to localize to telomeres and suppress ALT activity and telomeric replication stress. We propose that PC4 supports ALT cell viability, at least partly, by averting telomere dysfunction. Further studies of PC4 interactions at ALT telomeres may hold promise for innovative therapies to eradicate ALT cancers.
激活了端粒替代性延长(ALT)机制的癌细胞会通过同源定向修复来延长端粒。持续的端粒复制压力是 ALT 活性的重要触发因素;但是,如果不加以适当限制,它可能会导致细胞死亡。通过分析从全基因组 CRISPR KO 筛选中公开获得的数据,我们发现多功能蛋白 PC4 是 ALT 细胞存活所必需的新型因子。消耗 PC4 会导致 ALT 细胞快速死亡,而端粒酶阳性细胞受到的影响最小。PC4 的耗竭主要会诱导 ALT 细胞的复制压力和端粒脆性,并增加 ALT 的活性。PC4 可与细胞中的端粒 DNA 结合,端粒复制压力可增强其结合力。最后,单链DNA结合活性部分受损的突变体PC4能够定位到端粒并抑制ALT活性和端粒复制压力。我们认为,PC4 至少部分地通过避免端粒功能障碍来支持 ALT 细胞的活力。进一步研究PC4在ALT端粒上的相互作用可能会为根除ALT癌症的创新疗法带来希望。
{"title":"Human PC4 supports telomere stability and viability in cells utilizing the alternative lengthening of telomeres mechanism.","authors":"Sara Salgado, Patricia L Abreu, Beatriz Moleirinho, Daniela S Guedes, Lee Larcombe, Claus M Azzalin","doi":"10.1038/s44319-024-00295-3","DOIUrl":"https://doi.org/10.1038/s44319-024-00295-3","url":null,"abstract":"<p><p>Cancer cells with an activated Alternative Lengthening of Telomeres (ALT) mechanism elongate telomeres via homology-directed repair. Sustained telomeric replication stress is an essential trigger of ALT activity; however, it can lead to cell death if not properly restricted. By analyzing publicly available data from genome-wide CRISPR KO screenings, we have identified the multifunctional protein PC4 as a novel factor essential for ALT cell viability. Depletion of PC4 results in rapid ALT cell death, while telomerase-positive cells show minimal effects. PC4 depletion induces replication stress and telomere fragility primarily in ALT cells, and increases ALT activity. PC4 binds to telomeric DNA in cells, and its binding can be enhanced by telomeric replication stress. Finally, a mutant PC4 with partly impaired single stranded DNA binding activity is capable to localize to telomeres and suppress ALT activity and telomeric replication stress. We propose that PC4 supports ALT cell viability, at least partly, by averting telomere dysfunction. Further studies of PC4 interactions at ALT telomeres may hold promise for innovative therapies to eradicate ALT cancers.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521372","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}
Pub Date : 2024-10-25DOI: 10.1038/s44319-024-00291-7
Haiyan Xue, Ziyan Xiao, Xiujuan Zhao, Shu Li, Qian Cheng, Chun Fu, Fengxue Zhu
Regulation of neutrophil activation plays a significant role in managing sepsis. CKLF-like MARVEL transmembrane domain containing (CMTM)3 is a membrane protein involved in immune response. Here, we find that CMTM3 expression is elevated in sepsis and plays a crucial role in mediating the imbalance of neutrophil migration. Cmtm3 knockout improves the survival rate of septic mice, mitigate inflammatory responses, and ameliorate organ damage. Mechanistically, the deletion of Cmtm3 reduced the expression of Toll-like receptor 4 (TLR4) on neutrophils, leading to a decrease in the expression of C-X-C motif chemokine receptor 2 (CXCR2) on the cell membrane. This resulted in a reduced migration of neutrophils from the bone marrow to the bloodstream, thereby attenuating their recruitment to vital organs. Our findings suggest that targeting CMTM3 holds promise as a therapeutic approach to ameliorate the dysregulation of neutrophil migration and multi-organ damage associated with sepsis.
{"title":"CMTM3 regulates neutrophil activation and aggravates sepsis through TLR4 signaling.","authors":"Haiyan Xue, Ziyan Xiao, Xiujuan Zhao, Shu Li, Qian Cheng, Chun Fu, Fengxue Zhu","doi":"10.1038/s44319-024-00291-7","DOIUrl":"https://doi.org/10.1038/s44319-024-00291-7","url":null,"abstract":"<p><p>Regulation of neutrophil activation plays a significant role in managing sepsis. CKLF-like MARVEL transmembrane domain containing (CMTM)3 is a membrane protein involved in immune response. Here, we find that CMTM3 expression is elevated in sepsis and plays a crucial role in mediating the imbalance of neutrophil migration. Cmtm3 knockout improves the survival rate of septic mice, mitigate inflammatory responses, and ameliorate organ damage. Mechanistically, the deletion of Cmtm3 reduced the expression of Toll-like receptor 4 (TLR4) on neutrophils, leading to a decrease in the expression of C-X-C motif chemokine receptor 2 (CXCR2) on the cell membrane. This resulted in a reduced migration of neutrophils from the bone marrow to the bloodstream, thereby attenuating their recruitment to vital organs. Our findings suggest that targeting CMTM3 holds promise as a therapeutic approach to ameliorate the dysregulation of neutrophil migration and multi-organ damage associated with sepsis.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497197","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}
Bone cancer pain (BCP) affects ~70% of patients in advanced stages, primarily due to bone metastasis, presenting a substantial therapeutic challenge. Here, we profile orphan G protein-coupled receptors in the dorsal root ganglia (DRG) following tumor infiltration, and observe a notable increase in GPR160 expression. Elevated Gpr160 mRNA and protein levels persist from postoperative day 6 for over 18 days in the affected DRG, predominantly in small-diameter C-fiber type neurons specific to the tibia. Targeted interventions, including DRG microinjection of siRNA or AAV delivery, mitigate mechanical allodynia, cold, and heat hyperalgesia induced by the tumor. Tumor infiltration increases DRG neuron excitability in wild-type mice, but not in Gpr160 gene knockout mice. Tumor infiltration results in reduced H3K27me3 and increased H3K27ac modifications, enhanced binding of the transcription activator Sp1 to the Gpr160 gene promoter region, and induction of GPR160 expression. Modulating histone-modifying enzymes effectively alleviated pain behavior. Our study delineates a novel mechanism wherein elevated Sp1 levels facilitate Gpr160 gene transcription in nociceptive DRG neurons during BCP in rodents.
{"title":"Histone modifications and Sp1 promote GPR160 expression in bone cancer pain within rodent models.","authors":"Chengfei Xu, Yahui Wang, Chaobo Ni, Miao Xu, Chengyu Yin, Qiuli He, Bing Ma, Jie Fu, Baoxia Zhao, Liping Chen, Tong Zhi, Shirong Wei, Liang Cheng, Hui Xu, Jiajun Xiao, Lei Yang, Qingqing Xu, Jiao Kuang, Boyi Liu, Qinghe Zhou, Xuewu Lin, Ming Yao, Huadong Ni","doi":"10.1038/s44319-024-00292-6","DOIUrl":"https://doi.org/10.1038/s44319-024-00292-6","url":null,"abstract":"<p><p>Bone cancer pain (BCP) affects ~70% of patients in advanced stages, primarily due to bone metastasis, presenting a substantial therapeutic challenge. Here, we profile orphan G protein-coupled receptors in the dorsal root ganglia (DRG) following tumor infiltration, and observe a notable increase in GPR160 expression. Elevated Gpr160 mRNA and protein levels persist from postoperative day 6 for over 18 days in the affected DRG, predominantly in small-diameter C-fiber type neurons specific to the tibia. Targeted interventions, including DRG microinjection of siRNA or AAV delivery, mitigate mechanical allodynia, cold, and heat hyperalgesia induced by the tumor. Tumor infiltration increases DRG neuron excitability in wild-type mice, but not in Gpr160 gene knockout mice. Tumor infiltration results in reduced H3K27me3 and increased H3K27ac modifications, enhanced binding of the transcription activator Sp1 to the Gpr160 gene promoter region, and induction of GPR160 expression. Modulating histone-modifying enzymes effectively alleviated pain behavior. Our study delineates a novel mechanism wherein elevated Sp1 levels facilitate Gpr160 gene transcription in nociceptive DRG neurons during BCP in rodents.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497198","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}
Pub Date : 2024-10-23DOI: 10.1038/s44319-024-00294-4
Philip Hunter
{"title":"The controversy around anti-amyloid antibodies for treating Alzheimer's disease : The European Medical Agency's ruling against the latest anti-amyloid drugs highlights the ongoing debate about their safety and efficacy.","authors":"Philip Hunter","doi":"10.1038/s44319-024-00294-4","DOIUrl":"10.1038/s44319-024-00294-4","url":null,"abstract":"","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497200","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}
Pub Date : 2024-10-21DOI: 10.1038/s44319-024-00290-8
Qian Zheng, Pengfei Li, Yulong Qiang, Jiachen Fan, Yuzhu Xing, Ying Zhang, Fan Yang, Feng Li, Jie Xiong
An understanding of the enzymatic and scaffolding functions of epigenetic modifiers is important for the development of epigenetic therapies for cancer. The H3K4me2/3 histone demethylase KDM5C has been shown to regulate transcription. The diverse roles of KDM5C are likely determined by its interacting partners, which are still largely unknown. In this study, we screen for KDM5C-binding proteins and show that YY1 interacts with KDM5C. A synergistic antitumor effect is exerted when both KDM5C and YY1 are depleted, and targeting YY1 appears to be a vulnerability in KDM5C-deficient cancer cells. Mechanistically, KDM5C promotes global YY1 chromatin recruitment, especially at promoters. Moreover, an intact KDM5C JmjC domain but not KDM5C histone demethylase activity is required for KDM5C-mediated YY1 chromatin binding. Transcriptional profiling reveals that dual inhibition of KDM5C and YY1 increases transcriptional repression of cell cycle- and apoptosis-related genes. In summary, our work demonstrates a synthetic lethal interaction between YY1 and KDM5C and suggests combination therapies for cancer treatments.
{"title":"Targeting the transcription factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C.","authors":"Qian Zheng, Pengfei Li, Yulong Qiang, Jiachen Fan, Yuzhu Xing, Ying Zhang, Fan Yang, Feng Li, Jie Xiong","doi":"10.1038/s44319-024-00290-8","DOIUrl":"https://doi.org/10.1038/s44319-024-00290-8","url":null,"abstract":"<p><p>An understanding of the enzymatic and scaffolding functions of epigenetic modifiers is important for the development of epigenetic therapies for cancer. The H3K4me2/3 histone demethylase KDM5C has been shown to regulate transcription. The diverse roles of KDM5C are likely determined by its interacting partners, which are still largely unknown. In this study, we screen for KDM5C-binding proteins and show that YY1 interacts with KDM5C. A synergistic antitumor effect is exerted when both KDM5C and YY1 are depleted, and targeting YY1 appears to be a vulnerability in KDM5C-deficient cancer cells. Mechanistically, KDM5C promotes global YY1 chromatin recruitment, especially at promoters. Moreover, an intact KDM5C JmjC domain but not KDM5C histone demethylase activity is required for KDM5C-mediated YY1 chromatin binding. Transcriptional profiling reveals that dual inhibition of KDM5C and YY1 increases transcriptional repression of cell cycle- and apoptosis-related genes. In summary, our work demonstrates a synthetic lethal interaction between YY1 and KDM5C and suggests combination therapies for cancer treatments.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460726","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}