首页 > 最新文献

EMBO Reports最新文献

英文 中文
CMTM3 regulates neutrophil activation and aggravates sepsis through TLR4 signaling. CMTM3 通过 TLR4 信号调节中性粒细胞的活化并加重败血症。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-25 DOI: 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.

中性粒细胞活化的调节在脓毒症的治疗中发挥着重要作用。CKLF-like MARVEL transmembrane domain containing (CMTM)3 是一种参与免疫反应的膜蛋白。在这里,我们发现 CMTM3 在脓毒症中表达升高,并在介导中性粒细胞迁移失衡方面起着至关重要的作用。Cmtm3基因敲除可提高脓毒症小鼠的存活率,减轻炎症反应和器官损伤。从机理上讲,Cmtm3 的缺失会降低中性粒细胞上 Toll 样受体 4(TLR4)的表达,从而导致细胞膜上 C-X-C motif 趋化因子受体 2(CXCR2)的表达减少。这导致中性粒细胞从骨髓向血液的迁移减少,从而减少了它们向重要器官的募集。我们的研究结果表明,以 CMTM3 为靶点有望成为一种治疗方法,改善脓毒症引起的中性粒细胞迁移失调和多器官损伤。
{"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":" ","pages":""},"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}
引用次数: 0
Histone modifications and Sp1 promote GPR160 expression in bone cancer pain within rodent models. 在啮齿动物模型中,组蛋白修饰和 Sp1 可促进骨癌疼痛中 GPR160 的表达。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-24 DOI: 10.1038/s44319-024-00292-6
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

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.

骨癌疼痛(BCP)影响着约 70% 的晚期患者,主要是由于骨转移所致,给治疗带来了巨大挑战。在这里,我们对肿瘤浸润后背根神经节(DRG)中的孤儿G蛋白偶联受体进行了分析,观察到GPR160的表达明显增加。Gpr160 mRNA和蛋白水平的升高从术后第6天开始在受影响的DRG中持续超过18天,主要存在于胫骨特异的小直径C纤维型神经元中。靶向干预(包括 DRG 显微注射 siRNA 或 AAV 传播)可减轻肿瘤诱导的机械异感、冷痛和热痛。肿瘤浸润会增加野生型小鼠的DRG神经元兴奋性,但不会增加Gpr160基因敲除小鼠的DRG神经元兴奋性。肿瘤浸润导致 H3K27me3 减少和 H3K27ac 修饰增加,转录激活剂 Sp1 与 Gpr160 基因启动子区域的结合增强,并诱导 GPR160 的表达。调节组蛋白修饰酶可有效缓解疼痛行为。我们的研究阐明了一种新的机制,即在啮齿类动物的 BCP 过程中,Sp1 水平的升高促进了痛觉 DRG 神经元中 Gpr160 基因的转录。
{"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":" ","pages":""},"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}
引用次数: 0
Scientific truth: an endangered species. 科学真理:濒临灭绝的物种
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-24 DOI: 10.1038/s44319-024-00293-5
Frank Gannon
{"title":"Scientific truth: an endangered species.","authors":"Frank Gannon","doi":"10.1038/s44319-024-00293-5","DOIUrl":"https://doi.org/10.1038/s44319-024-00293-5","url":null,"abstract":"","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497199","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 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. 围绕用于治疗阿尔茨海默病的抗淀粉样蛋白抗体的争议:欧洲医学机构针对最新抗淀粉样蛋白药物的规定凸显了对其安全性和有效性的持续争论。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-23 DOI: 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":" ","pages":""},"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}
引用次数: 0
Targeting the transcription factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C. 靶向转录因子 YY1 与组蛋白去甲基化酶 KDM5C 的缺失是合成致死的。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-21 DOI: 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.

了解表观遗传修饰因子的酶和支架功能对于开发癌症表观遗传疗法非常重要。H3K4me2/3组蛋白去甲基化酶KDM5C已被证明能调节转录。KDM5C 的多种作用可能是由其相互作用伙伴决定的,而这些伙伴在很大程度上还不为人所知。在这项研究中,我们筛选了 KDM5C 结合蛋白,结果表明 YY1 与 KDM5C 有相互作用。当KDM5C和YY1都被耗尽时,会产生协同抗肿瘤效应,而靶向YY1似乎是KDM5C缺陷癌细胞的一个弱点。从机理上讲,KDM5C 可促进 YY1 染色质的全局招募,尤其是在启动子处。此外,KDM5C介导的YY1染色质结合需要完整的KDM5C JmjC结构域,而非KDM5C组蛋白去甲基化酶活性。转录谱分析显示,KDM5C 和 YY1 的双重抑制增加了细胞周期和细胞凋亡相关基因的转录抑制。总之,我们的工作证明了 YY1 和 KDM5C 之间的合成致死相互作用,并提出了癌症治疗的组合疗法。
{"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":" ","pages":""},"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}
引用次数: 0
Glycogenesis and glyconeogenesis from glutamine, lactate and glycerol support human macrophage functions. 谷氨酰胺、乳酸和甘油的糖生成和糖醛酸生成支持人体巨噬细胞的功能。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-18 DOI: 10.1038/s44319-024-00278-4
Najia Jeroundi, Charlotte Roy, Laetitia Basset, Pascale Pignon, Laurence Preisser, Simon Blanchard, Cinzia Bocca, Cyril Abadie, Julie Lalande, Naïg Gueguen, Guillaume Mabilleau, Guy Lenaers, Aurélie Moreau, Marie-Christine Copin, Guillaume Tcherkez, Yves Delneste, Dominique Couez, Pascale Jeannin

Macrophages fight infection and ensure tissue repair, often operating at nutrient-poor wound sites. We investigated the ability of human macrophages to metabolize glycogen. We observed that the cytokines GM-CSF and M-CSF plus IL-4 induced glycogenesis and the accumulation of glycogen by monocyte-derived macrophages. Glyconeogenesis occurs in cells cultured in the presence of the inflammatory cytokines GM-CSF and IFNγ (M1 cells), via phosphoenolpyruvate carboxykinase 2 (PCK2) and fructose-1,6-bisphosphatase 1 (FBP1). Enzyme inhibition with drugs or gene silencing techniques and 13C-tracing demonstrate that glutamine (metabolized by the TCA cycle), lactic acid, and glycerol were substrates of glyconeogenesis only in M1 cells. Tumor-associated macrophages (TAMs) also store glycogen and can perform glyconeogenesis. Finally, macrophage glycogenolysis and the pentose phosphate pathway (PPP) support cytokine secretion and phagocytosis regardless of the availability of extracellular glucose. Thus, glycogen metabolism supports the functions of human M1 and M2 cells, with inflammatory M1 cells displaying a possible dependence on glyconeogenesis.

巨噬细胞能抗感染并确保组织修复,但通常在缺乏营养的伤口部位工作。我们研究了人类巨噬细胞代谢糖原的能力。我们观察到,细胞因子 GM-CSF 和 M-CSF 加 IL-4 可诱导单核巨噬细胞糖原生成和糖原累积。在有炎症细胞因子 GM-CSF 和 IFNγ(M1 细胞)存在的情况下培养的细胞会通过磷酸烯醇丙酮酸羧激酶 2(PCK2)和果糖-1,6-二磷酸酶 1(FBP1)发生糖原生成。通过药物或基因沉默技术抑制酶的活性,以及 13C 追踪技术证明,只有在 M1 细胞中,谷氨酰胺(通过 TCA 循环代谢)、乳酸和甘油才是糖元生成的底物。肿瘤相关巨噬细胞(TAMs)也储存糖原,并能进行糖元生成。最后,无论细胞外葡萄糖是否存在,巨噬细胞糖原分解和磷酸戊糖途径(PPP)都支持细胞因子分泌和吞噬作用。因此,糖原代谢支持人类 M1 和 M2 细胞的功能,炎症性 M1 细胞可能依赖于糖原生成。
{"title":"Glycogenesis and glyconeogenesis from glutamine, lactate and glycerol support human macrophage functions.","authors":"Najia Jeroundi, Charlotte Roy, Laetitia Basset, Pascale Pignon, Laurence Preisser, Simon Blanchard, Cinzia Bocca, Cyril Abadie, Julie Lalande, Naïg Gueguen, Guillaume Mabilleau, Guy Lenaers, Aurélie Moreau, Marie-Christine Copin, Guillaume Tcherkez, Yves Delneste, Dominique Couez, Pascale Jeannin","doi":"10.1038/s44319-024-00278-4","DOIUrl":"https://doi.org/10.1038/s44319-024-00278-4","url":null,"abstract":"<p><p>Macrophages fight infection and ensure tissue repair, often operating at nutrient-poor wound sites. We investigated the ability of human macrophages to metabolize glycogen. We observed that the cytokines GM-CSF and M-CSF plus IL-4 induced glycogenesis and the accumulation of glycogen by monocyte-derived macrophages. Glyconeogenesis occurs in cells cultured in the presence of the inflammatory cytokines GM-CSF and IFNγ (M1 cells), via phosphoenolpyruvate carboxykinase 2 (PCK2) and fructose-1,6-bisphosphatase 1 (FBP1). Enzyme inhibition with drugs or gene silencing techniques and <sup>13</sup>C-tracing demonstrate that glutamine (metabolized by the TCA cycle), lactic acid, and glycerol were substrates of glyconeogenesis only in M1 cells. Tumor-associated macrophages (TAMs) also store glycogen and can perform glyconeogenesis. Finally, macrophage glycogenolysis and the pentose phosphate pathway (PPP) support cytokine secretion and phagocytosis regardless of the availability of extracellular glucose. Thus, glycogen metabolism supports the functions of human M1 and M2 cells, with inflammatory M1 cells displaying a possible dependence on glyconeogenesis.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460724","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
RNA binding protein ZCCHC24 promotes tumorigenicity in triple-negative breast cancer. RNA 结合蛋白 ZCCHC24 促进了三阴性乳腺癌的致瘤性。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-17 DOI: 10.1038/s44319-024-00282-8
Yutaro Uchida, Ryota Kurimoto, Tomoki Chiba, Takahide Matsushima, Goshi Oda, Iichiroh Onishi, Yasuto Takeuchi, Noriko Gotoh, Hiroshi Asahara

Triple-negative breast cancer (TNBC) lacks the expression of hormone and HER2 receptors and is highly malignant with no effective therapeutic targets. In TNBC, the cancer stem-like cell (CSC) population is considered to be the main cause of resistance to treatment. Thus, the therapeutic targeting of this population could substantially improve patient survival. Here, we identify the RNA-binding protein ZCCHC24 as enriched in the mesenchymal-like TNBC population. ZCCHC24 promotes the expression of a set of genes related to tumorigenicity and treatment resistance by directly binding to the cis-element "UGUWHWWA" in their mRNAs, thereby stabilizing them. One of the ZCCHC24 targets, ZEB1, is a transcription factor that promotes the expression of cancer stemness genes and reciprocally induces ZCCHC24 expression. ZCCHC24 knockdown by siRNAs shows a therapeutic effect and reduces the mesenchymal-like cell population in TNBC patient-derived xenografts. ZCCHC24 knockdown also has additive effects with the BET inhibitor JQ1 in suppressing tumor growth in TNBC patient-derived xenografts.

三阴性乳腺癌(TNBC)缺乏激素和 HER2 受体的表达,恶性程度高,但没有有效的治疗靶点。在 TNBC 中,癌症干样细胞(CSC)群被认为是导致耐药性的主要原因。因此,针对这一群体的治疗可以大大提高患者的生存率。在这里,我们发现RNA结合蛋白ZCCHC24在间质样TNBC群体中富集。ZCCHC24通过直接与mRNA中的顺式元件 "UGUWHWWA "结合,促进了一组与肿瘤致病性和耐药性相关的基因的表达,从而稳定了这些基因。ZCCHC24 的靶标之一 ZEB1 是一种转录因子,它能促进癌症干性基因的表达,并相互诱导 ZCCHC24 的表达。通过 siRNA 敲除 ZCCHC24 有治疗效果,并能减少 TNBC 患者异种移植中的间质样细胞数量。在抑制 TNBC 患者异种移植的肿瘤生长方面,ZCCHC24 基因敲除与 BET 抑制剂 JQ1 还具有叠加效应。
{"title":"RNA binding protein ZCCHC24 promotes tumorigenicity in triple-negative breast cancer.","authors":"Yutaro Uchida, Ryota Kurimoto, Tomoki Chiba, Takahide Matsushima, Goshi Oda, Iichiroh Onishi, Yasuto Takeuchi, Noriko Gotoh, Hiroshi Asahara","doi":"10.1038/s44319-024-00282-8","DOIUrl":"https://doi.org/10.1038/s44319-024-00282-8","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) lacks the expression of hormone and HER2 receptors and is highly malignant with no effective therapeutic targets. In TNBC, the cancer stem-like cell (CSC) population is considered to be the main cause of resistance to treatment. Thus, the therapeutic targeting of this population could substantially improve patient survival. Here, we identify the RNA-binding protein ZCCHC24 as enriched in the mesenchymal-like TNBC population. ZCCHC24 promotes the expression of a set of genes related to tumorigenicity and treatment resistance by directly binding to the cis-element \"UGUWHWWA\" in their mRNAs, thereby stabilizing them. One of the ZCCHC24 targets, ZEB1, is a transcription factor that promotes the expression of cancer stemness genes and reciprocally induces ZCCHC24 expression. ZCCHC24 knockdown by siRNAs shows a therapeutic effect and reduces the mesenchymal-like cell population in TNBC patient-derived xenografts. ZCCHC24 knockdown also has additive effects with the BET inhibitor JQ1 in suppressing tumor growth in TNBC patient-derived xenografts.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460725","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
Nup358 restricts ER-mitochondria connectivity by modulating mTORC2/Akt/GSK3β signalling. Nup358通过调节mTORC2/Akt/GSK3β信号限制ER-线粒体的连接。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-18 DOI: 10.1038/s44319-024-00204-8
Misha Kalarikkal, Rimpi Saikia, Lizanne Oliveira, Yashashree Bhorkar, Akshay Lonare, Pallavi Varshney, Prathamesh Dhamale, Amitabha Majumdar, Jomon Joseph

ER-mitochondria contact sites (ERMCSs) regulate processes, including calcium homoeostasis, energy metabolism and autophagy. Previously, it was shown that during growth factor signalling, mTORC2/Akt gets recruited to and stabilizes ERMCSs. Independent studies showed that GSK3β, a well-known Akt substrate, reduces ER-mitochondria connectivity by disrupting the VAPB-PTPIP51 tethering complex. However, the mechanisms that regulate ERMCSs are incompletely understood. Here we find that annulate lamellae (AL), relatively unexplored subdomains of ER enriched with a subset of nucleoporins, are present at ERMCSs. Depletion of Nup358, an AL-resident nucleoporin, results in enhanced mTORC2/Akt activation, GSK3β inhibition and increased ERMCSs. Depletion of Rictor, a mTORC2-specific subunit, or exogenous expression of GSK3β, was sufficient to reverse the ERMCS-phenotype in Nup358-deficient cells. We show that growth factor-mediated activation of mTORC2 requires the VAPB-PTPIP51 complex, whereas, Nup358's association with this tether restricts mTORC2/Akt signalling and ER-mitochondria connectivity. Expression of a Nup358 fragment that is sufficient for interaction with the VAPB-PTPIP51 complex suppresses mTORC2/Akt activation and disrupts ERMCSs. Collectively, our study uncovers a novel role for Nup358 in controlling ERMCSs by modulating the mTORC2/Akt/GSK3β axis.

ER-线粒体接触点(ERMCSs)调控着钙平衡、能量代谢和自噬等过程。此前有研究表明,在生长因子信号传导过程中,mTORC2/Akt会被招募到ERMCS并使其稳定。独立研究表明,众所周知的 Akt 底物 GSK3β 通过破坏 VAPB-PTPIP51 系链复合物,降低了 ER-线粒体的连接性。然而,ERMCS 的调控机制尚不完全清楚。在这里,我们发现环状薄片(AL)存在于ERMCS,这是ER中相对未被探索的子域,富含核蛋白亚群。缺失 AL 驻留核蛋白 Nup358 会导致 mTORC2/Akt 激活增强、GSK3β 抑制和 ERMCS 增加。mTORC2特异性亚基Rictor的耗竭或GSK3β的外源表达足以逆转Nup358缺陷细胞的ERMCS表型。我们发现,生长因子介导的 mTORC2 激活需要 VAPB-PTPIP51 复合物,而 Nup358 与该系链的结合限制了 mTORC2/Akt 信号传导和 ER 线粒体连接。表达足以与 VAPB-PTPIP51 复合物相互作用的 Nup358 片段可抑制 mTORC2/Akt 激活并破坏 ERMCS。总之,我们的研究发现了 Nup358 通过调节 mTORC2/Akt/GSK3β 轴在控制 ERMCS 中的新作用。
{"title":"Nup358 restricts ER-mitochondria connectivity by modulating mTORC2/Akt/GSK3β signalling.","authors":"Misha Kalarikkal, Rimpi Saikia, Lizanne Oliveira, Yashashree Bhorkar, Akshay Lonare, Pallavi Varshney, Prathamesh Dhamale, Amitabha Majumdar, Jomon Joseph","doi":"10.1038/s44319-024-00204-8","DOIUrl":"10.1038/s44319-024-00204-8","url":null,"abstract":"<p><p>ER-mitochondria contact sites (ERMCSs) regulate processes, including calcium homoeostasis, energy metabolism and autophagy. Previously, it was shown that during growth factor signalling, mTORC2/Akt gets recruited to and stabilizes ERMCSs. Independent studies showed that GSK3β, a well-known Akt substrate, reduces ER-mitochondria connectivity by disrupting the VAPB-PTPIP51 tethering complex. However, the mechanisms that regulate ERMCSs are incompletely understood. Here we find that annulate lamellae (AL), relatively unexplored subdomains of ER enriched with a subset of nucleoporins, are present at ERMCSs. Depletion of Nup358, an AL-resident nucleoporin, results in enhanced mTORC2/Akt activation, GSK3β inhibition and increased ERMCSs. Depletion of Rictor, a mTORC2-specific subunit, or exogenous expression of GSK3β, was sufficient to reverse the ERMCS-phenotype in Nup358-deficient cells. We show that growth factor-mediated activation of mTORC2 requires the VAPB-PTPIP51 complex, whereas, Nup358's association with this tether restricts mTORC2/Akt signalling and ER-mitochondria connectivity. Expression of a Nup358 fragment that is sufficient for interaction with the VAPB-PTPIP51 complex suppresses mTORC2/Akt activation and disrupts ERMCSs. Collectively, our study uncovers a novel role for Nup358 in controlling ERMCSs by modulating the mTORC2/Akt/GSK3β axis.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4226-4251"},"PeriodicalIF":6.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723245","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
Environmental DNA without borders : Let's embrace decentralised genomics to meet the UN's biodiversity targets. 环境 DNA 无国界:让我们拥抱分散的基因组学,实现联合国的生物多样性目标。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-09-25 DOI: 10.1038/s44319-024-00264-w
Maximilian R Stammnitz, Amber Hartman Scholz, David J Duffy
{"title":"Environmental DNA without borders : Let's embrace decentralised genomics to meet the UN's biodiversity targets.","authors":"Maximilian R Stammnitz, Amber Hartman Scholz, David J Duffy","doi":"10.1038/s44319-024-00264-w","DOIUrl":"10.1038/s44319-024-00264-w","url":null,"abstract":"","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4095-4099"},"PeriodicalIF":6.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343798","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
Cytoplasmic FBXO38 mediates PD-1 degradation. 细胞质中的 FBXO38 介导了 PD-1 的降解。
IF 5.3 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-09-16 DOI: 10.1038/s44319-024-00254-y
Xiwei Liu, Xiangbo Meng, Zuomiao Lin, Shutan Jiang, Haifeng Liu, Shao-Cong Sun, Xiaolong Liu, Penghui Zhou, Xiaowu Huang, Lai Wei, Wei Yang, Chenqi Xu
{"title":"Cytoplasmic FBXO38 mediates PD-1 degradation.","authors":"Xiwei Liu, Xiangbo Meng, Zuomiao Lin, Shutan Jiang, Haifeng Liu, Shao-Cong Sun, Xiaolong Liu, Penghui Zhou, Xiaowu Huang, Lai Wei, Wei Yang, Chenqi Xu","doi":"10.1038/s44319-024-00254-y","DOIUrl":"10.1038/s44319-024-00254-y","url":null,"abstract":"","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4168-4171"},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282176","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
期刊
EMBO Reports
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1