Pub Date : 2024-08-14DOI: 10.1038/s41418-024-01361-y
Zuyi Ma, Jia Sun, Zhenchong Li, Shanzhou Huang, Binglu Li
Cholangiocarcinoma (CCA) is a malignant tumor of the digestive system, characterized by its aggressive behavior and the absence of effective therapeutic biomarkers. Although recent studies have implicated AMDHD1 in tumor formation, its role in CCA development has been insufficiently explored. We utilized multiple bioinformatic datasets alongside 108 clinical samples to examine AMDHD1 expression in CCA. Then, in vitro and in vivo experiments were conducted to assess its impact on tumor growth and metastasis. Furthermore, proteomic analysis and immunoprecipitation mass spectrometry were employed to identify the downstream effectors of AMDHD1. We discovered that AMDHD1 was down-regulated in CCA and this down-regulation was associated with adverse clinicopathological features and prognosis. We also demonstrated that overexpression of AMDHD1 hindered G1/S progression in the cell cycle and promoted apoptosis, thereby inhibiting tumor growth and metastasis. Mechanistically, we found that AMDHD1 operated in a TGF-β-dependent manner and the inhibition of TGF-β signaling abrogated the effect of AMDHD1 overexpression on CCA cells. Specifically, AMDHD1 inhibited the ubiquitination and degradation of the SMAD4 protein through binding to the MH2 domain and synergistically enhanced SMAD2/3 phosphorylation, which activated of TGF-β signaling pathway and resulted in the suppression of CCA cell proliferation and migration. Our study identifies AMDHD1 as a significant prognostic biomarker and a tumor suppressor in CCA. It underscores the pivotal role of the AMDHD1/TGF-β signaling pathway in the development and progression of CCA.
胆管癌（CCA）是消化系统的一种恶性肿瘤，其特点是具有侵袭性和缺乏有效的治疗生物标志物。尽管最近的研究表明 AMDHD1 与肿瘤的形成有关，但其在 CCA 发展过程中的作用尚未得到充分探讨。我们利用多个生物信息数据集和 108 个临床样本研究了 AMDHD1 在 CCA 中的表达。然后，我们进行了体外和体内实验，评估其对肿瘤生长和转移的影响。此外，我们还采用了蛋白质组分析和免疫沉淀质谱法来确定AMDHD1的下游效应因子。我们发现 AMDHD1 在 CCA 中被下调，而这种下调与不良的临床病理特征和预后有关。我们还证实，AMDHD1的过表达会阻碍细胞周期的G1/S进展，促进细胞凋亡，从而抑制肿瘤的生长和转移。从机理上讲，我们发现AMDHD1以依赖于TGF-β的方式运行，而抑制TGF-β信号传导可减弱AMDHD1过表达对CCA细胞的影响。具体而言，AMDHD1通过与MH2结构域结合抑制SMAD4蛋白的泛素化和降解，并协同增强SMAD2/3磷酸化，从而激活TGF-β信号通路，抑制CCA细胞的增殖和迁移。我们的研究发现，AMDHD1是CCA的重要预后生物标志物和肿瘤抑制因子。它强调了AMDHD1/TGF-β信号通路在CCA的发生和发展中的关键作用。
{"title":"AMDHD1 acts as a tumor suppressor and contributes to activation of TGF-β signaling pathway in cholangiocarcinoma.","authors":"Zuyi Ma, Jia Sun, Zhenchong Li, Shanzhou Huang, Binglu Li","doi":"10.1038/s41418-024-01361-y","DOIUrl":"https://doi.org/10.1038/s41418-024-01361-y","url":null,"abstract":"<p><p>Cholangiocarcinoma (CCA) is a malignant tumor of the digestive system, characterized by its aggressive behavior and the absence of effective therapeutic biomarkers. Although recent studies have implicated AMDHD1 in tumor formation, its role in CCA development has been insufficiently explored. We utilized multiple bioinformatic datasets alongside 108 clinical samples to examine AMDHD1 expression in CCA. Then, in vitro and in vivo experiments were conducted to assess its impact on tumor growth and metastasis. Furthermore, proteomic analysis and immunoprecipitation mass spectrometry were employed to identify the downstream effectors of AMDHD1. We discovered that AMDHD1 was down-regulated in CCA and this down-regulation was associated with adverse clinicopathological features and prognosis. We also demonstrated that overexpression of AMDHD1 hindered G1/S progression in the cell cycle and promoted apoptosis, thereby inhibiting tumor growth and metastasis. Mechanistically, we found that AMDHD1 operated in a TGF-β-dependent manner and the inhibition of TGF-β signaling abrogated the effect of AMDHD1 overexpression on CCA cells. Specifically, AMDHD1 inhibited the ubiquitination and degradation of the SMAD4 protein through binding to the MH2 domain and synergistically enhanced SMAD2/3 phosphorylation, which activated of TGF-β signaling pathway and resulted in the suppression of CCA cell proliferation and migration. Our study identifies AMDHD1 as a significant prognostic biomarker and a tumor suppressor in CCA. It underscores the pivotal role of the AMDHD1/TGF-β signaling pathway in the development and progression of CCA.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981814","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 : 2024-08-14DOI: 10.1038/s41418-024-01358-7
Shangnan Dai, Yunpeng Peng, Guangfu Wang, Chongfa Chen, Qiuyang Chen, Lingdi Yin, Han Yan, Kai Zhang, Min Tu, Zipeng Lu, Jishu Wei, Qiang Li, Junli Wu, Kuirong Jiang, Yi Zhu, Yi Miao
With advancements in genomics and immunology, immunotherapy has emerged as a revolutionary strategy for tumor treatment. However, pancreatic ductal adenocarcinoma (PDAC), an immunologically "cold" tumor, exhibits limited responsiveness to immunotherapy. This study aimed to address the urgent need to uncover PDAC's immune microenvironment heterogeneity and identify the molecular mechanisms driving immune evasion. Using single-cell RNA sequencing datasets and spatial proteomics, we discovered LIM domain only 7 (LMO7) in PDAC cells as a previously unrecognized driver of immune evasion through Treg cell enrichment. LMO7 was positively correlated with infiltrating regulatory T cells (Tregs) and dysfunctional CD8+ T cells. A series of in vitro and in vivo experiments demonstrated LMO7's significant role in promoting Treg cell differentiation and chemotaxis while inhibiting CD8+ T cells and natural killer cell cytotoxicity. Mechanistically, LMO7, through its LIM domain, directly bound and promoted the ubiquitination and degradation of Foxp1. Foxp1 negatively regulated transforming growth factor-beta (TGF-β) and C-C motif chemokine ligand 5 (CCL5) expression by binding to sites 2 and I/III, respectively. Elevated TGF-β and CCL5 levels contribute to Treg cell enrichment, inducing immune evasion in PDAC. Combined treatment with TGF-β/CCL5 antibodies, along with LMO7 inhibition, effectively reversed immune evasion in PDAC, activated the immune response, and prolonged mouse survival. Therefore, this study identified LMO7 as a novel facilitator in driving immune evasion by promoting Treg cell enrichment and inhibiting cytotoxic effector functions. Targeting the LMO7-Foxp1-TGF-β/CCL5 axis holds promise as a therapeutic strategy for PDAC. Graphical abstract revealing LMO7 as a novel facilitator in driving immune evasion by promoting Tregs differentiation and chemotaxis, inducing CD8+ T/natural killer cells inhibition.
随着基因组学和免疫学的进步，免疫疗法已成为一种革命性的肿瘤治疗策略。然而，胰腺导管腺癌（PDAC）是一种免疫 "冷 "肿瘤，对免疫疗法的反应有限。本研究旨在满足揭示PDAC免疫微环境异质性和鉴定驱动免疫逃避的分子机制的迫切需要。利用单细胞RNA测序数据集和空间蛋白质组学，我们在PDAC细胞中发现了LIM domain only 7 (LMO7)，它是之前未被发现的通过Treg细胞富集驱动免疫逃避的因素。LMO7 与浸润性调节性 T 细胞（Tregs）和功能失调的 CD8+ T 细胞呈正相关。一系列体外和体内实验证明，LMO7 在促进 Treg 细胞分化和趋化，同时抑制 CD8+ T 细胞和自然杀伤细胞细胞毒性方面发挥着重要作用。从机理上讲，LMO7 通过其 LIM 结构域直接结合并促进 Foxp1 的泛素化和降解。Foxp1 通过分别与位点 2 和位点 I/III 结合，负向调节转化生长因子-β（TGF-β）和 C-C motif 趋化因子配体 5（CCL5）的表达。TGF-β和CCL5水平的升高有助于Treg细胞的富集，诱导PDAC的免疫逃避。TGF-β/CCL5抗体与LMO7抑制剂联合治疗可有效逆转PDAC的免疫逃避，激活免疫反应，延长小鼠存活时间。因此，本研究发现LMO7是通过促进Treg细胞富集和抑制细胞毒性效应因子功能来驱动免疫逃避的新型促进因子。以LMO7-Foxp1-TGF-β/CCL5轴为靶点有望成为PDAC的治疗策略。图解摘要揭示了 LMO7 通过促进集落细胞分化和趋化，诱导 CD8+ T/自然杀伤细胞抑制，成为驱动免疫逃避的新型促进因子。
{"title":"LIM domain only 7: a novel driver of immune evasion through regulatory T cell differentiation and chemotaxis in pancreatic ductal adenocarcinoma.","authors":"Shangnan Dai, Yunpeng Peng, Guangfu Wang, Chongfa Chen, Qiuyang Chen, Lingdi Yin, Han Yan, Kai Zhang, Min Tu, Zipeng Lu, Jishu Wei, Qiang Li, Junli Wu, Kuirong Jiang, Yi Zhu, Yi Miao","doi":"10.1038/s41418-024-01358-7","DOIUrl":"https://doi.org/10.1038/s41418-024-01358-7","url":null,"abstract":"<p><p>With advancements in genomics and immunology, immunotherapy has emerged as a revolutionary strategy for tumor treatment. However, pancreatic ductal adenocarcinoma (PDAC), an immunologically \"cold\" tumor, exhibits limited responsiveness to immunotherapy. This study aimed to address the urgent need to uncover PDAC's immune microenvironment heterogeneity and identify the molecular mechanisms driving immune evasion. Using single-cell RNA sequencing datasets and spatial proteomics, we discovered LIM domain only 7 (LMO7) in PDAC cells as a previously unrecognized driver of immune evasion through Treg cell enrichment. LMO7 was positively correlated with infiltrating regulatory T cells (Tregs) and dysfunctional CD8<sup>+</sup> T cells. A series of in vitro and in vivo experiments demonstrated LMO7's significant role in promoting Treg cell differentiation and chemotaxis while inhibiting CD8<sup>+</sup> T cells and natural killer cell cytotoxicity. Mechanistically, LMO7, through its LIM domain, directly bound and promoted the ubiquitination and degradation of Foxp1. Foxp1 negatively regulated transforming growth factor-beta (TGF-β) and C-C motif chemokine ligand 5 (CCL5) expression by binding to sites 2 and I/III, respectively. Elevated TGF-β and CCL5 levels contribute to Treg cell enrichment, inducing immune evasion in PDAC. Combined treatment with TGF-β/CCL5 antibodies, along with LMO7 inhibition, effectively reversed immune evasion in PDAC, activated the immune response, and prolonged mouse survival. Therefore, this study identified LMO7 as a novel facilitator in driving immune evasion by promoting Treg cell enrichment and inhibiting cytotoxic effector functions. Targeting the LMO7-Foxp1-TGF-β/CCL5 axis holds promise as a therapeutic strategy for PDAC. Graphical abstract revealing LMO7 as a novel facilitator in driving immune evasion by promoting Tregs differentiation and chemotaxis, inducing CD8<sup>+</sup> T/natural killer cells inhibition.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981815","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 : 2024-08-13DOI: 10.1038/s41418-024-01364-9
Hyemin Lee, Li Zhuang, Boyi Gan
{"title":"Rewiring cancer cell death: LPCAT1 shapes lipid composition and ferroptosis resistance","authors":"Hyemin Lee, Li Zhuang, Boyi Gan","doi":"10.1038/s41418-024-01364-9","DOIUrl":"10.1038/s41418-024-01364-9","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 9","pages":"1101-1103"},"PeriodicalIF":13.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973804","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}
Hyperglycaemia-induced ferroptosis is a significant contributor to kidney dysfunction in diabetic nephropathy (DN) patients. In addition, targeting ferroptosis has clinical implications for the treatment of DN. However, effective therapeutic targets for ferroptosis have not been identified. In this study, we aimed to explore the precise role of protein arginine methyltransferase 6 (PRMT6) in regulating ferroptosis in DN. In the present study, we utilized a mouse DN model consisting of both wild-type and PRMT6-knockout (PRMT6−/−) mice. Transcriptomic and lipidomic analyses, along with various molecular biological methodologies, were used to determine the potential mechanism by which PRMT6 regulates ferroptosis in DN. Our results indicate that PRMT6 downregulation participates in kidney dysfunction and renal cell death via the modulation of ferroptosis in DN. Moreover, PRMT6 reduction induced lipid peroxidation by upregulating acyl-CoA synthetase long-chain family member 1 (ACSL1) expression, ultimately contributing to ferroptosis. Furthermore, we investigated the molecular mechanism by which PRMT6 interacts with signal transducer and activator of transcription 1 (STAT1) to jointly regulate ACSL1 transcription. Additionally, treatment with the STAT1-specific inhibitor fludarabine delayed DN progression. Furthermore, we observed that PRMT6 and STAT1 synergistically regulate ACSL1 transcription to mediate ferroptosis in hyperglycaemic cells. Our study demonstrated that PRMT6 and STAT1 comodulate ACSL1 transcription to induce the production of phospholipid-polyunsaturated fatty acids (PL-PUFAs), thus participating in ferroptosis in DN. These findings suggest that the PRMT6/STAT1/ACSL1 axis is a new therapeutic target for the prevention and treatment of DN.
{"title":"The PRMT6/STAT1/ACSL1 axis promotes ferroptosis in diabetic nephropathy","authors":"Jia Hong, Xue Li, Yingxiang Hao, Hongjiao Xu, Lang Yu, Zhipeng Meng, Jianhai Zhang, Minmin Zhu","doi":"10.1038/s41418-024-01357-8","DOIUrl":"10.1038/s41418-024-01357-8","url":null,"abstract":"Hyperglycaemia-induced ferroptosis is a significant contributor to kidney dysfunction in diabetic nephropathy (DN) patients. In addition, targeting ferroptosis has clinical implications for the treatment of DN. However, effective therapeutic targets for ferroptosis have not been identified. In this study, we aimed to explore the precise role of protein arginine methyltransferase 6 (PRMT6) in regulating ferroptosis in DN. In the present study, we utilized a mouse DN model consisting of both wild-type and PRMT6-knockout (PRMT6−/−) mice. Transcriptomic and lipidomic analyses, along with various molecular biological methodologies, were used to determine the potential mechanism by which PRMT6 regulates ferroptosis in DN. Our results indicate that PRMT6 downregulation participates in kidney dysfunction and renal cell death via the modulation of ferroptosis in DN. Moreover, PRMT6 reduction induced lipid peroxidation by upregulating acyl-CoA synthetase long-chain family member 1 (ACSL1) expression, ultimately contributing to ferroptosis. Furthermore, we investigated the molecular mechanism by which PRMT6 interacts with signal transducer and activator of transcription 1 (STAT1) to jointly regulate ACSL1 transcription. Additionally, treatment with the STAT1-specific inhibitor fludarabine delayed DN progression. Furthermore, we observed that PRMT6 and STAT1 synergistically regulate ACSL1 transcription to mediate ferroptosis in hyperglycaemic cells. Our study demonstrated that PRMT6 and STAT1 comodulate ACSL1 transcription to induce the production of phospholipid-polyunsaturated fatty acids (PL-PUFAs), thus participating in ferroptosis in DN. These findings suggest that the PRMT6/STAT1/ACSL1 axis is a new therapeutic target for the prevention and treatment of DN.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 11","pages":"1561-1575"},"PeriodicalIF":13.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970698","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}
The survival and suppressive function of regulatory T (Treg) cells rely on various intracellular metabolic and physiological processes. Our study demonstrates that Vps34 plays a critical role in maintaining Treg cell homeostasis and function by regulating cellular metabolic activities. Disruption of Vps34 in Treg cells leads to spontaneous fatal systemic autoimmune disorder and multi-tissue inflammatory damage, accompanied by a reduction in the number of Treg cells, particularly eTreg cells with highly immunosuppressive activity. Mechanistically, the poor survival of Vps34-deficient Treg cells is attributed to impaired endocytosis, intracellular vesicular trafficking and autophagosome formation, which further results in enhanced mitochondrial respiration and excessive ROS production. Removal of excessive ROS can effectively rescue the death of Vps34-deficient Treg cells. Functionally, acute deletion of Vps34 within established Treg cells enhances anti-tumor immunity in a malignant melanoma model by boosting T-cell-mediated anti-tumor activity. Overall, our results underscore the pivotal role played by Vps34 in orchestrating Treg cell homeostasis and function towards establishing immune homeostasis and tolerance.
{"title":"Vps34 sustains Treg cell survival and function via regulating intracellular redox homeostasis","authors":"Peiran Feng, Quanli Yang, Liang Luo, Zerong Guan, Jiamin Fu, Mingyue Zhao, Wanqing Meng, Shuo Wan, Junming He, Zhizhong Li, Guang Wang, Guodong Sun, Zhongjun Dong, Meixiang Yang","doi":"10.1038/s41418-024-01353-y","DOIUrl":"10.1038/s41418-024-01353-y","url":null,"abstract":"The survival and suppressive function of regulatory T (Treg) cells rely on various intracellular metabolic and physiological processes. Our study demonstrates that Vps34 plays a critical role in maintaining Treg cell homeostasis and function by regulating cellular metabolic activities. Disruption of Vps34 in Treg cells leads to spontaneous fatal systemic autoimmune disorder and multi-tissue inflammatory damage, accompanied by a reduction in the number of Treg cells, particularly eTreg cells with highly immunosuppressive activity. Mechanistically, the poor survival of Vps34-deficient Treg cells is attributed to impaired endocytosis, intracellular vesicular trafficking and autophagosome formation, which further results in enhanced mitochondrial respiration and excessive ROS production. Removal of excessive ROS can effectively rescue the death of Vps34-deficient Treg cells. Functionally, acute deletion of Vps34 within established Treg cells enhances anti-tumor immunity in a malignant melanoma model by boosting T-cell-mediated anti-tumor activity. Overall, our results underscore the pivotal role played by Vps34 in orchestrating Treg cell homeostasis and function towards establishing immune homeostasis and tolerance.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 11","pages":"1519-1533"},"PeriodicalIF":13.7,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904492","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 : 2024-08-06DOI: 10.1038/s41418-024-01354-x
Shanshan Nai, Meijie Wang, Jiao Yang, Bin Ling, Qiman Dong, Xiaoqiong Yang, Xiaoling Du, Man Lu, Lin Liu, Zhongbo Yu, Lingyi Chen
Erk signaling is indispensable for the self-renewal and differentiation of mouse embryonic stem cells (ESCs), as well as telomere homeostasis. But how Erk regulates these biological processes remains unclear. We identified 132 Erk2 interacting proteins by co-immunoprecipitation and mass spectrometric analysis, and focused on Ddx39 as a potential Erk2 substrate. We demonstrated that Erk2 phosphorylates Ddx39 on Y132 and Y138. Ddx39 knockout (KO) ESCs are defective in differentiation, due to reduced H3K27ac level upon differentiation. Phosphorylation of Ddx39 promotes the recruitment of Hat1 to acetylate H3K27 and activate differentiation genes. In addition, Ddx39 KO leads to telomere elongation in ESCs. Ddx39 is recruited to telomeres by the telomere-binding protein Trf1, consequently disrupting the DNA loop formed by Trf1 and suppressing the alternative lengthening of telomeres (ALT). Phosphorylation of Ddx39 weakens its interaction with Trf1, releasing it from telomeres. Thus, ALT activity is enhanced, and telomeres are elongated. Altogether, our studies reveal an essential role of Ddx39 in the differentiation and telomere homeostasis of ESCs.
{"title":"Novel role for Ddx39 in differentiation and telomere length regulation of embryonic stem cells","authors":"Shanshan Nai, Meijie Wang, Jiao Yang, Bin Ling, Qiman Dong, Xiaoqiong Yang, Xiaoling Du, Man Lu, Lin Liu, Zhongbo Yu, Lingyi Chen","doi":"10.1038/s41418-024-01354-x","DOIUrl":"10.1038/s41418-024-01354-x","url":null,"abstract":"Erk signaling is indispensable for the self-renewal and differentiation of mouse embryonic stem cells (ESCs), as well as telomere homeostasis. But how Erk regulates these biological processes remains unclear. We identified 132 Erk2 interacting proteins by co-immunoprecipitation and mass spectrometric analysis, and focused on Ddx39 as a potential Erk2 substrate. We demonstrated that Erk2 phosphorylates Ddx39 on Y132 and Y138. Ddx39 knockout (KO) ESCs are defective in differentiation, due to reduced H3K27ac level upon differentiation. Phosphorylation of Ddx39 promotes the recruitment of Hat1 to acetylate H3K27 and activate differentiation genes. In addition, Ddx39 KO leads to telomere elongation in ESCs. Ddx39 is recruited to telomeres by the telomere-binding protein Trf1, consequently disrupting the DNA loop formed by Trf1 and suppressing the alternative lengthening of telomeres (ALT). Phosphorylation of Ddx39 weakens its interaction with Trf1, releasing it from telomeres. Thus, ALT activity is enhanced, and telomeres are elongated. Altogether, our studies reveal an essential role of Ddx39 in the differentiation and telomere homeostasis of ESCs.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 11","pages":"1534-1544"},"PeriodicalIF":13.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896902","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}
Ferroptosis holds significant potential for application in cancer therapy. However, ferroptosis inducers are not cell-specific and can cause phospholipid peroxidation in both tumor and non-tumor cells. This limitation greatly restricts the use of ferroptosis therapy as a safe and effective anticancer strategy. Our previous study demonstrated that macrophages can engulf ferroptotic cells through Toll-like receptor 2 (TLR2). Despite this advancement, the precise mechanism by which phospholipid peroxidation in macrophages affects their phagocytotic capability during treatment of tumors with ferroptotic agents is still unknown. Here, we utilized flow sorting combined with redox phospholipidomics to determine that phospholipid peroxidation in tumor microenvironment (TME) macrophages impaired the macrophages ability to eliminate ferroptotic tumor cells by phagocytosis, ultimately fostering tumor resistance to ferroptosis therapy. Mechanistically, the accumulation of phospholipid peroxidation in the macrophage endoplasmic reticulum (ER) repressed TLR2 trafficking to the plasma membrane and caused its retention in the ER by disrupting the interaction between TLR2 and its chaperone CNPY3. Subsequently, this ER-retained TLR2 recruited E3 ligase MARCH6 and initiated the proteasome-dependent degradation. Using redox phospholipidomics, we identified 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH) as the crucial mediator of these effects. Conclusively, our discovery elucidates a novel molecular mechanism underlying macrophage phospholipid peroxidation-induced tumor resistance to ferroptosis therapy and highlights the TLR2-MARCH6 axis as a potential therapeutic target for cancer therapy.
{"title":"Phospholipid peroxidation in macrophage confers tumor resistance by suppressing phagocytic capability towards ferroptotic cells","authors":"Xiang Luo, Hai-Biao Gong, Zi-Chun Li, Dong-Dong Li, Zi-Xuan Li, Jie Sun, Chang-Yu Yan, Rui-Ting Huang, Yue Feng, Shu-Rui Chen, Yun-Feng Cao, Mingxian Liu, Rong Wang, Feng Huang, Wan-Yang Sun, Hiroshi Kurihara, Wen-Jun Duan, Lei Liang, Wen Jin, Yan-Ping Wu, Rong-Rong He, Yi-Fang Li","doi":"10.1038/s41418-024-01351-0","DOIUrl":"10.1038/s41418-024-01351-0","url":null,"abstract":"Ferroptosis holds significant potential for application in cancer therapy. However, ferroptosis inducers are not cell-specific and can cause phospholipid peroxidation in both tumor and non-tumor cells. This limitation greatly restricts the use of ferroptosis therapy as a safe and effective anticancer strategy. Our previous study demonstrated that macrophages can engulf ferroptotic cells through Toll-like receptor 2 (TLR2). Despite this advancement, the precise mechanism by which phospholipid peroxidation in macrophages affects their phagocytotic capability during treatment of tumors with ferroptotic agents is still unknown. Here, we utilized flow sorting combined with redox phospholipidomics to determine that phospholipid peroxidation in tumor microenvironment (TME) macrophages impaired the macrophages ability to eliminate ferroptotic tumor cells by phagocytosis, ultimately fostering tumor resistance to ferroptosis therapy. Mechanistically, the accumulation of phospholipid peroxidation in the macrophage endoplasmic reticulum (ER) repressed TLR2 trafficking to the plasma membrane and caused its retention in the ER by disrupting the interaction between TLR2 and its chaperone CNPY3. Subsequently, this ER-retained TLR2 recruited E3 ligase MARCH6 and initiated the proteasome-dependent degradation. Using redox phospholipidomics, we identified 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH) as the crucial mediator of these effects. Conclusively, our discovery elucidates a novel molecular mechanism underlying macrophage phospholipid peroxidation-induced tumor resistance to ferroptosis therapy and highlights the TLR2-MARCH6 axis as a potential therapeutic target for cancer therapy.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 9","pages":"1184-1201"},"PeriodicalIF":13.7,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892928","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 : 2024-08-02DOI: 10.1038/s41418-024-01344-z
Dritan Liko, Louise Mitchell, Kirsteen J. Campbell, Rachel A. Ridgway, Carolyn Jones, Kate Dudek, Ayala King, Sheila Bryson, David Stevenson, Karen Blyth, Douglas Strathdee, Jennifer P. Morton, Thomas G. Bird, John R. P. Knight, Anne E. Willis, Owen J. Sansom
{"title":"Correction to: Brf1 loss and not overexpression disrupts tissues homeostasis in the intestine, liver and pancreas","authors":"Dritan Liko, Louise Mitchell, Kirsteen J. Campbell, Rachel A. Ridgway, Carolyn Jones, Kate Dudek, Ayala King, Sheila Bryson, David Stevenson, Karen Blyth, Douglas Strathdee, Jennifer P. Morton, Thomas G. Bird, John R. P. Knight, Anne E. Willis, Owen J. Sansom","doi":"10.1038/s41418-024-01344-z","DOIUrl":"10.1038/s41418-024-01344-z","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 9","pages":"1235-1237"},"PeriodicalIF":13.7,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01344-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878449","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}
Pub Date : 2024-07-30DOI: 10.1038/s41418-024-01349-8
Shimei Chen, Dandan Sun, Shuchang Zhang, Li Xu, Ning Wang, Huiming Li, Xun Xu, Fang Wei
Progressive dysfunction of the retinal pigment epithelium (RPE) and the adjacent photoreceptor cells in the outer retina plays a pivotal role in the pathogenesis of diabetic retinopathy (DR). Here, we observed a marked increase in oxidative stress-induced apoptosis in parallel with higher expression of telomeric protein TIN2 in RPE cells under hyperglycemia in vivo and in vitro. Delving deeper, we confirm that high glucose-induced elevation of mitochondria-localized TIN2 compromises mitochondrial activity and weakens the intrinsic antioxidant defense, thereby leading to the activation of mitochondria-dependent apoptotic pathways. Mechanistically, mitochondrial TIN2 promotes the phosphorylation of FOXO1 and its relocation to the mitochondria. Such translocation of transcription factor FOXO1 not only promotes its binding to the D-loop region of mitochondrial DNA—resulting in the inhibition of mitochondrial respiration—but also hampers its availability to nuclear target DNA, thereby undermining the intrinsic antioxidant defense. Moreover, TIN2 knockdown effectively mitigates oxidative-induced apoptosis in diabetic mouse RPE by preserving mitochondrial homeostasis, which concurrently prevents secondary photoreceptor damage. Our study proposes the potential of TIN2 as a promising molecular target for therapeutic interventions for diabetic retinopathy, which emphasizes the potential significance of telomeric proteins in the regulation of metabolism and mitochondrial function.
{"title":"TIN2 modulates FOXO1 mitochondrial shuttling to enhance oxidative stress-induced apoptosis in retinal pigment epithelium under hyperglycemia","authors":"Shimei Chen, Dandan Sun, Shuchang Zhang, Li Xu, Ning Wang, Huiming Li, Xun Xu, Fang Wei","doi":"10.1038/s41418-024-01349-8","DOIUrl":"10.1038/s41418-024-01349-8","url":null,"abstract":"Progressive dysfunction of the retinal pigment epithelium (RPE) and the adjacent photoreceptor cells in the outer retina plays a pivotal role in the pathogenesis of diabetic retinopathy (DR). Here, we observed a marked increase in oxidative stress-induced apoptosis in parallel with higher expression of telomeric protein TIN2 in RPE cells under hyperglycemia in vivo and in vitro. Delving deeper, we confirm that high glucose-induced elevation of mitochondria-localized TIN2 compromises mitochondrial activity and weakens the intrinsic antioxidant defense, thereby leading to the activation of mitochondria-dependent apoptotic pathways. Mechanistically, mitochondrial TIN2 promotes the phosphorylation of FOXO1 and its relocation to the mitochondria. Such translocation of transcription factor FOXO1 not only promotes its binding to the D-loop region of mitochondrial DNA—resulting in the inhibition of mitochondrial respiration—but also hampers its availability to nuclear target DNA, thereby undermining the intrinsic antioxidant defense. Moreover, TIN2 knockdown effectively mitigates oxidative-induced apoptosis in diabetic mouse RPE by preserving mitochondrial homeostasis, which concurrently prevents secondary photoreceptor damage. Our study proposes the potential of TIN2 as a promising molecular target for therapeutic interventions for diabetic retinopathy, which emphasizes the potential significance of telomeric proteins in the regulation of metabolism and mitochondrial function.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 11","pages":"1487-1505"},"PeriodicalIF":13.7,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854869","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}
Nuclear factors TOX and TOX2 upregulate TIM3 expression and lead to T-cell exhaustion in malignancies. Here, we demonstrate two distinct TIM3 expression patterns (high & low) with high TOX and TOX2 levels in T-cell acute lymphoblastic leukemia (T-ALL) specimens and cell lines. However, the mechanisms regulated by TOX and TIM3 signaling in leukemogenesis are unclear. We found that TOX and TOX2 proteins each directly upregulated HAVCR2 transcription, while the cellular localization of TOX2 was different in Jurkat and MOLT3 cells (nucleus) and lymphoblastic cell T2 and normal T cells (cytoplasm). Nuclear TOX and TOX2 formed a protein complex and repressed HAVCR2 promoter activity by recruiting transcriptional corepressor LCOR and deacetylase HDAC3. The nuclear-cytosol translocation of TOX2 was deacetylation-dependent and cooperatively mediated by deacetylase Sirt1 and kinase TBK1. Radiation damage induced TOX2 nuclear translocation and decreased Sirt1, TIM3, and caspase 1 expression in normal T cells. Accordingly, knockdown of TOX, TOX2 or LCOR; HDAC3 inhibition; or TIM3 overexpression induced Jurkat cell apoptosis in vitro and slow growth in vivo. Thus, our findings demonstrate a novel regulatory mechanism involving TOX-TOX2 and the TIM3 pathway in the leukemogenesis of T-ALL.
{"title":"TOX2 nuclear-cytosol translocation is linked to leukemogenesis of acute T-cell leukemia by repressing TIM3 transcription","authors":"Anzhou Li, Junbao Zhang, Liangping Zhan, Xiufeng Liu, Xiliang Zeng, Qian Zhu, Zifeng Wang, Jiang Li","doi":"10.1038/s41418-024-01352-z","DOIUrl":"10.1038/s41418-024-01352-z","url":null,"abstract":"Nuclear factors TOX and TOX2 upregulate TIM3 expression and lead to T-cell exhaustion in malignancies. Here, we demonstrate two distinct TIM3 expression patterns (high & low) with high TOX and TOX2 levels in T-cell acute lymphoblastic leukemia (T-ALL) specimens and cell lines. However, the mechanisms regulated by TOX and TIM3 signaling in leukemogenesis are unclear. We found that TOX and TOX2 proteins each directly upregulated HAVCR2 transcription, while the cellular localization of TOX2 was different in Jurkat and MOLT3 cells (nucleus) and lymphoblastic cell T2 and normal T cells (cytoplasm). Nuclear TOX and TOX2 formed a protein complex and repressed HAVCR2 promoter activity by recruiting transcriptional corepressor LCOR and deacetylase HDAC3. The nuclear-cytosol translocation of TOX2 was deacetylation-dependent and cooperatively mediated by deacetylase Sirt1 and kinase TBK1. Radiation damage induced TOX2 nuclear translocation and decreased Sirt1, TIM3, and caspase 1 expression in normal T cells. Accordingly, knockdown of TOX, TOX2 or LCOR; HDAC3 inhibition; or TIM3 overexpression induced Jurkat cell apoptosis in vitro and slow growth in vivo. Thus, our findings demonstrate a novel regulatory mechanism involving TOX-TOX2 and the TIM3 pathway in the leukemogenesis of T-ALL.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 11","pages":"1506-1518"},"PeriodicalIF":13.7,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01352-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854870","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}
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