Immune cells modify their metabolic pathways in response to fungal infections. Nevertheless, the biochemical underpinnings need to be better understood. This study reports that fungal infection drives a switch from glycolysis to the serine synthesis pathway (SSP) and one-carbon metabolism by inducing the interaction of spleen tyrosine kinase (SYK) and phosphoglycerate dehydrogenase (PHGDH). As a result, PHGDH promotes SYK phosphorylation, leading to the recruitment of SYK to C-type lectin receptors (CLRs). The CLR/SYK complex initiates signaling cascades that lead to transcription factor activation and pro-inflammatory cytokine production. SYK activates SSP and one-carbon metabolism by inducing PHGDH activity. Then, one-carbon metabolism supports S-adenosylmethionine and histone H3 lysine 36 trimethylation to drive the production of pro-inflammatory cytokines and chemokines. These findings reveal the crosstalk between amino acid metabolism, epigenetic modification, and CLR signaling during fungal infection.
{"title":"PHGDH/SYK: a hub integrating anti-fungal immunity and serine metabolism","authors":"Xinyong Zhang, Dongdong Hu, Xiaoyan Sun, Yichun Gu, Yong Zhou, Chuanxin Su, Shi Liu, Caiyan Zhang, Guoping Lu, Qiwen Wu, Aidong Chen","doi":"10.1038/s41418-024-01374-7","DOIUrl":"10.1038/s41418-024-01374-7","url":null,"abstract":"Immune cells modify their metabolic pathways in response to fungal infections. Nevertheless, the biochemical underpinnings need to be better understood. This study reports that fungal infection drives a switch from glycolysis to the serine synthesis pathway (SSP) and one-carbon metabolism by inducing the interaction of spleen tyrosine kinase (SYK) and phosphoglycerate dehydrogenase (PHGDH). As a result, PHGDH promotes SYK phosphorylation, leading to the recruitment of SYK to C-type lectin receptors (CLRs). The CLR/SYK complex initiates signaling cascades that lead to transcription factor activation and pro-inflammatory cytokine production. SYK activates SSP and one-carbon metabolism by inducing PHGDH activity. Then, one-carbon metabolism supports S-adenosylmethionine and histone H3 lysine 36 trimethylation to drive the production of pro-inflammatory cytokines and chemokines. These findings reveal the crosstalk between amino acid metabolism, epigenetic modification, and CLR signaling during fungal infection.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 12","pages":"1664-1678"},"PeriodicalIF":13.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160449","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}
Transcription factor Foxk1 can regulate cell proliferation, differentiation, metabolism, and promote skeletal muscle regeneration and cardiogenesis. However, the roles of Foxk1 in bone formation is unknown. Here, we found that Foxk1 expression decreased in the bone tissue of aged mice and osteoporosis patients. Knockdown of Foxk1 in primary murine calvarial osteoblasts suppressed osteoblast differentiation and proliferation. Conditional knockout of Foxk1 in preosteoblasts and mature osteoblasts in mice exhibited decreased bone mass and mechanical strength due to reduced bone formation. Mechanistically, we identified Foxk1 targeted the promoter region of many genes of glycolytic enzyme by CUT&Tag analysis. Lacking of Foxk1 in primary murine calvarial osteoblasts resulted in reducing aerobic glycolysis. Inhibition of glycolysis by 2DG hindered osteoblast differentiation and proliferation induced by Foxk1 overexpression. Finally, specific overexpression of Foxk1 in preosteoblasts, driven by a preosteoblast specific osterix promoter, increased bone mass and bone mechanical strength of aged mice, which could be suppressed by inhibiting glycolysis. In summary, these findings reveal that Foxk1 plays a vital role in the osteoblast metabolism regulation and bone formation stimulation, offering a promising approach for preventing age-related bone loss.
{"title":"Foxk1 promotes bone formation through inducing aerobic glycolysis","authors":"Chungeng Liu, Naibo Feng, Zhenmin Wang, Kangyan Zheng, Yongheng Xie, Hongyu Wang, Houqing Long, Songlin Peng","doi":"10.1038/s41418-024-01371-w","DOIUrl":"10.1038/s41418-024-01371-w","url":null,"abstract":"Transcription factor Foxk1 can regulate cell proliferation, differentiation, metabolism, and promote skeletal muscle regeneration and cardiogenesis. However, the roles of Foxk1 in bone formation is unknown. Here, we found that Foxk1 expression decreased in the bone tissue of aged mice and osteoporosis patients. Knockdown of Foxk1 in primary murine calvarial osteoblasts suppressed osteoblast differentiation and proliferation. Conditional knockout of Foxk1 in preosteoblasts and mature osteoblasts in mice exhibited decreased bone mass and mechanical strength due to reduced bone formation. Mechanistically, we identified Foxk1 targeted the promoter region of many genes of glycolytic enzyme by CUT&Tag analysis. Lacking of Foxk1 in primary murine calvarial osteoblasts resulted in reducing aerobic glycolysis. Inhibition of glycolysis by 2DG hindered osteoblast differentiation and proliferation induced by Foxk1 overexpression. Finally, specific overexpression of Foxk1 in preosteoblasts, driven by a preosteoblast specific osterix promoter, increased bone mass and bone mechanical strength of aged mice, which could be suppressed by inhibiting glycolysis. In summary, these findings reveal that Foxk1 plays a vital role in the osteoblast metabolism regulation and bone formation stimulation, offering a promising approach for preventing age-related bone loss.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 12","pages":"1650-1663"},"PeriodicalIF":13.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131921","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}
Defects in meiotic prophase can cause meiotic chromosome missegregation and aneuploid gamete formation. Meiotic checkpoints are activated in germ cells with meiotic defects, and cells with unfixed errors are eliminated by apoptosis. How such a surveillance process is regulated remains elusive. Here, we report that a chromosome-coupled ubiquitin-proteasome pathway (UPP) regulates meiotic checkpoint activation and promotes germ cell apoptosis in C. elegans meiosis-defective mutants. We identified an F-box protein, FBXL-2, that functions as a core component within the pathway. This chromosome-coupled UPP regulates meiotic DSB repair kinetics and chromosome dynamic behaviors in synapsis defective mutants. Disrupted UPP impairs the axial recruitment of the HORMA domain protein HIM-3, which is required for efficient germ cell apoptosis in synapsis defective mutants. Our data suggest that an efficient chromosome-coupled UPP functions as a part of the meiotic surveillance system by enhancing the integrity of the meiotic chromosome axis.
减数分裂前期的缺陷可导致减数分裂染色体错误分离和非整倍体配子的形成。在存在减数分裂缺陷的生殖细胞中，减数分裂检查点会被激活，错误未被修复的细胞会被细胞凋亡所淘汰。这种监控过程是如何调控的仍是个谜。在这里，我们报告了染色体组偶联泛素-蛋白酶体途径（UPP）调节减数分裂检查点的激活，并促进秀丽隐杆线虫减数分裂缺陷突变体中生殖细胞的凋亡。我们发现了一种 F-box 蛋白 FBXL-2，它是该通路的核心成分。这种与染色体耦合的 UPP 调节减数分裂 DSB 修复动力学以及突触缺陷突变体的染色体动态行为。中断的UPP会影响HORMA结构域蛋白HIM-3的轴向招募，而HIM-3是突触缺陷突变体中有效生殖细胞凋亡所必需的。我们的数据表明，有效的染色体耦合 UPP 可通过增强减数分裂染色体轴的完整性来发挥减数分裂监控系统的作用。
{"title":"A chromosome-coupled ubiquitin-proteasome pathway is required for meiotic surveillance","authors":"Ruirui Zhang, Bohan Liu, Yuqi Tian, Mingyu Xin, Qian Li, Xiuhua Huang, Yuanyuan Liu, Li Zhao, Feifei Qi, Ruoxi Wang, Xiaoqian Meng, Jianguo Chen, Jun Zhou, Jinmin Gao","doi":"10.1038/s41418-024-01375-6","DOIUrl":"10.1038/s41418-024-01375-6","url":null,"abstract":"Defects in meiotic prophase can cause meiotic chromosome missegregation and aneuploid gamete formation. Meiotic checkpoints are activated in germ cells with meiotic defects, and cells with unfixed errors are eliminated by apoptosis. How such a surveillance process is regulated remains elusive. Here, we report that a chromosome-coupled ubiquitin-proteasome pathway (UPP) regulates meiotic checkpoint activation and promotes germ cell apoptosis in C. elegans meiosis-defective mutants. We identified an F-box protein, FBXL-2, that functions as a core component within the pathway. This chromosome-coupled UPP regulates meiotic DSB repair kinetics and chromosome dynamic behaviors in synapsis defective mutants. Disrupted UPP impairs the axial recruitment of the HORMA domain protein HIM-3, which is required for efficient germ cell apoptosis in synapsis defective mutants. Our data suggest that an efficient chromosome-coupled UPP functions as a part of the meiotic surveillance system by enhancing the integrity of the meiotic chromosome axis.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 12","pages":"1730-1745"},"PeriodicalIF":13.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137989","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}
Impaired callus remodeling significantly contributes to the delayed healing of osteoporotic fractures; however, the underlying mechanisms remain unclear. Sensory neuronal signaling plays a crucial role in bone repair. In this study, we aimed to investigate the pathological mechanisms hindering bone remodeling in osteoporotic fractures, particularly focusing on the role of sensory neuronal signaling. We demonstrate that in ovariectomized (OVX) mice, the loss of CGRP+TrkA+ sensory neuronal signaling during callus remodeling correlates with increased Cx3cr1+iOCs expression within the bone callus. Conditional knockout of Cx3cr1+iOCs restored CGRP+TrkA+ sensory neuronal, enabling normal callus remodeling progression. Mechanistically, we further demonstrate that Cx3cr1+iOCs secrete Sema3A in the osteoporotic fracture repair microenvironment, inhibiting CGRP+TrkA+ sensory neurons’ axonal regeneration and suppressing nerve–bone signaling exchange, thus hindering bone remodeling. Lastly, in human samples, we observed an association between the loss of CGRP+TrkA+ sensory neuronal signaling and increased expression of Cx3cr1+iOCs. In conclusion, enhancing CGRP+TrkA+ sensory nerve signaling by inhibiting Cx3cr1+iOCs activity presents a potential strategy for treating delayed healing in osteoporotic fractures.
{"title":"Inhibition of inflammatory osteoclasts accelerates callus remodeling in osteoporotic fractures by enhancing CGRP+TrkA+ signaling","authors":"Yuexia Shu, Zhenyu Tan, Zhen Pan, Yujie Chen, Jielin Wang, Jieming He, Jia Wang, Yuan Wang","doi":"10.1038/s41418-024-01368-5","DOIUrl":"10.1038/s41418-024-01368-5","url":null,"abstract":"Impaired callus remodeling significantly contributes to the delayed healing of osteoporotic fractures; however, the underlying mechanisms remain unclear. Sensory neuronal signaling plays a crucial role in bone repair. In this study, we aimed to investigate the pathological mechanisms hindering bone remodeling in osteoporotic fractures, particularly focusing on the role of sensory neuronal signaling. We demonstrate that in ovariectomized (OVX) mice, the loss of CGRP+TrkA+ sensory neuronal signaling during callus remodeling correlates with increased Cx3cr1+iOCs expression within the bone callus. Conditional knockout of Cx3cr1+iOCs restored CGRP+TrkA+ sensory neuronal, enabling normal callus remodeling progression. Mechanistically, we further demonstrate that Cx3cr1+iOCs secrete Sema3A in the osteoporotic fracture repair microenvironment, inhibiting CGRP+TrkA+ sensory neurons’ axonal regeneration and suppressing nerve–bone signaling exchange, thus hindering bone remodeling. Lastly, in human samples, we observed an association between the loss of CGRP+TrkA+ sensory neuronal signaling and increased expression of Cx3cr1+iOCs. In conclusion, enhancing CGRP+TrkA+ sensory nerve signaling by inhibiting Cx3cr1+iOCs activity presents a potential strategy for treating delayed healing in osteoporotic fractures.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 12","pages":"1695-1706"},"PeriodicalIF":13.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01368-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118152","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 : 2024-09-02DOI: 10.1038/s41418-024-01362-x
Kim Lecomte, Annagiada Toniolo, Esther Hoste
{"title":"Publisher Correction: Cell death as an architect of adult skin stem cell niches","authors":"Kim Lecomte, Annagiada Toniolo, Esther Hoste","doi":"10.1038/s41418-024-01362-x","DOIUrl":"10.1038/s41418-024-01362-x","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 10","pages":"1390-1390"},"PeriodicalIF":13.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01362-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119106","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 : 2024-08-30DOI: 10.1038/s41418-024-01355-w
Yu-Guang Chen, Eva Rieser, Amandeep Bhamra, Silvia Surinova, Peter Kreuzaler, Meng-Hsing Ho, Wen-Chiuan Tsai, Nieves Peltzer, Diego de Miguel, Henning Walczak
Lymphotoxin β receptor (LTβR), a member of the TNF receptor superfamily (TNFR-SF), is essential for development and maturation of lymphoid organs. In addition, LTβR activation promotes carcinogenesis by inducing a proinflammatory secretome. Yet, we currently lack a detailed understanding of LTβR signaling. In this study we discovered the linear ubiquitin chain assembly complex (LUBAC) as a previously unrecognized and functionally crucial component of the native LTβR signaling complex (LTβR-SC). Mechanistically, LUBAC-generated linear ubiquitin chains enable recruitment of NEMO, OPTN and A20 to the LTβR-SC, where they act coordinately to regulate the balance between canonical and non-canonical NF-κB pathways. Thus, different from death receptor signaling, where LUBAC prevents inflammation through inhibition of cell death, in LTβR signaling LUBAC is required for inflammatory signaling by enabling canonical and interfering with non-canonical NF-κB activation. This results in a LUBAC-dependent LTβR-driven inflammatory, protumorigenic secretome. Intriguingly, in liver cancer patients with high LTβR expression, high expression of LUBAC correlates with poor prognosis, providing clinical relevance for LUBAC-mediated inflammatory LTβR signaling.
{"title":"LUBAC enables tumor-promoting LTβ receptor signaling by activating canonical NF-κB","authors":"Yu-Guang Chen, Eva Rieser, Amandeep Bhamra, Silvia Surinova, Peter Kreuzaler, Meng-Hsing Ho, Wen-Chiuan Tsai, Nieves Peltzer, Diego de Miguel, Henning Walczak","doi":"10.1038/s41418-024-01355-w","DOIUrl":"10.1038/s41418-024-01355-w","url":null,"abstract":"Lymphotoxin β receptor (LTβR), a member of the TNF receptor superfamily (TNFR-SF), is essential for development and maturation of lymphoid organs. In addition, LTβR activation promotes carcinogenesis by inducing a proinflammatory secretome. Yet, we currently lack a detailed understanding of LTβR signaling. In this study we discovered the linear ubiquitin chain assembly complex (LUBAC) as a previously unrecognized and functionally crucial component of the native LTβR signaling complex (LTβR-SC). Mechanistically, LUBAC-generated linear ubiquitin chains enable recruitment of NEMO, OPTN and A20 to the LTβR-SC, where they act coordinately to regulate the balance between canonical and non-canonical NF-κB pathways. Thus, different from death receptor signaling, where LUBAC prevents inflammation through inhibition of cell death, in LTβR signaling LUBAC is required for inflammatory signaling by enabling canonical and interfering with non-canonical NF-κB activation. This results in a LUBAC-dependent LTβR-driven inflammatory, protumorigenic secretome. Intriguingly, in liver cancer patients with high LTβR expression, high expression of LUBAC correlates with poor prognosis, providing clinical relevance for LUBAC-mediated inflammatory LTβR signaling.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 10","pages":"1267-1284"},"PeriodicalIF":13.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01355-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100896","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 : 2024-08-24DOI: 10.1038/s41418-024-01367-6
Jiyeon Lee, Fumiyuki Sasaki, Eri Koike, Minjeong Cho, Yeongun Lee, So Hee Dho, Jina Lee, Eunji Lee, Eri Toyohara, Mika Sunakawa, Mariko Ishibashi, Huynh Hiep Hung, Saki Nishioka, Ritsuko Komine, Chiaki Okura, Masumi Shimizu, Masahito Ikawa, Akihiko Yoshimura, Rimpei Morita, Lark Kyun Kim
Despite numerous biomarkers being proposed for rheumatoid arthritis (RA), a gap remains in our understanding of their mechanisms of action. In this study, we discovered a novel role for gelsolin (GSN), an actin-binding protein whose levels are notably reduced in the plasma of RA patients. We elucidated that GSN is a key regulator of NLRP3 inflammasome activation in macrophages, providing a plausible explanation for the decreased secretion of GSN in RA patients. We found that GSN interacts with NLRP3 in LPS-primed macrophages, hence modulating the formation of the NLRP3 inflammasome complex. Reducing GSN expression significantly enhanced NLRP3 inflammasome activation. GSN impeded NLRP3 translocation to the mitochondria; it contributed to the maintenance of intracellular calcium equilibrium and mitochondrial stability. This maintenance is crucial for controlling the inflammatory response associated with RA. Furthermore, the exacerbation of arthritic symptoms in GSN-deficient mice indicates the potential of GSN as both a diagnostic biomarker and a therapeutic target. Moreover, not limited to RA models, GSN has demonstrated a protective function in diverse disease models associated with the NLRP3 inflammasome. Myeloid cell-specific GSN-knockout mice exhibited aggravated inflammatory responses in models of MSU-induced peritonitis, folic acid-induced acute tubular necrosis, and LPS-induced sepsis. These findings suggest novel therapeutic approaches that modulate GSN activity, offering promise for more effective management of RA and a broader spectrum of inflammatory conditions.
尽管针对类风湿性关节炎（RA）提出了许多生物标志物，但我们对其作用机制的了解仍然存在差距。在这项研究中，我们发现了凝胶蛋白（GSN）的新作用，凝胶蛋白是一种肌动蛋白结合蛋白，在类风湿性关节炎患者血浆中的含量明显降低。我们阐明了GSN是巨噬细胞中NLRP3炎性体活化的关键调节因子，为RA患者GSN分泌减少提供了合理解释。我们发现，在LPS刺激的巨噬细胞中，GSN与NLRP3相互作用，从而调节NLRP3炎性体复合物的形成。减少GSN的表达会明显增强NLRP3炎性体的激活。GSN 阻碍了 NLRP3 向线粒体的转运；它有助于维持细胞内钙平衡和线粒体的稳定性。这种维持对于控制与 RA 相关的炎症反应至关重要。此外，GSN 缺陷小鼠关节炎症状的加重表明，GSN 具有作为诊断生物标志物和治疗靶点的潜力。此外，GSN不仅限于RA模型，还在与NLRP3炎性体相关的多种疾病模型中显示出保护功能。在MSU诱导的腹膜炎、叶酸诱导的急性肾小管坏死和LPS诱导的败血症模型中，髓系细胞特异性GSN基因敲除小鼠表现出加重的炎症反应。这些发现提出了调节 GSN 活性的新型治疗方法，有望更有效地治疗 RA 和更广泛的炎症。
{"title":"Gelsolin alleviates rheumatoid arthritis by negatively regulating NLRP3 inflammasome activation","authors":"Jiyeon Lee, Fumiyuki Sasaki, Eri Koike, Minjeong Cho, Yeongun Lee, So Hee Dho, Jina Lee, Eunji Lee, Eri Toyohara, Mika Sunakawa, Mariko Ishibashi, Huynh Hiep Hung, Saki Nishioka, Ritsuko Komine, Chiaki Okura, Masumi Shimizu, Masahito Ikawa, Akihiko Yoshimura, Rimpei Morita, Lark Kyun Kim","doi":"10.1038/s41418-024-01367-6","DOIUrl":"10.1038/s41418-024-01367-6","url":null,"abstract":"Despite numerous biomarkers being proposed for rheumatoid arthritis (RA), a gap remains in our understanding of their mechanisms of action. In this study, we discovered a novel role for gelsolin (GSN), an actin-binding protein whose levels are notably reduced in the plasma of RA patients. We elucidated that GSN is a key regulator of NLRP3 inflammasome activation in macrophages, providing a plausible explanation for the decreased secretion of GSN in RA patients. We found that GSN interacts with NLRP3 in LPS-primed macrophages, hence modulating the formation of the NLRP3 inflammasome complex. Reducing GSN expression significantly enhanced NLRP3 inflammasome activation. GSN impeded NLRP3 translocation to the mitochondria; it contributed to the maintenance of intracellular calcium equilibrium and mitochondrial stability. This maintenance is crucial for controlling the inflammatory response associated with RA. Furthermore, the exacerbation of arthritic symptoms in GSN-deficient mice indicates the potential of GSN as both a diagnostic biomarker and a therapeutic target. Moreover, not limited to RA models, GSN has demonstrated a protective function in diverse disease models associated with the NLRP3 inflammasome. Myeloid cell-specific GSN-knockout mice exhibited aggravated inflammatory responses in models of MSU-induced peritonitis, folic acid-induced acute tubular necrosis, and LPS-induced sepsis. These findings suggest novel therapeutic approaches that modulate GSN activity, offering promise for more effective management of RA and a broader spectrum of inflammatory conditions.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 12","pages":"1679-1694"},"PeriodicalIF":13.7,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01367-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045556","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 : 2024-08-22DOI: 10.1038/s41418-024-01365-8
Jia Xiu Zhang, Pei Pei Chen, Xue Qi Li, Liang Li, Qin Yi Wu, Gui Hua Wang, Xiong Zhong Ruan, Kun Ling Ma
One of the main characteristics of diabetic kidney disease (DKD) is abnormal renal tubular fatty acid metabolism, especially defective fatty acid oxidation (FAO), accelerating tubular injury and tubulointerstitial fibrosis. Thiosulfate sulfurtransferase (TST), a mitochondrial enzyme essential for sulfur transfer, is reduced in metabolic diseases like diabetes and obesity. However, the potential role of TST in regulating fatty acid metabolic abnormalities in DKD remains unclear. Here, our data revealed decreased TST expression in the renal cortex of DKD patients. TST deficiency exacerbated tubular impairment in both diabetic and renal fibrosis mouse models, while sodium thiosulfate treatment or TST overexpression mitigated renal tubular injury with high-glucose exposure. TST downregulation mediated the decrease in S-sulfhydration of very long-chain specific acyl-CoA dehydrogenase, resulting in mitochondrial FAO dysfunction. This sequence of events exacerbates the progression of tubulointerstitial injury in DKD. Together, our findings demonstrate TST as a regulator of renal tubular injury in DKD.
{"title":"Deficiency of thiosulfate sulfurtransferase mediates the dysfunction of renal tubular mitochondrial fatty acid oxidation in diabetic kidney disease","authors":"Jia Xiu Zhang, Pei Pei Chen, Xue Qi Li, Liang Li, Qin Yi Wu, Gui Hua Wang, Xiong Zhong Ruan, Kun Ling Ma","doi":"10.1038/s41418-024-01365-8","DOIUrl":"10.1038/s41418-024-01365-8","url":null,"abstract":"One of the main characteristics of diabetic kidney disease (DKD) is abnormal renal tubular fatty acid metabolism, especially defective fatty acid oxidation (FAO), accelerating tubular injury and tubulointerstitial fibrosis. Thiosulfate sulfurtransferase (TST), a mitochondrial enzyme essential for sulfur transfer, is reduced in metabolic diseases like diabetes and obesity. However, the potential role of TST in regulating fatty acid metabolic abnormalities in DKD remains unclear. Here, our data revealed decreased TST expression in the renal cortex of DKD patients. TST deficiency exacerbated tubular impairment in both diabetic and renal fibrosis mouse models, while sodium thiosulfate treatment or TST overexpression mitigated renal tubular injury with high-glucose exposure. TST downregulation mediated the decrease in S-sulfhydration of very long-chain specific acyl-CoA dehydrogenase, resulting in mitochondrial FAO dysfunction. This sequence of events exacerbates the progression of tubulointerstitial injury in DKD. Together, our findings demonstrate TST as a regulator of renal tubular injury in DKD.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 12","pages":"1636-1649"},"PeriodicalIF":13.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016446","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 : 2024-08-22DOI: 10.1038/s41418-024-01356-9
Yunying Yang, Sichun Chen, Li Zhang, Guoxin Zhang, Yan Liu, Yiming Li, Li Zou, Lanxia Meng, Ye Tian, Lijun Dai, Min Xiong, Lina Pan, Jing Xiong, Liam Chen, Hua Hou, Zhui Yu, Zhentao Zhang
Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (α-Syn) aggregates. However, the molecular mechanisms regulating α-Syn aggregation and neuronal degeneration remain poorly understood. The peptidase M20 domain containing 1 (PM20D1) gene lies within the PARK16 locus genetically linked to PD. Single nucleotide polymorphisms regulating PM20D1 expression are associated with changed risk of PD. Dopamine (DA) metabolism and DA metabolites have been reported to regulate α-Syn pathology. Here we report that PM20D1 catalyzes the conversion of DA to N-arachidonoyl dopamine (NADA), which interacts with α-Syn and inhibits its aggregation. Simultaneously, NADA competes with α-Syn fibrils to regulate TRPV4-mediated calcium influx and downstream phosphatases, thus alleviating α-Syn phosphorylation. The expression of PM20D1 decreases during aging. Overexpression of PM20D1 or the administration of NADA in a mouse model of synucleinopathy alleviated α-Syn pathology, dopaminergic neurodegeneration, and motor impairments. These observations support the protective effect of the PM20D1-NADA pathway against the progression of α-Syn pathology in PD.
{"title":"The PM20D1-NADA pathway protects against Parkinson’s disease","authors":"Yunying Yang, Sichun Chen, Li Zhang, Guoxin Zhang, Yan Liu, Yiming Li, Li Zou, Lanxia Meng, Ye Tian, Lijun Dai, Min Xiong, Lina Pan, Jing Xiong, Liam Chen, Hua Hou, Zhui Yu, Zhentao Zhang","doi":"10.1038/s41418-024-01356-9","DOIUrl":"10.1038/s41418-024-01356-9","url":null,"abstract":"Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (α-Syn) aggregates. However, the molecular mechanisms regulating α-Syn aggregation and neuronal degeneration remain poorly understood. The peptidase M20 domain containing 1 (PM20D1) gene lies within the PARK16 locus genetically linked to PD. Single nucleotide polymorphisms regulating PM20D1 expression are associated with changed risk of PD. Dopamine (DA) metabolism and DA metabolites have been reported to regulate α-Syn pathology. Here we report that PM20D1 catalyzes the conversion of DA to N-arachidonoyl dopamine (NADA), which interacts with α-Syn and inhibits its aggregation. Simultaneously, NADA competes with α-Syn fibrils to regulate TRPV4-mediated calcium influx and downstream phosphatases, thus alleviating α-Syn phosphorylation. The expression of PM20D1 decreases during aging. Overexpression of PM20D1 or the administration of NADA in a mouse model of synucleinopathy alleviated α-Syn pathology, dopaminergic neurodegeneration, and motor impairments. These observations support the protective effect of the PM20D1-NADA pathway against the progression of α-Syn pathology in PD.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 11","pages":"1545-1560"},"PeriodicalIF":13.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142021863","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}
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