Cell Death and Differentiation最新文献

{"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}

{"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}

{"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}

{"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}

{"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}

{"title":"CCKBR+ cancer cells contribute to the intratumor heterogeneity of gastric cancer and confer sensitivity to FOXO inhibition","authors":"Zhenya Tan, Ke Pan, Minqiong Sun, Xianzhu Pan, Zhi Yang, Zhiling Chang, Xue Yang, Jicheng Zhu, Li Zhan, Yakun Liu, Xiaofei Li, Keqiong Lin, Lin Chen, Hui Mo, Wei Luo, Chen Kan, Lunxi Duan, Hong Zheng","doi":"10.1038/s41418-024-01360-z","DOIUrl":"10.1038/s41418-024-01360-z","url":null,"abstract":"The existence of heterogeneity has plunged cancer treatment into a challenging dilemma. We profiled malignant epithelial cells from 5 gastric adenocarcinoma patients through single-cell sequencing (scRNA-seq) analysis, demonstrating the heterogeneity of gastric adenocarcinoma (GA), and identified the CCKBR+ stem cell-like cancer cells associated poorly differentiated and worse prognosis. We further conducted targeted analysis using single-cell transcriptome libraries, including 40 samples, to confirm these screening results. In addition, we revealed that FOXOs are involved in the progression and development of CCKBR+ gastric adenocarcinoma. Inhibited the expression of FOXOs and disrupting cancer cell stemness reduce the CCKBR+ GA organoid formation and impede tumor progression. Mechanically, CUT&Tag sequencing and Lectin pulldown revealed that FOXOs can activate ST3GAL3/4/5 as well as ST6GALNAC6, promoting elevated sialyation levels in CCKBR+ tumor cells. This FOXO-sialyltransferase axis contributes to the maintenance of homeostasis and the growth of CCKBR+ tumor cells. This insight provides novel perspectives for developing targeted therapeutic strategies aimed at the treating CCKBR associated gastric cancer.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 10","pages":"1302-1317"},"PeriodicalIF":13.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008377","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}

{"title":"Adapting cytoskeleton-mitochondria patterning with myocyte differentiation by promyogenic PRR33","authors":"Xuyang Fu, Feng Zhang, Xiaoxuan Dong, Linbin Pu, Yan Feng, Yang Xu, Feng Gao, Tian Liang, Jianmeng Kang, Hongke Sun, Tingting Hong, Yunxia Liu, Hongmei Zhou, Jun Jiang, Deling Yin, Xinyang Hu, Da-Zhi Wang, Jian Ding, Jinghai Chen","doi":"10.1038/s41418-024-01363-w","DOIUrl":"10.1038/s41418-024-01363-w","url":null,"abstract":"Coordinated cytoskeleton-mitochondria organization during myogenesis is crucial for muscle development and function. Our understanding of the underlying regulatory mechanisms remains inadequate. Here, we identified a novel muscle-enriched protein, PRR33, which is upregulated during myogenesis and acts as a promyogenic factor. Depletion of Prr33 in C2C12 represses myoblast differentiation. Genetic deletion of Prr33 in mice reduces myofiber size and decreases muscle strength. The Prr33 mutant mice also exhibit impaired myogenesis and defects in muscle regeneration in response to injury. Interactome and transcriptome analyses reveal that PRR33 regulates cytoskeleton and mitochondrial function. Remarkably, PRR33 interacts with DESMIN, a key regulator of cytoskeleton-mitochondria organization in muscle cells. Abrogation of PRR33 in myocytes substantially abolishes the interaction of DESMIN filaments with mitochondria, leading to abnormal intracellular accumulation of DESMIN and mitochondrial disorganization/dysfunction in myofibers. Together, our findings demonstrate that PRR33 and DESMIN constitute an important regulatory module coordinating mitochondrial organization with muscle differentiation.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"32 1","pages":"177-193"},"PeriodicalIF":13.7,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01363-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987507","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}

{"title":"Cullin 4B-RING E3 ligase negatively regulates the immunosuppressive capacity of mesenchymal stem cells by suppressing iNOS","authors":"Ruiqi Yu, Hong Han, Shuxian Chu, Liping Qin, Mengying Du, Yanyan Ma, Yufeng Wang, Wei Jiang, Yu Song, Yongxin Zou, Molin Wang, Qiao Liu, Baichun Jiang, Yaoqin Gong, Gongping Sun","doi":"10.1038/s41418-024-01359-6","DOIUrl":"10.1038/s41418-024-01359-6","url":null,"abstract":"Mesenchymal stem cells (MSCs) are multipotent stem cells that can exert immunomodulatory capacity upon stimulation with pro-inflammatory cytokines. Our previous work has identified Cullin 4B (CUL4B), a scaffold protein in the CUL4B-RING E3 ligase (CRL4B) complex, as a key regulator in the differentiation of MSCs. Here, we demonstrate the critical role of CUL4B in regulating the immunosuppressive function of MSCs. When stimulated with pro-inflammatory cytokines, MSCs lacking CUL4B display enhanced immunosuppressive capacity, which is mediated by the elevated inducible nitric oxide synthase (iNOS). TGF-β signaling can suppress iNOS by inhibiting its transcription as well as promoting its protein degradation. We show that the CRL4B complex cooperates with PRC2 complex and HDACs to repress transcription of Dlx1 and Pmepa1, two inhibitors of TGF-β signaling, leading to decreased expression and accelerated degradation of iNOS. Our study unveils the CRL4B complex as a potential therapeutic target in promoting the immunosuppressive capacity of MSCs.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"32 1","pages":"149-161"},"PeriodicalIF":13.7,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975157","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}

{"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⁺ 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.</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}

{"title":"AMDHD1 acts as a tumor suppressor and contributes to activation of TGF-β signaling pathway in cholangiocarcinoma","authors":"Zuyi Ma,&nbsp;Jia Sun,&nbsp;Zhenchong Li,&nbsp;Shanzhou Huang,&nbsp;Binglu Li","doi":"10.1038/s41418-024-01361-y","DOIUrl":"10.1038/s41418-024-01361-y","url":null,"abstract":"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.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"32 1","pages":"162-176"},"PeriodicalIF":13.7,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41418-024-01361-y.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}