Cell Death and Differentiation最新文献

{"title":"GCLC desuccinylation regulated by oxidative stress protects human cancer cells from ferroptosis","authors":"Zixiang Chen, Kaifeng Niu, Mengge Li, Yuchun Deng, Ji Zhang, Di Wei, Jiaqi Wang, Yongliang Zhao","doi":"10.1038/s41418-025-01505-8","DOIUrl":"https://doi.org/10.1038/s41418-025-01505-8","url":null,"abstract":"<p>Tumor cells evolve strong antioxidant capacities to counteract the abnormal high level of reactive oxygen species (ROS) in the tumor microenvironment. Glutamate-cysteine ligase catalyzing subunit (GCLC) for synthesis of antioxidant glutathione (GSH) represents the key enzyme to maintain redox homeostasis of tumor cells, however, whether its activity is regulated by posttranslational modifications, such as succinylation, remains to be clarified. Here, we demonstrate the existence of succinylation modification on GCLC by in vitro and in vivo assays. NAD-dependent deacetylase Sirtuin-2 (SIRT2) serves as the desuccinylase and catalyzes GCLC desuccinylation at sites of K38, K126, and K326. Specifically, GCLC directly interacts with SIRT2, which can be substantially enhanced upon ROS treatment. This strengthened association results in GCLC desuccinylation and activation, consequently promoting GSH synthesis and rendering cancer cells resistant to ferroptosis induction. Depletion of SIRT2 decreases total GSH level and meanwhile increases the cellular susceptibility to ferroptosis, which can mostly be rescued by introducing wild-type GCLC, but not its 3K-E mutant. We further demonstrated that histone acetyltransferase P300 serves as the succinyltransferase of GCLC, and their association is remarkably decreased after ROS treatment. Thus, SIRT2-regulated GCLC succinylation represents an essential signaling axis for cancer cells to maintain their redox balance in coping with oxidative stress-induced ferroptosis.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"23 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784727","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":"Lactylation-driven USP4-mediated ANXA2 stabilization and activation promotes maintenance and radioresistance of glioblastoma stem cells","authors":"Yiming Tu, Lei Xu, Guoqiang Fu, Jichen Wang, Pengfei Xia, Zeqiang Tao, Yangfan Ye, Jingming Hu, Wanzhi Cai, Hang Zhu, Qing Wu, Jing Ji","doi":"10.1038/s41418-025-01494-8","DOIUrl":"https://doi.org/10.1038/s41418-025-01494-8","url":null,"abstract":"<p>Glioblastoma (GBM) is the most primary lethal brain cancer, characterized by the presence of glioblastoma stem cells (GSCs) that initiate and sustain tumor growth and induce radioresistance. Annexin A2 (ANXA2) has been reported to contribute to glioblastoma progression and impart stem cell-like properties to GSCs, however, its post-translational modifications and mechanisms in GSCs maintenance remain poorly understood. Here, we identify that USP4 is preferentially expressed by GSCs in GBM, USP4/ANXA2 supports GSCs maintenance and radioresistance. Specifically, USP4 interacts with ANXA2, stabilizing its protein by deubiquitinating ANXA2, which mediates its proteasomal degradation and Y24 phosphorylation. USP4 directly cleaves Lys48- and Lys63-linked polyubiquitin chains of ANXA2, with the Lys63-linked polyubiquitin chains of ANXA2 K28 mediating its Y24 phosphorylation. Moreover, K10 acetylation of ANXA2 enhances its interaction with USP4. Importantly, USP4/ANXA2 promotes GSCs maintenance and radioresistance by activating BMX-mediated STAT3 activation. H3K18 lactylation is responsible for the upregulation of USP4 in GSCs. Our studies reveal that USP4/ANXA2 plays critical roles in maintaining GSCs and therapeutic resistance, highlighting the importance of lactylation, acetylation, ubiquitination, and phosphorylation as critical post-translational modifications for USP4-mediated stabilization and activity of ANXA2.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"8 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782640","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":"TM9SF1 inhibits colorectal cancer metastasis by targeting Vimentin for Tollip-mediated selective autophagic degradation","authors":"Huifen Wang, Jia Hu, Di Wang, Yudie Cai, Weiwei Zhu, Rui Deng, Yize Zhang, Zihui Dong, Zhe Yang, Juan Xiao, Ang Li, Zhibo Liu","doi":"10.1038/s41418-025-01498-4","DOIUrl":"https://doi.org/10.1038/s41418-025-01498-4","url":null,"abstract":"<p>Selective autophagy is a finely regulated degradation pathway that can either promote or suppress cancer progression depending on its specific target cargoes. In this study, we report that transmembrane 9 superfamily member 1 (TM9SF1) suppresses colorectal cancer metastasis via selective autophagic degradation of Vimentin. <i>Tm9sf1</i> knockout significantly increases tumor numbers and size, as well as enhances tumor invasion in colorectal cancer model. In vitro and in vivo phenotypical analyses reveal that TM9SF1 functions as a metastasis suppressor in colorectal cancer. Mechanistically, TM9SF1 facilitates the K63-linked ubiquitination of Vimentin by the E3 ligase TRIM21. The K63-linked ubiquitination of Vimentin serves as a recognition signal for autophagic degradation mediated by autophagic cargo receptor Tollip. Consequently, the downregulation of Vimentin results in a decreased number of F-actin-rich stress fibers and filopodium-like protrusions, ultimately inhibiting colorectal cancer metastasis. Moreover, TM9SF1 is downregulated in colorectal cancer patients with advanced stage compared to those with early stage and associated with favorable prognosis. Overall, our findings identify a novel TM9SF1-TRIM21-Vimentin-Tollip pathway involved in colorectal cancer metastasis, which may provide promising therapeutic targets for the treatment of metastatic colorectal cancer.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"22 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766504","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":"DEPTOR suppresses lymphomagenesis by promoting EGFR degradation via HUWE1 E3 ligase","authors":"Xiufang Xiong, Xiaoyu Chen, Shengpeng Shao, Danrui Cui, Ruirui Qu, Baohui Wang, Ying Ma, Hui Pan, Yi Sun, Yongchao Zhao","doi":"10.1038/s41418-025-01497-5","DOIUrl":"https://doi.org/10.1038/s41418-025-01497-5","url":null,"abstract":"<p>DEPTOR, a naturally occurring inhibitor of mTOR, plays crucial roles in tumorigenesis and is frequently dysregulated in a variety of human cancers. Interestingly, DEPTOR could act either as a tumor suppressor or as an oncogene in a manner dependent of cellular context or tissue environment. Whether and how DEPTOR regulates lymphomagenesis remains elusive. In this study, we report that in a mouse lymphoma model induced by heterozygous <i>Pten</i> loss, <i>Deptor</i> knockout (KO) markedly accelerates lymphomagenesis, whereas degradation-resistant <i>Deptor</i>^<i>S275A</i> knock-in (KI) variant significantly inhibits it. Furthermore, <i>Deptor</i> KO mice spontaneously developed lymphomas in the later stages of their lifespan, and <i>Deptor</i> KO further shortened overall lifespan in <i>Pten</i>^<i>fl/fl</i><i>;MMTV-Cre</i> mice. Consistently, DEPTOR protein levels are significantly lower in human lymphoma tissues, as compared to normal lymph nodes. Mechanistically, DEPTOR, on one hand, enhances the interaction of EGFR to HUWE1 E3 ubiquitin ligase for targeted ubiquitination and proteasomal degradation, and subsequent inactivation of the MAPK signal. On the other hand, DEPTOR inactivates both mTORC1 and mTORC2 signals. Collectively, our study demonstrated that DEPTOR is a tumor suppressor that inhibits lymphomagenesis upon <i>Pten</i>-loss. The strategy that reactivates DEPTOR could be a promising approach for the treatment of lymphoma.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"22 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758170","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":"Retraction Note: Silencing of membrane-associated sialidase Neu3 diminishes apoptosis resistance and triggers megakaryocytic differentiation of chronic myeloid leukemic cells K562 through the increase of ganglioside GM3.","authors":"C Tringali, B Lupo, F Cirillo, N Papini, L Anastasia, G Lamorte, P Colombi, R Bresciani, E Monti, G Tettamanti, B Venerando","doi":"10.1038/s41418-024-01420-4","DOIUrl":"10.1038/s41418-024-01420-4","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":"792"},"PeriodicalIF":13.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11982555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715560","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":"Cell differentiation, aging, and death in spatially organized yeast communities: mechanisms and consequences","authors":"Zdena Palková, Libuše Váchová","doi":"10.1038/s41418-025-01485-9","DOIUrl":"https://doi.org/10.1038/s41418-025-01485-9","url":null,"abstract":"<p>Cell death is a natural part of the development of multicellular organisms and is central to their physiological and pathological states. However, the existence of regulated cell death in unicellular microorganisms, including eukaryotic and prokaryotic microbes, has been a topic of debate. One reason for the continued debate is the lack of obvious benefit from cell death in the context of a single cell. However, unicellularity is relative, as most of these microbes dwell in communities of varying complexities, often with complicated spatial organization. In these spatially organized microbial communities, such as yeast and bacterial colonies and biofilms growing on solid surfaces, cells differentiate into specialized types, and the whole community often behaves like a simple multicellular organism. As these communities develop and age, cell death appears to offer benefits to the community as a whole. This review explores the potential roles of cell death in spatially organized communities of yeasts and draws analogies to similar communities of bacteria. The natural dying processes in microbial cell communities are only partially understood and may result from suicidal death genes, (self-)sabotage (without death effectors), or from non-autonomous mechanisms driven by interactions with other differentiated cells. We focus on processes occurring during the stratification of yeast colonies, the formation of the extracellular matrix in biofilms, and discuss potential roles of cell death in shaping the organization, differentiation, and overall physiology of these microbial structures.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"95 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734071","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":"Correction: Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells.","authors":"Guan Wang, Kai Cao, Keli Liu, Yueqing Xue, Arthur I Roberts, Fengying Li, Yanyan Han, Arnold B Rabson, Ying Wang, Yufang Shi","doi":"10.1038/s41418-025-01484-w","DOIUrl":"https://doi.org/10.1038/s41418-025-01484-w","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742329","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":"Macrophage junctional adhesion molecule-like (JAML) protein promotes NLRP3 inflammasome activation in the development of atherosclerosis","authors":"Huiliang Cui, Lin Xie, Hanlin Lu, Cheng Cheng, Fei Xue, Zhenguo Wu, Li Liu, Lei Qiao, Cheng Zhang, Wencheng Zhang, Jianmin Yang","doi":"10.1038/s41418-025-01489-5","DOIUrl":"https://doi.org/10.1038/s41418-025-01489-5","url":null,"abstract":"<p>Inflammation plays a crucial role in the progression of atherosclerosis. Junctional adhesion molecule-like protein (JAML), a type-I transmembrane glycoprotein, activates downstream signaling pathways. However, the precise role of macrophage-derived JAML in inflammation and atherosclerosis remains unclear. This study aimed to generate mice with macrophage-specific deletion or overexpression of JAML, with the focus of assessing its impact on macrophage function and elucidating its regulatory mechanism in atherosclerosis. High-throughput data screening was employed to investigate JAML expression in atherosclerosis, and macrophage-specific JAML-knockout and transgenic mice models were utilized to examine the effects of JAML on atherosclerosis. Furthermore, the role of JAML was assessed using Oil Red O staining, RNA-sequencing analysis, and co-immunoprecipitation techniques. Increased JAML expression was observed in macrophages from both mice and patients with atherosclerosis. Macrophage-specific JAML deletion attenuated atherosclerosis and inflammation, whereas macrophage-specific JAML overexpression exacerbated these conditions. Mechanistically, JAML deletion inhibited inflammation by decreasing nuclear translocation of pyruvate kinase M2 (PKM2) and PKM2/p65 complex formation, which consequently suppressed the nuclear factor kappa B (NF-κB) pathway and NLRP3 inflammasome activation. Taken together, these findings demonstrate that macrophage-expressed JAML facilitates the progression of atherosclerosis by activating the NF-κB pathway and NLRP3 inflammasome through nuclear migration and phosphorylation of PKM2. Notably, our study revealed a novel mechanism for the regulation of NLRP3 inflammasome activation in atherosclerosis. Therefore, targeting JAML may be an effective treatment strategy for atherosclerosis, a condition characterized by chronic inflammation.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"4 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723214","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 USP43/RNF2 axis negatively regulates antiviral innate immunity by promoting TBK1 ubiquitination and degradation","authors":"Xibao Zhao, Qianqian Di, Jin Chen, Jing Ling, Jiazheng Quan, Zizhao Zhao, Hongrui Li, Shaoying Chen, Xunwei Li, Xiwei Guo, Han Wu, Yue Xiao, Weilin Chen","doi":"10.1038/s41418-025-01491-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01491-x","url":null,"abstract":"<p>The E3 ubiquitin ligase usually regulates the substrate proteins ubiquitination and degradation, but the study of itself post-translational modification and stability is still elusive. Here, we reveal that E3 ubiquitin ligase ring finger protein 2 (RNF2) is deubiquitinated and stabilized by ubiquitin specific peptidase 43 (USP43) through interactome and quantitative ubiquitinome mass spectrometry analysis. This study demonstrated that USP43, as a deubiquitinating enzyme, negatively regulates the expression of type I interferon (IFN) and the <i>Usp43</i> deficient enhances antiviral innate immune response against VSV infection both in vitro and in vivo. Mechanistically, USP43 negatively regulates antiviral immunity by promoting RNF2-mediated TBK1 ubiquitination and degradation. USP43 stabilizes RNF2 by removing K48-linked ubiquitination of RNF2 at Lys239 and Lys249, while RNF2 promotes TBK1 degradation by increasing K48-linked ubiquitination of TBK1 at Lys670. These findings uncover the E3 ubiquitin ligase RNF2 post-translational ubiquitination modification and stability regulation, and reveals a novel mechanism that the USP43/RNF2 axis in regulating antiviral innate immunity.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"17 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723215","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 transcription factor LHX2 mediates and enhances oncogenic BMP signaling in medulloblastoma","authors":"Yae Ohata, Mohamad M. Ali, Yutaro Tsubakihara, Yuka Itoh, Gabriela Rosén, Tobias Bergström, Anita Morén, Irene Golán-Cancela, Ayana Nakada, Oleksandr Voytyuk, Maiko Tsuchiya, Rei Fukui, Kouhei Yamamoto, Paula Martín-Rubio, Patricia Sancho, Carina Strell, Patrick Micke, Robert J. Wechsler-Reya, Yoshinobu Hashizume, Kohei Miyazono, Laia Caja, Carl-Henrik Heldin, Fredrik J. Swartling, Aristidis Moustakas","doi":"10.1038/s41418-025-01488-6","DOIUrl":"https://doi.org/10.1038/s41418-025-01488-6","url":null,"abstract":"<p>Oncogenic events perturb cerebellar development leading to medulloblastoma, a common childhood brain malignancy. Molecular analyses classify medulloblastoma into the WNT, SHH, Group 3 and Group 4 subgroups. Bone morphogenetic protein (BMP) pathways control cerebellar development and have been linked to the progression of medulloblastoma disease, with major remaining gaps in their mechanistic and clinically-relevant roles. We therefore aimed at exploring BMP mechanisms of action in medulloblastoma. Patient-derived tumors from different subgroups were analyzed in mouse xenografts, complemented by independent tumor immunohistochemical analysis. Cell-based assays analyzed signaling mechanisms. Medulloblastoma cell orthotopic xenografts analyzed tumor growth and metastasis in vivo. Active BMP signaling, detected as nuclear and phosphorylated SMAD1/5, characterized several medulloblastoma subgroups, with enrichment in Group 4, SHH and Group 3 tumors. Spatial transcriptomics in tumor areas, complemented by transcriptomic analysis of multiple cell models, identified BMP-dependent transcriptional induction of the <i>LIM-homeobox gene 2</i> (<i>LHX2</i>). BMP signaling via SMADs induced <i>LHX2</i> expression and LHX2 transcriptionally induced BMP type I receptor (ACVR1) expression by association with the proximal promoter region of the <i>ACVR1</i> gene. BMP signaling and LHX2 gain-of-function expression led to enriched stemness and associated chemoresistance in medulloblastoma cultures. In-mouse orthotopic transplantation of paired primary/recurrent Group 4 medulloblastoma cell populations, correspondingly expressing LHX2-low/BMP-low signaling and LHX2-high/BMP-high signaling, ascribed to the latter (high) group more efficient tumor propagation and spinal cord metastatic potential. Depletion of LHX2 in these recurrent tumor cells suppressed both BMP signaling and tumor propagation in vivo. Thus, LHX2 cooperates with, and enhances, oncogenic BMP signaling in medulloblastoma tumors. The molecular pathway that couples LHX2 function to BMP signaling in medulloblastoma deepens our understanding this malignancy.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"30 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723209","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}