Liangbo Sun, Meng He, Dong Liu, Meihua Shan, Lingxi Chen, Mingzhen Yang, Xufang Dai, Jie Yao, Tao Li, Yan Zhang, Yang Zhang, Li Xiang, An Chen, Yingxue Hao, Fengtian He, Haojun Xiong, Jiqin Lian
{"title":"Deacetylation of ANXA2 by SIRT2 desensitizes hepatocellular carcinoma cells to donafenib via promoting protective autophagy","authors":"Liangbo Sun, Meng He, Dong Liu, Meihua Shan, Lingxi Chen, Mingzhen Yang, Xufang Dai, Jie Yao, Tao Li, Yan Zhang, Yang Zhang, Li Xiang, An Chen, Yingxue Hao, Fengtian He, Haojun Xiong, Jiqin Lian","doi":"10.1038/s41418-025-01499-3","DOIUrl":"https://doi.org/10.1038/s41418-025-01499-3","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is one of the most lethal forms of cancer globally. HCC cells frequently undergo macroautophagy, also known as autophagy, which can lead to tumor progression and chemotherapy resistance. Annexin A2 (ANXA2) has been identified as a potential therapeutic target in HCC and is involved in the regulation of autophagic process. Here, we for the first time showed that ANXA2 deacetylation plays a crucial role in donafenib-induced autophagy. Mechanistically, donafenib increased SIRT2 activity via triggering both SIRT2 dephosphorylation and deacetylation by respectively downregulating cyclin E/CDK and p300. Moreover, elevation of SIRT2 activity by donafenib caused ANXA2 deacetylation at K81/K206 sites, leading to a reduction of the binding between ANXA2 and mTOR, which resulted in a decrease of mTOR phosphorylation and activity, and ultimately promoted protective autophagy and donafenib insensitivity in HCC cells. Additionally, ANXA2 deacetylation at K81/K206 sites was positively correlated with poor prognosis in HCC patients. Meanwhile, we found that selective inhibition of SIRT2 increased the sensitivity of donafenib in HCC cells by strengthening ANXA2 acetylation. In summary, this study reveals that donafenib induces protective autophagy and decreases its sensitivity in HCC cells through enhancing SIRT2-mediated ANXA2 deacetylation, which suggest that targeting ANXA2 acetylation/deacetylation may be a promising strategy for improving the sensitivity of donafenib in HCC treatment.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"8 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901808","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}
Yun Qiu, Juliana A. Hüther, Bianca Wank, Antonia Rath, René Tykwe, Maceler Aldrovandi, Bernhard Henkelmann, Julia Mergner, Toshitaka Nakamura, Sabine Laschat, Marcus Conrad, Daniela Stöhr, Markus Rehm
{"title":"Interplay of ferroptotic and apoptotic cell death and its modulation by BH3-mimetics","authors":"Yun Qiu, Juliana A. Hüther, Bianca Wank, Antonia Rath, René Tykwe, Maceler Aldrovandi, Bernhard Henkelmann, Julia Mergner, Toshitaka Nakamura, Sabine Laschat, Marcus Conrad, Daniela Stöhr, Markus Rehm","doi":"10.1038/s41418-025-01514-7","DOIUrl":"https://doi.org/10.1038/s41418-025-01514-7","url":null,"abstract":"<p>Ferroptosis and apoptosis are widely considered to be independent cell death modalities. Ferroptotic cell death is a consequence of insufficient radical detoxification and progressive lipid peroxidation, which is counteracted by glutathione peroxidase-4 (GPX4). Apoptotic cell death can be triggered by a wide variety of stresses, including oxygen radicals, and can be suppressed by anti-apoptotic members of the BCL-2 protein family. Mitochondria are the main interaction site of BCL-2 family members and likewise a major source of oxygen radical stress. We therefore studied if ferroptosis and apoptosis might intersect and possibly interfere with one another. Indeed, cells dying from impaired GPX4 activity displayed hallmarks of both ferroptotic and apoptotic cell death, with the latter including (transient) membrane blebbing, submaximal cytochrome-c release and caspase activation. Targeting BCL-2, MCL-1 or BCL-XL with BH3-mimetics under conditions of moderate ferroptotic stress in many cases synergistically enhanced overall cell death and frequently skewed primarily ferroptotic into apoptotic outcomes. Surprisingly though, in other cases BH3-mimetics, most notably the BCL-XL inhibitor WEHI-539, counter-intuitively suppressed cell death and promoted cell survival following GPX4 inhibition. Further studies revealed that most BH3-mimetics possess previously undescribed antioxidant activities that counteract ferroptotic cell death at commonly employed concentration ranges. Our results therefore show that ferroptosis and apoptosis can intersect. We also show that combining ferroptotic stress with BH3-mimetics, context-dependently can either enhance and convert cell death outcomes between ferroptosis and apoptosis or can also suppress cell death by intrinsic antioxidant activities.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"18 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884735","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}
Congyang Li, Jiashuo Li, Siyu Du, Yunfei Ma, Yueshuai Guo, Xiangzheng Zhang, Bing Wang, Shuai Zhu, Huiqing An, Ming Chen, Junjie Guo, Longsen Han, Juan Ge, Xu Qian, Tim Schedl, Xuejiang Guo, Qiang Wang
{"title":"FTDC1/2, oocyte-specific cofactors of DNMT1 required for epigenetic regulation and embryonic development","authors":"Congyang Li, Jiashuo Li, Siyu Du, Yunfei Ma, Yueshuai Guo, Xiangzheng Zhang, Bing Wang, Shuai Zhu, Huiqing An, Ming Chen, Junjie Guo, Longsen Han, Juan Ge, Xu Qian, Tim Schedl, Xuejiang Guo, Qiang Wang","doi":"10.1038/s41418-025-01518-3","DOIUrl":"https://doi.org/10.1038/s41418-025-01518-3","url":null,"abstract":"<p>The unique epigenetic patterns during gametogenesis and embryonic development indicate the existence of specialized methylation machinery. In the present study, we describe the discovery of two oocyte-specific cofactors of DNA methyltransferase 1 (DNMT1), encoded by uncharacterized genes, ferritin domain containing 1 and 2 (<i>Ftdc1</i> and <i>Ftdc2</i>). Genetic ablation of <i>Ftdc1</i> or <i>Ftdc2</i> causes midgestation defects and female infertility. FTDC1 or FTDC2 depletion induces the progressive loss of DNA methylation including imprinted regions in early embryos. This loss correlates with a marked reduction in DNMT1 protein due to increased degradation, likely via the ubiquitin-proteasome pathway. Mechanistically, we find that FTDC1, FTDC2 and DNMT1 form a complex by direct interactions, thereby stabilizing each other. Surprisingly, knockout of <i>Ftdc1</i> or <i>Ftdc2</i> displayed stronger DNA demethylation phenotypes and earlier embryonic lethality than the <i>Dnmt1</i>-null mutant, implying their unique functions. These data suggest that FTDC1/2 are crucial players specifically involved in maintaining genomic methylation during embryogenesis, offering new insights into the epigenetic control of mammalian development.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880752","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}
F. Isil Yapici, Eric Seidel, Alina Dahlhaus, Josephine Weber, Christina Schmidt, Adriano de Britto Chaves Filho, Ming Yang, Maria Nenchova, Emre Güngör, Jenny Stroh, Ioanna Kotouza, Julia Beck, Ali T. Abdallah, Jan-Wilm Lackmann, Christina M. Bebber, Ariadne Androulidaki, Peter Kreuzaler, Almut Schulze, Christian Frezza, Silvia von Karstedt
{"title":"An atlas of ferroptosis-induced secretomes","authors":"F. Isil Yapici, Eric Seidel, Alina Dahlhaus, Josephine Weber, Christina Schmidt, Adriano de Britto Chaves Filho, Ming Yang, Maria Nenchova, Emre Güngör, Jenny Stroh, Ioanna Kotouza, Julia Beck, Ali T. Abdallah, Jan-Wilm Lackmann, Christina M. Bebber, Ariadne Androulidaki, Peter Kreuzaler, Almut Schulze, Christian Frezza, Silvia von Karstedt","doi":"10.1038/s41418-025-01517-4","DOIUrl":"https://doi.org/10.1038/s41418-025-01517-4","url":null,"abstract":"<p>Cells undergoing regulated necrosis systemically communicate with the immune system via the release of protein and non-protein secretomes. Ferroptosis is a recently described iron-dependent type of regulated necrosis driven by massive lipid peroxidation. While membrane rupture occurs during ferroptosis, a comprehensive appraisal of ferroptotic secretomes and their potential biological activity has been lacking. Here, we apply a multi-omics approach to provide an atlas of ferroptosis-induced secretomes and reveal a novel function in macrophage priming. Proteins with assigned DAMP and innate immune system function, such as MIF, heat shock proteins (HSPs), and chaperones, were released from ferroptotic cells. Non-protein secretomes with assigned inflammatory function contained oxylipins as well as TCA- and methionine-cycle metabolites. Interestingly, incubation of bone marrow-derived macrophages (BMDMs) with ferroptotic supernatants induced transcriptional reprogramming consistent with priming. Indeed, exposure to ferroptotic supernatants enhanced LPS-induced cytokine production. These results define a catalog of ferroptosis-induced secretomes and identify a biological activity in macrophage priming with important implications for the fine-tuning of inflammatory processes.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"30 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876133","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":"Alternative spliceosomal protein Eftud2 mediated Kif3a exon skipping promotes SHH-subgroup medulloblastoma progression","authors":"Ying Li, Liping Chen, Saisai Xue, Zhihong Song, Heli Liu, Hao Li, Wei Shen, Chen Zhang, Haitao Wu","doi":"10.1038/s41418-025-01512-9","DOIUrl":"https://doi.org/10.1038/s41418-025-01512-9","url":null,"abstract":"<p>Alternative splicing plays a pivotal role in various facets of organogenesis, immune response, and tumorigenesis. Medulloblastoma represents a prevalent childhood brain tumor, with approximately one-third classified as the Sonic Hedgehog (SHH) subgroup. Nevertheless, the contribution of alternative splicing to medulloblastoma oncogenesis remains elusive. This investigation delineated an upregulation of the spliceosomal protein Eftud2 in the SHH-subgroup medulloblastoma mouse model and human medulloblastoma patients. Targeted ablation of <i>Eftud2</i> in granule precursor cells (GNPs) within the cerebellum prolonged the survival of SHH-subgroup medulloblastoma mice, indicating a putative association between Eftud2 expression and medulloblastoma prognosis. Functional assays unveiled that <i>EFTUD2</i> depletion in human medulloblastoma cells significantly curtailed cellular proliferation by impeding the activation of the SHH signaling pathway. Through multi-omics sequencing analysis, it was discerned that Eftud2 influences exons 10–11 skipping of <i>Kif3a</i>, a kinesin motor critical for primary cilia formation. Notably, exons 10–11 skipping in <i>Kif3a</i> augmented human medulloblastoma cell proliferation by potentiating the transcriptional activity of Gli2. These findings underscore a robust correlation between Eftud2 and SHH-subgroup medulloblastoma, emphasizing its regulatory role in modulating downstream transcription factors through the alternative splicing of pivotal genes within the SHH signaling pathway, thereby propelling the aggressive proliferation of SHH-subgroup medulloblastoma.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"261 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866513","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":"TTK promotes mitophagy by regulating ULK1 phosphorylation and pre-mRNA splicing to inhibit mitochondrial apoptosis in bladder cancer","authors":"Kang Chen, Jinyu Chen, Yukun Cong, Qingliu He, Chunyu Liu, Jiawei Chen, Haoran Li, Yunjie Ju, Liang Chen, Yarong Song, Yifei Xing","doi":"10.1038/s41418-025-01492-w","DOIUrl":"https://doi.org/10.1038/s41418-025-01492-w","url":null,"abstract":"<p>Bladder cancer (BC) remains a major global health challenge, with poor prognosis and limited therapeutic options in advanced stages. TTK protein kinase (TTK), a serine/threonine kinase, has been implicated in the progression of various cancers, but its role in BC has not been fully elucidated. In this study, we show that TTK is significantly upregulated in BC tissues and cell lines, correlating with poor patient prognosis. Functional assays revealed that TTK promotes proliferation and inhibits apoptosis of BC cells. Mechanistically, TTK enhances mitophagy by directly phosphorylating ULK1 at Ser477, thereby activating the ULK1/FUNDC1-mediated mitophagy pathway. TTK knockdown disrupts mitophagy, leading to impaired clearance of damaged mitochondria, excessive accumulation of mitochondrial reactive oxygen species (mtROS), and activation of mitochondrial apoptosis. Furthermore, TTK phosphorylates SRSF3 at Ser108, preventing ULK1 exon 5 skipping and maintaining ULK1 mRNA stability. These findings show that TTK plays a key role in maintaining mitophagy in BC cells. Targeting TTK could offer a promising new approach for BC treatment by disrupting mitophagy and inducing mitochondrial apoptosis.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"46 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866545","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}
Lan Meng, Caoling Xu, Yuzhu Cao, Limin Wu, Yuzhang Zhu, Jiaqi Zou, Islam Uddin, Iqra Zafar, Azhar Muhammad, Xuemei Xing, Ren-tao Jin, Li He, Hongbin Liu, Wenqing Li, Jianqiang Bao
{"title":"Combinatorial tagging generates a multi-purpose knock-in mouse model revealing phase separation-dependent germ granules in RNA homeostasis and germline development","authors":"Lan Meng, Caoling Xu, Yuzhu Cao, Limin Wu, Yuzhang Zhu, Jiaqi Zou, Islam Uddin, Iqra Zafar, Azhar Muhammad, Xuemei Xing, Ren-tao Jin, Li He, Hongbin Liu, Wenqing Li, Jianqiang Bao","doi":"10.1038/s41418-025-01495-7","DOIUrl":"https://doi.org/10.1038/s41418-025-01495-7","url":null,"abstract":"<p>A large resource of epitope-tagged and Cre/CreERT2-expressing mouse models are available for studying germ granules and germline development. Germ granules are proteinaceous, membraneless organelles (MLO) involved in germ cell differentiation and maturation; however, their protein and RNA transcript constituents, as well as their functional mechanisms remain incompletely understood. Herein, we generated a versatile germline mouse model through combinatorially tagging DDX4 to enable simultaneous expression of three cistronic coding products (C-terminally tagged DDX4 - DDX4<sup>5HA</sup>, EGFP, and CreERT2) under the control of the endogenous <i>Ddx4</i> promoter. By leveraging the high-affinity HA tag, we optimized an efficient workflow to purify germ granules (Chromatoid body, CB) from spermatids, and characterized their protein and RNA transcript composition. Moreover, we explored and ascertained that DDX4-mediated, phase-separation dependent CB integrity is functionally important for recruiting distinctive long RNA transcripts and for the biogenesis of pachytene- and TE-derived piRNAs. Together, our study generated a versatile germline mouse model with a multiplicity of applications for germline study, and provided mechanistic insights into germline development as dictated by germ granules.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866547","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}
Anthony M. Boutelle, Aicha R. Mabene, David Yao, Haiqing Xu, Mengxiong Wang, Yuning J. Tang, Steven S. Lopez, Sauradeep Sinha, Janos Demeter, Ran Cheng, Brooks A. Benard, Edel M. McCrea, Liz J. Valente, Alexandros P. Drainas, Martin Fischer, Ravindra Majeti, Dmitri A. Petrov, Peter K. Jackson, Fan Yang, Monte M. Winslow, Michael C. Bassik, Laura D. Attardi
{"title":"Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network","authors":"Anthony M. Boutelle, Aicha R. Mabene, David Yao, Haiqing Xu, Mengxiong Wang, Yuning J. Tang, Steven S. Lopez, Sauradeep Sinha, Janos Demeter, Ran Cheng, Brooks A. Benard, Edel M. McCrea, Liz J. Valente, Alexandros P. Drainas, Martin Fischer, Ravindra Majeti, Dmitri A. Petrov, Peter K. Jackson, Fan Yang, Monte M. Winslow, Michael C. Bassik, Laura D. Attardi","doi":"10.1038/s41418-025-01513-8","DOIUrl":"https://doi.org/10.1038/s41418-025-01513-8","url":null,"abstract":"<p><i>TP53</i>, the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible gene <i>Zmat3</i> as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppression alone and in cooperation with other p53-inducible genes. To address these questions, we used Tuba-seq<sup>Ultra</sup> somatic genome editing and tumor barcoding in a mouse lung adenocarcinoma model, combinatorial in vivo CRISPR/Cas9 screens, meta-analyses of gene expression and Cancer Dependency Map data, and integrative RNA-sequencing and shotgun proteomic analyses. We established <i>Zmat3</i> as a core component of p53-mediated tumor suppression and identified <i>Cdkn1a</i> as the most potent cooperating p53-induced gene in tumor suppression. We discovered that ZMAT3/CDKN1A serve as near-universal effectors of p53-mediated tumor suppression that regulate cell division, migration, and extracellular matrix organization. Accordingly, combined <i>Zmat3</i>-<i>Cdkn1a</i> inactivation dramatically enhanced cell proliferation and migration compared to controls, akin to <i>p53</i> inactivation. Together, our findings place <i>ZMAT3</i> and <i>CDKN1A</i> as hubs of a p53-induced gene program that opposes tumorigenesis across various cellular and genetic contexts.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"5 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862873","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":"Age-associated reduction in ER-Mitochondrial contacts impairs mitochondrial lipid metabolism and autophagosome formation in the heart","authors":"Weilong Hong, Xue Zeng, Ruiyan Ma, Yu Tian, Huimin Miu, Xiaoping Ran, Rui Song, Zhenchun Luo, Dapeng Ju, Daqing Ma, Milad Ashrafizadeh, Sujit Kumar Bhutia, João Conde, Gautam Sethi, He Huang, Chenyang Duan","doi":"10.1038/s41418-025-01511-w","DOIUrl":"https://doi.org/10.1038/s41418-025-01511-w","url":null,"abstract":"<p>The accumulation of dysfunctional giant mitochondria is a hallmark of aged cardiomyocytes. This study investigated the core mechanism underlying this phenomenon, focusing on the disruption of mitochondrial lipid metabolism and its effects on mitochondrial dynamics and autophagy, using both naturally aging mouse models and etoposide-induced cellular senescence models. In aged cardiomyocytes, a reduction in endoplasmic reticulum-mitochondrial (ER-Mito) contacts impairs lipid transport and leads to insufficient synthesis of mitochondrial phosphatidylethanolamine (PE). A deficiency in phosphatidylserine decarboxylase (PISD) further hinders the conversion of phosphatidylserine to PE within mitochondria, exacerbating the deficit of PE production. This PE shortage disrupts autophagosomal membrane formation, leading to impaired autophagic flux and the accumulation of damaged mitochondria. Modulating LACTB expression to enhance PISD activity and PE production helps maintain mitochondrial homeostasis and the integrity of aging cardiomyocytes. These findings highlight the disruption of mitochondrial lipid metabolism as a central mechanism driving the accumulation of dysfunctional giant mitochondria in aged cardiomyocytes and suggest that inhibiting LACTB expression could serve as a potential therapeutic strategy for mitigating cardiac aging and preserving mitochondrial function.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"1 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851005","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}
Bincheng Zhou, Maojin Yin, Xian Su, Suhui Sheng, Xue Du, Jiangyun Shen, Kangmin Chen, Deqi Wang, Zhenhu Zhu, Yanqi Xu, Zhongding Li, Jianmin Li, Yuhua Li, Jing Ruan, Xu Wang
{"title":"DUBA sustains the stability of NOD2 and RIPK2 to enhance innate immune responses","authors":"Bincheng Zhou, Maojin Yin, Xian Su, Suhui Sheng, Xue Du, Jiangyun Shen, Kangmin Chen, Deqi Wang, Zhenhu Zhu, Yanqi Xu, Zhongding Li, Jianmin Li, Yuhua Li, Jing Ruan, Xu Wang","doi":"10.1038/s41418-025-01516-5","DOIUrl":"https://doi.org/10.1038/s41418-025-01516-5","url":null,"abstract":"<p>Nucleotide-binding oligomerization domain containing 2 (NOD2) detects conserved fragments of bacterial peptidoglycan in the cytosol and induces innate immune responses. Here, we found that the NOD2 signaling pathway was critically regulated by the deubiquitinating enzyme DUBA. DUBA-deficient macrophages were defective in NOD2 signaling and produced significantly lower amounts of cytokines and chemokines in response to muramyl dipeptide (MDP). DUBA potentiated NOD2-mediated signal transduction by maintaining the protein levels of NOD2 and receptor-interacting protein kinase 2 (RIPK2). Mechanistically, DUBA interacted with NOD2 and RIPK2 and removed K48-linked polyubiquitin chains from them through enzymatic activity, thereby inhibiting the proteasomal degradation of NOD2 and RIPK2. Macrophage-specific ablation of DUBA attenuated MDP-induced systematic inflammation and liver injury in mice. In addition, DUBA deficiency in macrophages rendered mice hypersensitive to DSS-induced colitis and eliminated the protective effect of MDP treatment in colitis. Thus, DUBA acts as an important regulator of NOD2-mediated signaling and innate immune responses.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"41 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836752","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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