Cell Death & Disease最新文献

{"title":"DARPins as a novel tool to detect and degrade p73.","authors":"Philipp Münick, Jasmin Zielinski, Alexander Strubel, Niklas Gutfreund, Birgit Dreier, Jonas V Schaefer, Birgit Schäfer, Jakob Gebel, Christian Osterburg, Apirat Chaikuad, Stefan Knapp, Andreas Plückthun, Volker Dötsch","doi":"10.1038/s41419-024-07304-2","DOIUrl":"https://doi.org/10.1038/s41419-024-07304-2","url":null,"abstract":"<p><p>The concept of Targeted Protein Degradation (TPD) has been introduced as an attractive alternative to the development of classical inhibitors. TPD can extend the range of proteins that can be pharmacologically targeted beyond the classical targets for small molecule inhibitors, as a binding pocket is required but its occupancy does not need to lead to inhibition. The method is based on either small molecules that simultaneously bind to a protein of interest and to a cellular E3 ligase and bring them in close proximity (molecular glue) or a bi-functional molecule synthesized from the chemical linkage of a target protein-specific small molecule and one that binds to an E3 ligase (Proteolysis Targeting Chimeras (PROTAC)). The further extension of this approach to bioPROTACs, in which a small protein-based binding module is fused directly to an E3 ligase or an E3 ligase adaptor protein, makes virtually all proteins amenable to targeted degradation, as this method eliminates the requirement for binding pockets for small molecules. Designed Ankyrin Repeat Proteins (DARPins) represent a very attractive class of small protein-based binding modules that can be used for the development of bioPTOTACS. Here we describe the characterization of two DARPins generated against the oligomerization domain and the SAM domain of the transcription factor p73, a member of the p53 protein family. The DARPins can be used for (isoform-)selective pulldown experiments both in cell culture as well as primary tissue lysates. We also demonstrate that they can be used for staining in cell culture experiments. Fusing them to the speckle type POZ protein (SPOP), an adaptor protein for cullin-3 E3 ligase complexes, yields highly selective and effective degraders. We demonstrate that selective degradation of the ΔNp73α isoform reactivates p53.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"909"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853154","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":"Epoxy metabolites of linoleic acid promote the development of breast cancer via orchestrating PLEC/NFκB1/CXCL9-mediated tumor growth and metastasis.","authors":"Kai-Di Ni, Xian Fu, Ying Luo, Xin He, Hou-Hua Yin, Dong-Ping Mo, Jing-Xian Wu, Ming-Jun Wu, Xiao Zheng, Ya-Nan Liu, Qing Jiang, Ling-Tong Zhang, Ai-Zhi Lin, Ling Huang, Qing-Jin Pan, Xue-Dong Yin, Huan-Yu Zhang, Yi-Wen Meng, Xue Zhou, Jianbo Pan, Zufeng Guo, Jun-Yan Liu","doi":"10.1038/s41419-024-07300-6","DOIUrl":"https://doi.org/10.1038/s41419-024-07300-6","url":null,"abstract":"<p><p>Breast cancer (BC) is a common malignant tumor in women and requires a comprehensive understanding of its pathogenesis for the development of new therapeutic strategies. Polyunsaturated fatty acids (PUFAs) metabolism-driven inflammation is a causative factor in cancer development. However, the function of PUFAs' metabolism in BC remains largely unknown. Here we report the role and underlying mechanism of epoxyoctadecenoic acids (EpOMEs), the metabolites of linoleic acid mediated by cytochrome P450 (CYP) monooxygenases, in promoting the development of BC, particularly triple-negative BC (TNBC). A metabolomics study identified that EpOMEs were significantly increased in the plasma of BC patients and MMTV-PyMT mice, which accounted for the upregulation of CYP2J2 in BC tumor tissues and tumor cells. Decreased EpOMEs by treatment of CYP monooxygenase inhibitors significantly alleviated tumor development in MMTV-PyMT mice. Treatment with EpOMEs and overexpression of CYP2J2 to increase EpOMEs in TNBC cells significantly promoted cellular proliferation, migration, tumor growth, and metastasis. Whereas knockdown of CYP2J2 to decrease EpOMEs inhibited tumorigenesis and lung metastasis of TNBC, which was reversed by EpOME administration. Transcriptomics and proteomics analyses revealed CXCL9 and PLEC were critical for EpOME-mediated promotion of TNBC. Knockdown of CXCL9 and PLEC inhibited TNBC progression and EpOME-mediated promotion of TNBC. Both overexpression of CYP2J2 and EpOME treatment upregulate PLEC, while PLEC upregulates NFκB1, which is a transcription regulator of CXCL9. This study extends the understanding of the function of PUFAs metabolism in BC development, providing potential therapeutic targets and dietary guidelines for patients with TNBC and other BCs. The illustration of the hypothetical mechanism CYP2J2/EpOMEs promotes the tumorigenesis and metastasis of TNBC via PLEC/NFKB1/CXCL9 signaling pathway.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"901"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853164","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: TSG101 depletion dysregulates mitochondria and PML NBs, triggering MAD2-overexpressing interphase cell death (MOID) through AIFM1-PML-DAXX pathway.","authors":"Yao Xi, Rui Xu, Shengnan Chen, Jiezhu Fang, Xiang Duan, Yidan Zhang, Guoli Zhong, Zhifei He, Yan Guo, Xinyu Li, Wenzhi Tao, Yang Li, Yan Li, Lei Fang, Yohei Niikura","doi":"10.1038/s41419-024-07294-1","DOIUrl":"https://doi.org/10.1038/s41419-024-07294-1","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"888"},"PeriodicalIF":8.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834039","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: The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma.","authors":"Jin Li, Zhongwu Li, Yaping Wu, Yanling Wang, Dongmiao Wang, Wei Zhang, Hua Yuan, Jinhai Ye, Xiaomeng Song, Jianrong Yang, Hongbing Jiang, Jie Cheng","doi":"10.1038/s41419-024-07280-7","DOIUrl":"https://doi.org/10.1038/s41419-024-07280-7","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"887"},"PeriodicalIF":8.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834020","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: NudCL2 regulates cell migration by stabilizing both myosin-9 and LIS1 with Hsp90.","authors":"Wenwen Chen, Wei Wang, Xiaoxia Sun, Shanshan Xie, Xiaoyang Xu, Min Liu, Chunxia Yang, Min Li, Wen Zhang, Wei Liu, Liangjing Wang, Tianhua Zhou, Yuehong Yang","doi":"10.1038/s41419-024-07256-7","DOIUrl":"10.1038/s41419-024-07256-7","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"886"},"PeriodicalIF":8.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806256","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":"Correction: CHAC1 blockade suppresses progression of lung adenocarcinoma by interfering with glucose metabolism via hijacking PKM2 nuclear translocation.","authors":"Junfan Pan, Sixuan Wu, Qihong Pan, Yuan Zhang, Liu He, Qiwei Yao, Jinyuan Chen, Jiancheng Li, Yiquan Xu","doi":"10.1038/s41419-024-07235-y","DOIUrl":"10.1038/s41419-024-07235-y","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"885"},"PeriodicalIF":8.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799457","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":"Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria.","authors":"Yusuke Hirata, Yuto Yamada, Soma Taguchi, Ryota Kojima, Haruka Masumoto, Shinnosuke Kimura, Takuya Niijima, Takashi Toyama, Ryoji Kise, Emiko Sato, Yasunori Uchida, Junya Ito, Kiyotaka Nakagawa, Tomohiko Taguchi, Asuka Inoue, Yoshiro Saito, Takuya Noguchi, Atsushi Matsuzawa","doi":"10.1038/s41419-024-07237-w","DOIUrl":"10.1038/s41419-024-07237-w","url":null,"abstract":"<p><p>Conjugated fatty acids (CFAs) have been known for their anti-tumor activity. However, the mechanism of action remains unclear. Here, we identify CFAs as inducers of glutathione peroxidase 4 (GPX4) degradation through chaperone-mediated autophagy (CMA). CFAs, such as (10E,12Z)-octadecadienoic acid and α-eleostearic acid (ESA), induced GPX4 degradation, generation of mitochondrial reactive oxygen species (ROS) and lipid peroxides, and ultimately ferroptosis in cancer cell lines, including HT1080 and A549 cells, which were suppressed by either pharmacological blockade of CMA or genetic deletion of LAMP2A, a crucial molecule for CMA. Mitochondrial ROS were sufficient and necessary for CMA-dependent GPX4 degradation. Oral administration of an ESA-rich oil attenuated xenograft tumor growth of wild-type, but not that of LAMP2A-deficient HT1080 cells, accompanied by increased lipid peroxidation, GPX4 degradation and cell death. Our study establishes mitochondria as the key target of CFAs to trigger lipid peroxidation and GPX4 degradation, providing insight into ferroptosis-based cancer therapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"884"},"PeriodicalIF":8.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11624192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791176","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":"KDM1A epigenetically enhances RAD51 expression to suppress the STING-associated anti-tumor immunity in esophageal squamous cell carcinoma.","authors":"Qingyuan Yang, Shiyin Wei, Cen Qiu, Chenjie Han, Zunguo Du, Ning Wu","doi":"10.1038/s41419-024-07275-4","DOIUrl":"10.1038/s41419-024-07275-4","url":null,"abstract":"<p><p>Histone lysine demethylase LSD1, also known as KDM1A, has been found to regulate multiple cancer hallmarks since it was first identified in 2004. Recently, it has emerged as a promising target for stimulating anti-tumor immunity, specifically boosting T cell activity. However, it remains unclear whether and how it remodels the tumor microenvironment to drive oncogenic processes in esophageal squamous cell carcinoma (ESCC). In this study, protein levels in ESCC tissues were evaluated by immunostaining of tissue microarrays. Cell growth was assessed by colony formation assays in vitro and subcutaneous xenograft models in vivo. High-throughput transcriptomics and spatial immune proteomics were performed using bulk RNA sequencing and digital spatial profiling techniques, respectively. Epigenetic regulation of RAD51 by methylated histone proteins was analyzed using chromatin immunoprecipitated quantitative PCR assays. Finally, our clinical data indicate that KDM1A precisely predicts the overall survival of patients with early-stage ESCC. Inhibition of KDM1A blocked the growth of ESCC cells in vitro and in vivo. Mechanistically, our transcriptomics and spatial immune proteomics data, together with rescue assays, demonstrated that KDM1A specifically removes methyl residues from the histone protein H3K9me2, a transcription repressive marker, thus reducing its enrichment at the promoter of RAD51 to epigenetically reactivate its transcription. Additionally, it significantly inhibits the expression of NF-κB signaling-dependent proinflammatory genes IL-6 and IL-1B through RAD51, thus blocking the STING-associated anti-tumor immunity in stromal tumor-infiltrating lymphocytes (sTIL). Overall, our findings not only indicate that KDM1A is a promising target for ESCC patients at early stages but also provide novel mechanistic insights into its spatial regulation of STING-associated anti-tumor immunity in sTILs to drive the oncogenic processes in ESCC. The translation of these findings will ultimately guide more appropriate combinations of spatial immunotherapies with KDM1A inhibitors to improve the overall survival of specific subgroups in ESCC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"882"},"PeriodicalIF":8.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11621790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784239","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":"Why Bax detection in >1400 publications might be flawed.","authors":"Kristin Entrop, Senait Wieske, Markus Rehm","doi":"10.1038/s41419-024-07273-6","DOIUrl":"10.1038/s41419-024-07273-6","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"880"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11621539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784242","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":"SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia.","authors":"Alice Zhao, Laura Maple, Juwei Jiang, Katie N Myers, Callum G Jones, Hannah Gagg, Connor McGarrity-Cottrell, Ola Rominiyi, Spencer J Collis, Greg Wells, Marufur Rahman, Sarah J Danson, Darren Robinson, Carl Smythe, Chun Guo","doi":"10.1038/s41419-024-07271-8","DOIUrl":"10.1038/s41419-024-07271-8","url":null,"abstract":"<p><p>SUMOylation, the covalent attachment of the small ubiquitin-like modifier (SUMO) to target proteins, and its reversal, deSUMOylation by SUMO proteases like Sentrin-specific proteases (SENPs), are crucial for initiating cellular responses to hypoxia. However, their roles in subsequent adaptation processes to hypoxia such as mitochondrial autophagy (mitophagy) remain unexplored. Here, we show that general SUMOylation, particularly SUMO2/3 modification, suppresses mitophagy under both normoxia and hypoxia. Furthermore, we identify deSUMO2/3-ylation enzyme SENP3 and mitochondrial Fission protein 1 (FIS1) as key players in hypoxia-induced mitophagy (HIM), with SUMOylatable FIS1 acting as a crucial regulator for SENP3-mediated HIM regulation. Interestingly, we find that hypoxia promotes FIS1 SUMO2/3-ylation and triggers an interaction between SUMOylatable FIS1 and Rab GTPase-activating protein Tre-2/Bub2/Cdc16 domain 1 family member 17 (TBC1D17), which in turn suppresses HIM. Therefore, we propose a novel SUMOylation-dependent pathway where the SENP3-FIS1 axis promotes HIM, with TBC1D17 acting as a fine-tuning regulator. Importantly, the SENP3-FIS1 axis plays a protective role against hypoxia-induced cell death, highlighting its physiological significance, and hypoxia-inducible FIS1-TBC1D17 interaction is detectable in primary glioma stem cell-like (GSC) cultures derived from glioblastoma patients, suggesting its disease relevance. Our findings not only provide new insights into SUMOylation/deSUMOylation regulation of HIM but also suggest the potential of targeting this pathway to enhance cellular resilience under hypoxic stress.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"881"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11621581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784240","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}