{"title":"Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanism.","authors":"Yangxia Tan, Jiawei Li, Shiyan Zhang, Yonglei Zhang, Zhiyi Zhuo, Xiaodan Ma, Yue Yin, Yanling Jiang, Yao Cong, Guoyu Meng","doi":"10.1038/s41421-024-00735-3","DOIUrl":"10.1038/s41421-024-00735-3","url":null,"abstract":"<p><p>Promyelocytic leukemia protein (PML) nuclear bodies (NBs) are essential in regulating tumor suppression, antiviral response, inflammation, metabolism, aging, and other important life processes. The re-assembly of PML NBs might lead to an ~100% cure of acute promyelocytic leukemia. However, until now, the molecular mechanism underpinning PML NB biogenesis remains elusive due to the lack of structural information. In this study, we present the cryo-electron microscopy (cryo-EM) structure of the PML dimer at an overall resolution of 5.3 Å, encompassing the RING, B-box1/2 and part of the coiled-coil (RBCC) domains. The integrated approach, combining crosslinking and mass spectrometry (XL-MS) and functional analyses, enabled us to observe a unique folding event within the RBCC domains. The RING and B-box1/2 domains fold around the α3 helix, and the α6 helix serves as a pivotal interface for PML dimerization. More importantly, further characterizations of the cryo-EM structure in conjugation with AlphaFold2 prediction, XL-MS, and NB formation assays, help unveil an unprecedented octopus-like mechanism in NB assembly, wherein each CC helix of a PML dimer (PML dimer A) interacts with a CC helix from a neighboring PML dimer (PML dimer B) in an anti-parallel configuration, ultimately leading to the formation of a 2 µm membrane-less subcellular organelle.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"118"},"PeriodicalIF":13.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11589706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715555","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}
Cell DiscoveryPub Date : 2024-11-19DOI: 10.1038/s41421-024-00725-5
Xinyi Wang, Zuoquan Xie, Jie Yuan, Enjing Jin, Wen Lian, Shuaishuai Chang, Guangqiang Sun, Zhengnan Feng, Hui Xu, Chen Du, Xinying Yang, Aihua Xia, Ji Qiu, Qingli Zhang, Feifei Lin, Jia Liu, Liang Li, Xiaoguang Du, Zhongping Xiao, Zhou Yi, Zhiyu Luo, Changrong Ge, Rui Li, Mingyue Zheng, Yi Jiang, Tao Wang, Jing Zhang, Qihao Guo, Meiyu Geng
{"title":"Sodium oligomannate disrupts the adherence of Rib<sup>high</sup> bacteria to gut epithelia to block SAA-triggered Th1 inflammation in 5XFAD transgenic mice.","authors":"Xinyi Wang, Zuoquan Xie, Jie Yuan, Enjing Jin, Wen Lian, Shuaishuai Chang, Guangqiang Sun, Zhengnan Feng, Hui Xu, Chen Du, Xinying Yang, Aihua Xia, Ji Qiu, Qingli Zhang, Feifei Lin, Jia Liu, Liang Li, Xiaoguang Du, Zhongping Xiao, Zhou Yi, Zhiyu Luo, Changrong Ge, Rui Li, Mingyue Zheng, Yi Jiang, Tao Wang, Jing Zhang, Qihao Guo, Meiyu Geng","doi":"10.1038/s41421-024-00725-5","DOIUrl":"10.1038/s41421-024-00725-5","url":null,"abstract":"<p><p>Sodium oligomannate (GV-971), an oligosaccharide drug approved in China for treating mild-to-moderate Alzheimer's disease (AD), was previously found to recondition the gut microbiota and limit altered peripheral Th1 immunity in AD transgenic mice. As a follow-up study, we here made advances by pinpointing a Lactobacillus murinus (L.m.) strain that highly expressed a gene encoding a putative adhesin containing Rib repeats (Rib<sup>high</sup>-L.m.) particularly enriched in 5XFAD transgenic mice. Mechanistically, Rib<sup>high</sup>-L.m. adherence to the gut epithelia upregulated fecal metabolites, among which lactate ranked as the top candidate. Excess lactate stimulated the epithelial production of serum amyloid A (SAA) in the gut via the GPR81-NFκB axis, contributing to peripheral Th1 activation. Moreover, GV-971 disrupted the adherence of Rib<sup>high</sup>-L.m. to gut epithelia via direct binding to Rib, which corrected the excess lactate, reduced SAA, and alleviated Th1-skewed inflammation. Together, we gained further insights into the molecular link between gut bacteria and AD progression and the mechanism of GV-971 in treating AD.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"115"},"PeriodicalIF":13.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667143","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}
Cell DiscoveryPub Date : 2024-11-12DOI: 10.1038/s41421-024-00732-6
Changhuo Cen, Bowen Liu, Limei Lin, Zhiming Shen, Nan Wang, Liangjun Zhang, Kai Meng, Min Chen, Fei Gao
{"title":"The -KTS isoform of Wt1 induces the transformation of Leydig cells into granulosa-like cells.","authors":"Changhuo Cen, Bowen Liu, Limei Lin, Zhiming Shen, Nan Wang, Liangjun Zhang, Kai Meng, Min Chen, Fei Gao","doi":"10.1038/s41421-024-00732-6","DOIUrl":"10.1038/s41421-024-00732-6","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"113"},"PeriodicalIF":13.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613657","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}
Cell DiscoveryPub Date : 2024-11-12DOI: 10.1038/s41421-024-00737-1
Xing Sun, Yangyang Zhou, Shengjie Sun, Siyuan Qiu, Menglan Peng, Han Gong, Junxiao Guo, Chengcai Wen, Yibin Zhang, Yifang Xie, Hui Li, Long Liang, Guoyan Luo, Wencan Wu, Jing Liu, Weihong Tan, Mao Ye
{"title":"Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching.","authors":"Xing Sun, Yangyang Zhou, Shengjie Sun, Siyuan Qiu, Menglan Peng, Han Gong, Junxiao Guo, Chengcai Wen, Yibin Zhang, Yifang Xie, Hui Li, Long Liang, Guoyan Luo, Wencan Wu, Jing Liu, Weihong Tan, Mao Ye","doi":"10.1038/s41421-024-00737-1","DOIUrl":"10.1038/s41421-024-00737-1","url":null,"abstract":"<p><p>Solid stress, originating from rigid and elastic components of extracellular matrix and cells, is a typical physical hallmark of tumors. Mounting evidence indicates that elevated solid stress drives metastasis and affects prognosis. However, the molecular mechanism of how cancer cells sense solid stress, thereby exacerbating malignancy, remains elusive. In this study, our clinical data suggest that elevated stress in metastatic solid tumors is highly associated with the expression of cytoskeleton-associated protein 4 (CKAP4). Intriguingly, CKAP4, as a sensitive intracellular mechanosensor, responds specifically to solid stress in a subset of studied tumor micro-environmental elements through liquid-liquid phase separation. These micron-scaled CKAP4 puncta adhere tightly onto microtubules and dramatically reorchestrate their curvature and branching to enhance cell spreading, which, as a result, boosts cancer cell motility and facilitates distant metastasis in vivo. Mechanistically, the intrinsically disordered region 1 (IDR1) of CKAP4 binds to microtubules, while IDR2 governs phase separation due to the Ca<sub>v</sub>1.2-dependent calcium influx, which collectively remodels microtubules. These findings reveal an unprecedented mechanism of how cancer cells sense solid stress for cancer malignancy and bridge the gap between cancer physics and cancer cell biology.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"114"},"PeriodicalIF":13.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142635897","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}
Cell DiscoveryPub Date : 2024-11-05DOI: 10.1038/s41421-024-00726-4
Long Yan, Wan Tu, Xuehan Zhao, Haifeng Wan, Jiaqi Wu, Yan Zhao, Jun Wu, Yingpu Sun, Lan Zhu, Yingying Qin, Linli Hu, Hua Yang, Qiong Ke, Wenzhe Zhang, Wei Luo, Zhenyu Xiao, Xueyu Chen, Qiqian Wu, Beijia He, Man Teng, Shanjun Dai, Jinglei Zhai, Hao Wu, Xiaokui Yang, Fan Guo, Hongmei Wang
{"title":"Stem cell transplantation extends the reproductive life span of naturally aging cynomolgus monkeys.","authors":"Long Yan, Wan Tu, Xuehan Zhao, Haifeng Wan, Jiaqi Wu, Yan Zhao, Jun Wu, Yingpu Sun, Lan Zhu, Yingying Qin, Linli Hu, Hua Yang, Qiong Ke, Wenzhe Zhang, Wei Luo, Zhenyu Xiao, Xueyu Chen, Qiqian Wu, Beijia He, Man Teng, Shanjun Dai, Jinglei Zhai, Hao Wu, Xiaokui Yang, Fan Guo, Hongmei Wang","doi":"10.1038/s41421-024-00726-4","DOIUrl":"10.1038/s41421-024-00726-4","url":null,"abstract":"<p><p>The ovary is crucial for female reproduction and health, as it generates oocytes and secretes sex hormones. Transplantation of mesenchymal stem cells (MSCs) has been shown to alleviate pathological ovarian aging. However, it is unclear whether MSCs could benefit the naturally aging ovary. In this study, we first examined the dynamics of ovarian reserve of Chinese women during perimenopause. Using a naturally aging cynomolgus monkey (Macaca fascicularis) model, we found that transplanting human embryonic stem cells-derived MSC-like cells, which we called M cells, into the aging ovaries significantly decreased ovarian fibrosis and DNA damage, enhanced secretion of sex hormones and improved fertility. Encouragingly, a healthy baby monkey was born after M-cell transplantation. Moreover, single-cell RNA sequencing analysis and in vitro functional validation suggested that apoptosis, oxidative damage, inflammation, and fibrosis were mitigated in granulosa cells and stromal cells following M-cell transplantation. Altogether, these findings demonstrate the beneficial effects of M-cell transplantation on aging ovaries and expand our understanding of the molecular mechanisms underlying ovarian aging and stem cell-based alleviation of this process.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"111"},"PeriodicalIF":13.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575097","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":"Bacterial toxins induce non-canonical migracytosis to aggravate acute inflammation.","authors":"Diyin Li, Qi Yang, Jianhua Luo, Yangyushuang Xu, Jingqing Li, Liang Tao","doi":"10.1038/s41421-024-00729-1","DOIUrl":"10.1038/s41421-024-00729-1","url":null,"abstract":"<p><p>Migracytosis is a recently described cellular process that generates and releases membrane-bound pomegranate-like organelles called migrasomes. Migracytosis normally occurs during cell migration, participating in various intercellular biological functions. Here, we report a new type of migracytosis induced by small GTPase-targeting toxins. Unlike classic migracytosis, toxin-induced migrasome formation does not rely on cell migration and thus can occur in both mobile and immobile cells. Such non-canonical migracytosis allows the cells to promptly respond to microbial stimuli such as bacterial toxins and effectors and release informative cellular contents in bulk. We demonstrated that C. difficile TcdB3 induces liver endothelial cells and Kupffer cells to produce migrasomes in vivo. Moreover, the migracytosis-defective Tspan9<sup>‒/‒</sup> mice show less acute inflammation and lower lethality rate in the toxin challenge assay. Therefore, we propose that the non-canonical migracytosis acts as a new mechanism for mammalian species to sense and exacerbate early immune response upon microbial infections.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"112"},"PeriodicalIF":13.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582149","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}
Cell DiscoveryPub Date : 2024-10-29DOI: 10.1038/s41421-024-00720-w
Yohei Saito, Yi Xiao, Jun Yao, Yunhai Li, Wendao Liu, Arseniy E Yuzhalin, Yueh-Ming Shyu, Hongzhong Li, Xiangliang Yuan, Ping Li, Qingling Zhang, Ziyi Li, Yongkun Wei, Xuedong Yin, Jun Zhao, Seyed M Kariminia, Yao-Chung Wu, Jinyang Wang, Jun Yang, Weiya Xia, Yutong Sun, Eek-Hoon Jho, Paul J Chiao, Rosa F Hwang, Haoqiang Ying, Huamin Wang, Zhongming Zhao, Anirban Maitra, Mien-Chie Hung, Ronald A DePinho, Dihua Yu
{"title":"Targeting a chemo-induced adaptive signaling circuit confers therapeutic vulnerabilities in pancreatic cancer.","authors":"Yohei Saito, Yi Xiao, Jun Yao, Yunhai Li, Wendao Liu, Arseniy E Yuzhalin, Yueh-Ming Shyu, Hongzhong Li, Xiangliang Yuan, Ping Li, Qingling Zhang, Ziyi Li, Yongkun Wei, Xuedong Yin, Jun Zhao, Seyed M Kariminia, Yao-Chung Wu, Jinyang Wang, Jun Yang, Weiya Xia, Yutong Sun, Eek-Hoon Jho, Paul J Chiao, Rosa F Hwang, Haoqiang Ying, Huamin Wang, Zhongming Zhao, Anirban Maitra, Mien-Chie Hung, Ronald A DePinho, Dihua Yu","doi":"10.1038/s41421-024-00720-w","DOIUrl":"10.1038/s41421-024-00720-w","url":null,"abstract":"<p><p>Advanced pancreatic ductal adenocarcinomas (PDACs) respond poorly to all therapies, including the first-line treatment, chemotherapy, the latest immunotherapies, and KRAS-targeting therapies. Despite an enormous effort to improve therapeutic efficacy in late-stage PDAC patients, effective treatment modalities remain an unmet medical challenge. To change the status quo, we explored the key signaling networks underlying the universally poor response of PDAC to therapy. Here, we report a previously unknown chemo-induced symbiotic signaling circuit that adaptively confers chemoresistance in patients and mice with advanced PDAC. By integrating single-cell transcriptomic data from PDAC mouse models and clinical pathological information from PDAC patients, we identified Yap1 in cancer cells and Cox2 in stromal fibroblasts as two key nodes in this signaling circuit. Co-targeting Yap1 in cancer cells and Cox2 in stroma sensitized PDAC to Gemcitabine treatment and dramatically prolonged survival of mice bearing late-stage PDAC, whereas simultaneously inhibiting Yap1 and Cox2 only in cancer cells was ineffective. Mechanistically, chemotherapy triggers non-canonical Yap1 activation by nemo-like kinase in 14-3-3ζ-overexpressing PDAC cells and increases secretion of CXCL2/5, which bind to CXCR2 on fibroblasts to induce Cox2 and PGE2 expression, which reciprocally facilitate PDAC cell survival. Finally, analyses of PDAC patient data revealed that patients who received Statins, which inhibit Yap1 signaling, and Cox2 inhibitors (including Aspirin) while receiving Gemcitabine displayed markedly prolonged survival compared to others. The robust anti-tumor efficacy of Statins and Aspirin, which co-target the chemo-induced adaptive circuit in the tumor cells and stroma, signifies a unique therapeutic strategy for PDAC.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"109"},"PeriodicalIF":13.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521126","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":"NUMB dysfunction defines a novel mechanism underlying hyperuricemia and gout.","authors":"Jingwei Chi, Ying Chen, Changgui Li, Shiguo Liu, Kui Che, Zili Kong, Ziheng Guo, Yanchen Chu, Yajing Huang, Libo Yang, Cunwei Sun, Yunyang Wang, Wenshan Lv, Qing Zhang, Hui Guo, Han Zhao, Zhitao Yang, Lili Xu, Ping Wang, Bingzi Dong, Jianxia Hu, Shihai Liu, Fei Wang, Yanyun Zhao, Mengmeng Qi, Yu Xin, Huiqi Nan, Xiangzhong Zhao, Wei Zhang, Min Xiao, Ke Si, Yangang Wang, Yihai Cao","doi":"10.1038/s41421-024-00708-6","DOIUrl":"10.1038/s41421-024-00708-6","url":null,"abstract":"<p><p>Defective renal excretion and increased production of uric acid engender hyperuricemia that predisposes to gout. However, molecular mechanisms underlying defective uric acid excretion remain largely unknown. Here, we report a rare genetic variant of gout-unprecedented NUMB gene within a hereditary human gout family, which was identified by an unbiased genome-wide sequencing approach. This dysfunctional missense variant within the conserved region of the NUMB gene (NUMB<sup>R630H</sup>) underwent intracellular redistribution and degradation through an autophagy-dependent mechanism. Mechanistically, we identified the uric acid transporter, ATP Binding Cassette Subfamily G Member 2 (ABCG2), as a novel NUMB-binding protein through its intracellular YxNxxF motif. In polarized renal tubular epithelial cells (RTECs), NUMB promoted ABCG2 trafficking towards the apical plasma membrane. Genetic loss-of-function of NUMB resulted in redistribution of ABCG2 in the basolateral domain and ultimately defective excretion of uric acid. To recapitulate the clinical situation in human gout patients, we generated a NUMB<sup>R630H</sup> knock-in mouse strain, which showed marked increases of serum urate and decreased uric acid excretion. The NUMB<sup>R630H</sup> knock-in mice exhibited clinically relevant hyperuricemia. In summary, we have uncovered a novel NUMB-mediated mechanism of uric acid excretion and a functional missense variant of NUMB in humans, which causes hyperuricemia and gout.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"106"},"PeriodicalIF":13.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458787","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}
Cell DiscoveryPub Date : 2024-10-22DOI: 10.1038/s41421-024-00736-2
Shanshan Li, Graham Redweik, Jason L J Lin, Yi-Ning Chen, Hanna S Yuan, Ding Xue
{"title":"Probing the importance of AIF interaction with endonuclease G in mitochondrial inheritance and neurodegeneration.","authors":"Shanshan Li, Graham Redweik, Jason L J Lin, Yi-Ning Chen, Hanna S Yuan, Ding Xue","doi":"10.1038/s41421-024-00736-2","DOIUrl":"https://doi.org/10.1038/s41421-024-00736-2","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"107"},"PeriodicalIF":13.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495675","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}