{"title":"Structural basis of the RNA-mediated Retron-Eco2 oligomerization.","authors":"Yanjing Wang, Chen Wang, Yongqi Yin, Yongqing Cui, Zhikang Dai, Chang Liu, Yanke Chen, Zeyuan Guan, Tingting Zou","doi":"10.1038/s41421-025-00823-y","DOIUrl":"10.1038/s41421-025-00823-y","url":null,"abstract":"<p><p>In the evolutionary arms race between bacteria and viruses, retrons have emerged as distinctive antiphage defense systems. Here, we elucidate the structure and function of Retron-Eco2, which comprises a non-coding RNA (ncRNA) that encodes multicopy single-stranded DNA (msDNA, a DNA‒RNA hybrid) and a fusion protein containing a reverse transcriptase (RT) domain and a topoisomerase-primase-like (Toprim) effector domain. The Eco2 msDNA and RT-Toprim fusion protein form a 1:1 stoichiometric nucleoprotein complex that further assembles into a trimer (msDNA:RT-Toprim ratio of 3:3) with a distinctive triangular configuration. The RNA portion of the msDNA in one protomer closely intertwines around the RT domain of an adjacent protomer, mediating the formation of this self-inhibitory assembly. Upon activation, the Toprim effector domain exhibits RNase activity, degrading RNA to arrest phage replication. We further reveal that phage mutants evading Eco2-mediated defense harbor mutations in the endonuclease IV-like protein DenB, underscoring DenB's critical role in triggering the activation of this system. Together, these findings provide key structural and functional insights into Retron-Eco2, laying the groundwork for harnessing its potential in biotechnology and synthetic biology applications.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"73"},"PeriodicalIF":12.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944266","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 : 2025-08-29DOI: 10.1038/s41421-025-00828-7
Cheng Zhou, Shenbing Shan, Lei Wen, Da Liu, Changguo Shan, Xin Jin, Zhaoming Zhou, Hainan Li, Juan Li, Luyue Wang, Junguo Bu, Bin Li, Weishan Huang, Junhao Hu, Hongbo Guo, Wu Wei
{"title":"Immunological and pathological characteristics of brain parenchymal and leptomeningeal metastases from non-small cell lung cancer.","authors":"Cheng Zhou, Shenbing Shan, Lei Wen, Da Liu, Changguo Shan, Xin Jin, Zhaoming Zhou, Hainan Li, Juan Li, Luyue Wang, Junguo Bu, Bin Li, Weishan Huang, Junhao Hu, Hongbo Guo, Wu Wei","doi":"10.1038/s41421-025-00828-7","DOIUrl":"10.1038/s41421-025-00828-7","url":null,"abstract":"<p><p>Brain parenchymal metastases (BM) and leptomeningeal metastases (LM) represent distinct subtypes of central nervous system metastases (CNSm) from lung cancer, posing significant clinical challenges. The local immune landscape of LM remains elusive. Herein, we utilized single-cell RNA sequencing to build a cell atlas of LM, and systematically examine the immune profiling and cell heterogeneity between BM and LM. Our analysis reveals that BM has more CXCL9<sup>+</sup> macrophages, CXCL13<sup>+</sup>CD4<sup>+</sup> T cells and B cells than LM, exhibiting the presence of tertiary lymphoid (TLS) structures, which is associated with a favorable response to tyrosine kinase inhibitors (TKI). Conversely, a remarkably immunosuppressive tumor microenvironment (TME) is detected in LM, characterized by lymphocyte depletion and a concurrent enrichment of SPP1<sup>+</sup> macrophages, compared to BM. Furthermore, we identified significant blood-brain barrier (BBB) cell discrepancies between BM and LM, and substantial phenotypic reprogramming of BBB cells in CNSm. This reprogramming encompassed alterations in transporter gene expression, extracellular matrix production and dysregulated cell-cell interactions, potentially contributing to the metastatic process. In summary, this study highlights the divergent cellular and molecular landscapes of BM vs LM, offering critical insights into potential therapeutic targets and informing the development of improved treatment strategies for non-small cell lung cancer patients with CSNm.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"72"},"PeriodicalIF":12.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944222","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 : 2025-08-26DOI: 10.1038/s41421-025-00822-z
Jiao Li, Ding Ma, Chunxue Zhang, Xueling Zheng, Ruihan Hao, Bin Zuo, Fei Xiao, Yang Li, Yuhang Liu, Zhouyi Duan, Yao Xiong, Orion R Fan, Wenmin Zhu, Liming Dai, Bingjun Zhang, Yi Eve Sun, Xiaoling Zhang
{"title":"Targeting miR-337 mitigates disuse-induced bone loss.","authors":"Jiao Li, Ding Ma, Chunxue Zhang, Xueling Zheng, Ruihan Hao, Bin Zuo, Fei Xiao, Yang Li, Yuhang Liu, Zhouyi Duan, Yao Xiong, Orion R Fan, Wenmin Zhu, Liming Dai, Bingjun Zhang, Yi Eve Sun, Xiaoling Zhang","doi":"10.1038/s41421-025-00822-z","DOIUrl":"10.1038/s41421-025-00822-z","url":null,"abstract":"<p><p>Disuse-induced bone loss occurs in long-term bed-ridden patients and in astronauts during spaceflight. The underlying mechanisms are poorly understood. In a rodent model of disuse-induced bone loss (called hindlimb unloading (HU)), we observed that decreased numbers of leptin receptor (LepR) positive mesenchymal stem cells (MSCs) in adult bone marrow, contribute to bone loss. MicroRNA-337-3p (miR-337) was upregulated in MSCs upon HU and inhibited MSC proliferation by directly targeting IRS-1 to suppress the PI3kinase-Akt-mTOR pathway. Piezo1 was the upstream receptor for sensing mechanical stress and regulated miR-337 through the Hippo-YAP signaling pathway. Remarkably, the knockout of miR-337 significantly attenuated HU-induced, but not ovariectomy-induced, bone loss by increasing MSC proliferation and osteogenesis. Finally, the transplantation of miR-337<sup>-/-</sup> MSCs into wild-type HU mice was sufficient to mitigate bone loss. These findings reveal the cellular and molecular mechanisms underlying disuse-induced bone loss and highlight a feasible therapeutic strategy to prevent disuse- or microgravity-induced bone loss on Earth and during spaceflight.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"71"},"PeriodicalIF":12.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12378244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944235","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 : 2025-08-19DOI: 10.1038/s41421-025-00820-1
Haozheng Li, Yuanming Zheng, Chunlei Yuan, Jiayi Wang, Xiaying Zhao, Ming Yang, Defei Xiong, Yenan Yang, Yunpeng Dai, Yiming Gao, Yuqi Wang, Lei Xue, Gang Wang
{"title":"A phosphorylation switch in the Mediator MED15 controls cellular senescence and cognitive decline.","authors":"Haozheng Li, Yuanming Zheng, Chunlei Yuan, Jiayi Wang, Xiaying Zhao, Ming Yang, Defei Xiong, Yenan Yang, Yunpeng Dai, Yiming Gao, Yuqi Wang, Lei Xue, Gang Wang","doi":"10.1038/s41421-025-00820-1","DOIUrl":"10.1038/s41421-025-00820-1","url":null,"abstract":"<p><p>A hallmark of aging is chronic systemic inflammation, which is exacerbated by the hypersecretory aging phenotype known as the senescence-associated secretory phenotype (SASP). How the SASP is initiated to accelerate tissue inflammation and aging is an outstanding question in aging biology. Here, we showed that phosphorylation of the Mediator subunit MED15 at T603 is able to control the SASP and aging. Transforming growth factor-β selectively induces CDK1-mediated MED15 T603 phosphorylation to control SASP gene expression. The MED15 T603 dephosphorylated mutant (T603A) inhibits the SASP and cell senescence, whereas the T603 phosphorylation-mimicking mutant (T603D) has the opposite effect. Mechanistically, forkhead box protein A1 preferentially binds to unphosphorylated but not phosphorylated MED15 at T603 to suppress SASP gene expression. Notably, aging mice harboring dephosphorylated mutation in this phosphosite exhibit improved learning and memory through the attenuation of the SASP across tissues. Overall, our study indicates that MED15 T603 phosphorylation serves as a control switch for SASP production, which underlies tissue aging and cognitive decline and provides a novel target for age-related pathogenesis.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"69"},"PeriodicalIF":12.5,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12365249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871675","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":"Breast cancer induces CD62L<sup>+</sup> Kupffer cells via DMBT1 to promote neutrophil extracellular trap formation and liver metastasis.","authors":"Pu Tian, Qiuyao Wu, Dasa He, Wenjing Zhao, Lichao Luo, Zhenchang Jia, Wenqian Luo, Xianzhe Lv, Yanan Liu, Yuan Wang, Qian Wang, Peiyuan Zhang, Yajun Liang, Qifeng Yang, Guohong Hu","doi":"10.1038/s41421-025-00819-8","DOIUrl":"10.1038/s41421-025-00819-8","url":null,"abstract":"<p><p>The liver is a major target organ for breast cancer metastasis, while the regulatory mechanism of liver colonization by breast cancer remains largely unclear. Neutrophils are known to play important roles in metastatic colonization of cancer cells by the formation of neutrophil extracellular traps (NETs). Here we show the role and mechanism of a subpopulation of Kupffer cells (KCs), the liver resident macrophages, in mediating tumoral induction of NETs and liver metastasis. NETs are activated more abundantly in liver metastases of breast cancer, as compared to metastases to other organs and primary tumors. Liver-tropic tumor cells induce CD62L-expressing KCs by a secretory protein DMBT1, and CD62L<sup>+</sup> KCs activate neutrophils for NETosis via the chemokine CCL8. Inhibition of CCL8 or its receptor on neutrophils, CCR1, impairs NETosis and metastasis. In addition, we identified a KC membrane protein MUC1 that binds to DMBT1 and subsequently activates NF-κB signaling in KCs, leading to CCL8 and CD62L expression. KCs with MUC1 inhibition effectively suppress liver metastasis. Furthermore, a DMBT1 neutralizing antibody was developed with the promise to inhibit tumor-KC interaction and treat metastatic cancer. In conclusion, our work reveals a KC subset that accounts for the liver tropism of breast cancer cells and NETs, and provides potential strategies in metastasis treatment.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"68"},"PeriodicalIF":12.5,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12343785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834086","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 : 2025-08-05DOI: 10.1038/s41421-025-00817-w
Sangsang Li, Yifan Zhang, Maoxing Luo, Weiwei Zhou, Yitong Chen, Dinglan Wu, Qiang Wei, Yan Chang, Hailiang Hu
{"title":"AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer.","authors":"Sangsang Li, Yifan Zhang, Maoxing Luo, Weiwei Zhou, Yitong Chen, Dinglan Wu, Qiang Wei, Yan Chang, Hailiang Hu","doi":"10.1038/s41421-025-00817-w","DOIUrl":"10.1038/s41421-025-00817-w","url":null,"abstract":"<p><p>Cancer cells can be induced to dormancy initially by specific cancer therapies, but can be reactivated for subsequent relapse as therapy-resistant cancer cells. Although the treatment-induced dormancy-to-reactivation switch is an important process in tumour spread and recurrence, little is known about the underlying molecular mechanisms, particularly the metabolic underpinnings. In this study, we demonstrated that the tryptophan catabolism-related tryptophan 2,3-dioxygenase (TDO2) -kynurenine (Kyn) -aryl hydrocarbon receptor (AhR) signalling axis was responsible for both sustaining the survival of dormant prostate cancer cells induced by androgen deprivation therapy (ADT) and promoting the reactivation of dormant cells and their recurrent outgrowth, which facilitated the development of therapeutic resistance by allowing the dormancy-to-reactivation switch. Mechanistically, we found that ADT upregulated the expression of TDO2 to produce Kyn, which activated AhR and maintained the survival of ADT-induced dormant cells. Interestingly, the switch of transcription factors from the androgen receptor (AR) to the glucocorticoid receptor (GR) modulated the persistent expression of TDO2 and promoted the reactivation of dormant cells through the same TDO2-Kyn-AhR signalling axis. Additionally, tumour recurrence following ADT was delayed by pharmacological suppression of TDO2-Kyn-AhR signalling with a TDO2 inhibitor or an AhR inhibitor. In summary, we describe a signalling circuit mediated by tryptophan metabolism for regulating tumour cell dormancy and recurrence and propose TDO2 as a new target for the treatment of androgen-sensitive prostate cancer patients in combination with ADT.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"67"},"PeriodicalIF":12.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783602","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 : 2025-08-01DOI: 10.1038/s41421-025-00816-x
Sherihan Samir, Sofía Doello, Andreas M Enkerlin, Erik Zimmer, Michael Haffner, Teresa Müller, Lisa Dengler, Stilianos P Lambidis, Shamphavi Sivabalasarma, Sonja-Verena Albers, Khaled A Selim
{"title":"The second messenger c-di-AMP controls natural competence via ComFB signaling protein.","authors":"Sherihan Samir, Sofía Doello, Andreas M Enkerlin, Erik Zimmer, Michael Haffner, Teresa Müller, Lisa Dengler, Stilianos P Lambidis, Shamphavi Sivabalasarma, Sonja-Verena Albers, Khaled A Selim","doi":"10.1038/s41421-025-00816-x","DOIUrl":"10.1038/s41421-025-00816-x","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"65"},"PeriodicalIF":12.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759200","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 : 2025-07-22DOI: 10.1038/s41421-025-00815-y
Xia Xu, Qinrui Wang, Tengfei Sun, Heyi Gao, Ruichu Gu, Junzhao Yang, Jiaqi Zhou, Peng Fu, Han Wen, Guanghui Yang
{"title":"Structural basis for the activity regulation of Medicago calcium channel CNGC15.","authors":"Xia Xu, Qinrui Wang, Tengfei Sun, Heyi Gao, Ruichu Gu, Junzhao Yang, Jiaqi Zhou, Peng Fu, Han Wen, Guanghui Yang","doi":"10.1038/s41421-025-00815-y","DOIUrl":"10.1038/s41421-025-00815-y","url":null,"abstract":"<p><p>Cyclic nucleotide-gated ion channels (CNGCs) in plants mediate Ca<sup>2+</sup> influx in response to environmental changes. Among numerous plant CNGCs, Medicago truncatula CNGC15a/b/c (MtCNGC15) is localized to the nuclear envelope. The opening and closing cycle of MtCNGC15 is tightly associated with the Ca<sup>2+</sup> oscillation in symbiosis. However, the molecular mechanism underlying MtCNGC15 activity regulation remains unclear. In this study, we present the structures of MtCNGC15 in its apo form and in the presence of CaM. The apo MtCNGC15b exhibits a flexible cytoplasmic domain (CPD), whereas binding of the MtCaM inhibits Ca<sup>2+</sup> currents and stabilizes the highly dynamic CPD. Furthermore, the activity of MtCNGC15b seems to be independent of cGMP. The hypothetical binding pocket for cGMP is occupied by an arginine residue. These findings elucidate the structural basis for the activity regulation of nuclear localized MtCNGC15.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"63"},"PeriodicalIF":12.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12284214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144689018","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}