Cell Discovery最新文献

{"title":"A basigin antibody modulates MCTs to impact tumor metabolism and immunity.","authors":"Heng Zhang, Xuemei Yang, Yue Xue, Yi Huang, Yingxi Mo, Yurun Huang, Hong Zhang, Xiaofei Zhang, Weixin Zhao, Bin Jia, Ningning Li, Ning Gao, Yue Yang, Dongxi Xiang, Shan Wang, Yi Qin Gao, Jun Liao","doi":"10.1038/s41421-025-00777-1","DOIUrl":"https://doi.org/10.1038/s41421-025-00777-1","url":null,"abstract":"<p><p>Lactate metabolism and signaling intricately intertwine in the context of cancer and immunity. Basigin, working alongside monocarboxylate transporters MCT1 and MCT4, orchestrates the movement of lactate across cell membranes. Despite their potential in treating formidable tumors, the mechanisms by which basigin antibodies affect basigin and MCTs remain unclear. Our research demonstrated that basigin positively modulates MCT activity. We subsequently developed a basigin antibody that converts basigin into a negative modulator, thereby suppressing lactate transport and enhancing anti-tumor immunity. Additionally, the antibody alters metabolic profiles in NSCLC-PDOs and T cells. Cryo-EM structural analysis and molecular dynamics simulations reveal that the extracellular Ig2 domain and transmembrane domain of basigin regulate MCT1 activity through an allosteric mechanism. The antibody decreases MCT1 transition rate by reducing the flexibility of basigin's Ig2 domain and diminishing interactions between basigin's transmembrane domain and MCT1. These findings underscore the promise of basigin antibodies in combating tumors by modulating metabolism and immunity, and the value of a common therapeutic subunit shared by multiple transporter targets.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"44"},"PeriodicalIF":13.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977614","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":"Transport and inhibition mechanisms of human creatine transporter.","authors":"Jiahui Chen, Yimin Zhang, Nanhao Chen, Jingpeng Ge, Jie Yu","doi":"10.1038/s41421-025-00801-4","DOIUrl":"https://doi.org/10.1038/s41421-025-00801-4","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"43"},"PeriodicalIF":13.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972987","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":"Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease.","authors":"Eswar Kumar Nadendla, Rebecca E Tweedell, Gary Kasof, Thirumala-Devi Kanneganti","doi":"10.1038/s41421-025-00791-3","DOIUrl":"https://doi.org/10.1038/s41421-025-00791-3","url":null,"abstract":"<p><p>Caspases are critical regulators of cell death, development, innate immunity, host defense, and disease. Upon detection of pathogens, damage-associated molecular patterns, cytokines, or other homeostatic disruptions, innate immune sensors, such as NLRs, activate caspases to initiate distinct regulated cell death pathways, including non-lytic (apoptosis) and innate immune lytic (pyroptosis and PANoptosis) pathways. These cell death pathways are driven by specific caspases and distinguished by their unique molecular mechanisms, supramolecular complexes, and enzymatic properties. Traditionally, caspases are classified as either apoptotic (caspase-2, -3, -6, -7, -8, -9, and -10) or inflammatory (caspase-1, -4, -5, and -11). However, extensive data from the past decades have shown that apoptotic caspases can also drive lytic inflammatory cell death downstream of innate immune sensing and inflammatory responses, such as in the case of caspase-3, -6, -7, and -8. Therefore, more inclusive classification systems based on function, substrate specificity, or the presence of pro-domains have been proposed to better reflect the multifaceted roles of caspases. In this review, we categorize caspases into CARD-, DED-, and short/no pro-domain-containing groups and examine their critical functions in innate immunity and cell death, along with their structural and molecular mechanisms, including active site/exosite properties and substrates. Additionally, we highlight the emerging roles of caspases in cellular homeostasis and therapeutic targeting. Given the clinical relevance of caspases across multiple diseases, improved understanding of these proteins and their structure-function relationships is critical for developing effective treatment strategies.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"42"},"PeriodicalIF":13.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968960","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":"The assembly of RAB22A/TMEM33/RTN4 initiates a secretory ER-phagy pathway.","authors":"Xueping Zheng, Dongmei Fang, Hao Shan, Beibei Xiao, Denghui Wei, Yingyi Ouyang, Lanqing Huo, Zhonghan Zhang, Yuanzhong Wu, Ruhua Zhang, Tiebang Kang, Ying Gao","doi":"10.1038/s41421-025-00792-2","DOIUrl":"https://doi.org/10.1038/s41421-025-00792-2","url":null,"abstract":"<p><p>Rafeesome, a newly identified multivesicular body (MVB)-like organelle, forms through the fusion of RAB22A-mediated ER-derived noncanonical autophagosomes with RAB22A-positive early endosomes. However, the mechanism underlying the formation of RAB22A-mediated noncanonical autophagosomes remains unclear. Herein, we report a secretory ER-phagy pathway in which the assembly of RAB22A/TMEM33/RTN4 induces the clustering of high-molecular-weight RTN4 oligomers, leading to ER membrane remodeling. This remodeling drives the biogenesis of ER-derived RTN4-positive noncanonical autophagosomes, which are ultimately secreted as TMEM33-marked RAB22A-induced extracellular vesicles (R-EVs) via Rafeesome. Specifically, RAB22A interacts with the tubular ER membrane protein TMEM33, which binds to the TM2 domain of the ER-shaping protein RTN4, promoting RTN4 homo-oligomerization and thereby generating RTN4-enriched microdomains. Consequently, the RTN4 microdomains may induce high curvature of the ER, facilitating the bud scission of RTN4-positive vesicles. These vesicles are transported by ATG9A and develop into isolation membranes (IMs), which are then anchored by LC3-II, a process catalyzed by the ATG12-ATG5-ATG16L1 complex, allowing them to grow into sealed RTN4 noncanonical autophagosome. While being packaged into these ER-derived intermediate compartments, ER cargoes bypass lysosomal degradation and are directed to secretory autophagy via the Rafeesome-R-EV route. Our findings reveal a secretory ER-phagy pathway initiated by the assembly of RAB22A/TMEM33/RTN4, providing new insights into the connection between ER-phagy and extracellular vesicles.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"41"},"PeriodicalIF":13.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968969","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":"The building blocks of embryo models: embryonic and extraembryonic stem cells.","authors":"Hongan Ren, Xiaojie Jia, Leqian Yu","doi":"10.1038/s41421-025-00780-6","DOIUrl":"https://doi.org/10.1038/s41421-025-00780-6","url":null,"abstract":"<p><p>The process of a single-celled zygote developing into a complex multicellular organism is precisely regulated at spatial and temporal levels in vivo. However, understanding the mechanisms underlying development, particularly in humans, has been constrained by technical and ethical limitations associated with studying natural embryos. Harnessing the intrinsic ability of embryonic stem cells (ESCs) to self-organize when induced and assembled, researchers have established several embryo models as alternative approaches to studying early development in vitro. Recent studies have revealed the critical role of extraembryonic cells in early development; and many groups have created more sophisticated and precise ESC-derived embryo models by incorporating extraembryonic stem cell lines, such as trophoblast stem cells (TSCs), extraembryonic mesoderm cells (EXMCs), extraembryonic endoderm cells (XENs, in rodents), and hypoblast stem cells (in primates). Here, we summarize the characteristics of existing mouse and human embryonic and extraembryonic stem cells and review recent advancements in developing mouse and human embryo models.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"40"},"PeriodicalIF":13.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961026","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":"Estrogen receptor 1 signaling in hepatic stellate cells designates resistance to liver fibrosis.","authors":"Tianhao Li, Gang Wang, Han Zhao, Fuhai Liu, Zhangyuzi Deng, Dingbao Chen, Xin Zhou, Ying Cao, Wei Fu, Haoyue Zhang, Jing Yang","doi":"10.1038/s41421-025-00783-3","DOIUrl":"https://doi.org/10.1038/s41421-025-00783-3","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"37"},"PeriodicalIF":13.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954346","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":"Distinct mammary stem cells orchestrate long-term homeostasis of adult mammary gland.","authors":"Zuobao Lin, Yajing Guo, Huiru Bai, Xiaoqin Liu, Meizhen Lin, Yue Zhang, Ruolan Tang, Tian'en Hu, Lili Yu, Chunhui Wang, Shang Cai","doi":"10.1038/s41421-025-00794-0","DOIUrl":"https://doi.org/10.1038/s41421-025-00794-0","url":null,"abstract":"<p><p>The murine mammary gland is sustained by distinct pools of stem cells that are limited in space and time, exhibiting both unipotency and bipotency. However, the specific identities of the bipotent and unipotent mammary stem cells remain unclear. In this study, we investigated spatial heterogeneity of the mammary gland at the single-cell transcriptional level. We found that mammary basal cells exhibited spatially distinct populations and characteristics, which can be further divided based on the expression of CD34 and CD200 markers. Notably, CD34^-CD200⁺ basal cells enriched at the nipple region demonstrated strong long-term self-renewal ability and possessed the highest stem cell frequency, while CD34⁺CD200^- basal cells enriched in the terminal end buds (TEBs) showed reduced stem cell potency. Through lineage tracing experiments based on their signature genes, we discovered that Bcl11b⁺ cells were enriched in the CD34^-CD200⁺ population and exhibited bipotency even in the postnatal mammary gland, with an increasing contribution to mammary epithelia observed during long-term tracing and after multiple rounds of pregnancies. Conversely, lineage tracing of Sema3a⁺ cells, enriched in the CD34⁺CD200^- population, predominantly revealed their unipotent nature and significant contribution during alveologenesis. Notably, the Bcl11b⁺ cells displayed a slow response to pregnancy but contributed to long-term mammary homeostasis, in contrast to the rapid response observed in Sema3a⁺ cells. In addition, Bcl11b progenies survived much better than Sema3a progenies during involution stage, thereby exhibiting increased coverage in the mammary gland after multiple rounds of pregnancies. Importantly, depletion of Bcl11b in Krt14⁺ mammary basal cells resulted in reduced bipotency of mammary stem cells and impaired their long-term contribution to the mammary gland. Overall, our study identifies distinct bipotent and unipotent populations of mammary basal cells with different dynamic properties that play critical roles in maintaining postnatal mammary homeostasis. These findings are crucial for advancing our understanding of breast health and breast cancer research.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"39"},"PeriodicalIF":13.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962116","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":"Senescence-induced p21^high macrophages contributed to CD8⁺ T cells-related immune hyporesponsiveness in kidney transplantation via Zfp36/IL-27 axis.","authors":"Tingting Zhu, Qixia Shen, Lingling Shen, Yucheng Wang, Bochen Zhu, Lifeng Ma, Shi Feng, Cuili Wang, Sijing Yan, Jingyi Li, Zhimin Chen, Jingyi Zhou, Hongfeng Huang, Bingjue Li, Zhouji Shen, Qian Wang, Jianwei Wang, Wilfried Gwinner, Irina Scheffner, Song Rong, Bing Yang, Junwen Wang, Hermann Haller, Xiaoping Han, Guoji Guo, Zhinan Yin, Jin Jin, Hui-Yao Lan, Jianghua Chen, Hong Jiang","doi":"10.1038/s41421-025-00784-2","DOIUrl":"https://doi.org/10.1038/s41421-025-00784-2","url":null,"abstract":"<p><p>Recipients' age has emerged as a key factor that impacts on acute renal allograft rejection and graft survival. Age-related functional and structural changes in the immune system have been observed, yet the precise influence of aged immunity on kidney transplant remains unclear. In an initial retrospective analysis of clinical data gathered from two major centers in China and Germany, we found a correlation between aging and mitigated rejection outcomes in kidney recipients. To study the mechanism, we performed kidney transplantation on mice and observed attenuated allograft rejection in senescent recipients. Single-cell transcriptome analysis of allograft kidneys indicated a protective role of p21^high macrophages in aged mice. Supernatant collected from p21^high macrophage primary culture inhibited the cytotoxic function and proliferation of CD8⁺ T cells. Zfp36 is highly expressed in senescent p21^high macrophages. To determine its role in renal allograft rejection, we studied mice with Zfp36 conditionally deleted in macrophages (Zfp36-cKO). These mice developed exacerbated allograft rejection with enhanced IL-27 production and CD8⁺ T cell hyperactivation. Inhibition of IL-27 with neutralizing antibody or deletion of IL-27 receptor on CD8⁺ T cells reversed acute renal allograft rejection in Zfp36-cKO mice. Moreover, in vitro silencing Zfp36 with siRNA led to impaired degradation of IL-27 p28 mRNA and a subsequent increase of IL-27 in p21^high macrophages. In conclusion, senescent macrophages protect renal allograft rejection by suppressing CD8⁺ T cells via a Zfp36/IL-27-dependent mechanism. These findings may provide innovative therapeutic strategies for addressing kidney allograft rejection.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"38"},"PeriodicalIF":13.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984863","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":"Mechanistic insights into the acetyl-CoA recognition by SLC33A1.","authors":"Dong Zhou, Nanhao Chen, Shitang Huang, Chen Song, Zhe Zhang","doi":"10.1038/s41421-025-00793-1","DOIUrl":"https://doi.org/10.1038/s41421-025-00793-1","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"36"},"PeriodicalIF":13.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11982209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985347","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":"Structural basis for allosteric agonism of human α7 nicotinic acetylcholine receptors.","authors":"Sanling Liu, Yining Zheng, Haopeng Chen, Xin Li, Qipeng Yan, Wenjun Mu, Yaning Fu, Huan Chen, Hongwei Hou, Lei Liu, Changlin Tian","doi":"10.1038/s41421-025-00788-y","DOIUrl":"10.1038/s41421-025-00788-y","url":null,"abstract":"<p><p>The α7 nicotinic acetylcholine receptor (nAChR), a pentameric ligand-gated ion channel, plays important roles in cognition, neuroprotection, and anti-inflammation. As a potential drug target, α7 nAChR has different binding sites for different ligands, particularly agonists and positive allosteric modulators (PAMs). Ago-PAMs can both directly activate and allosterically modulate α7 nAChR. However, the mechanism underlying α7 nAChR modulation by ago-PAM has yet to be fully elucidated. Here, we present cryo-EM structures of α7 nAChR in complex with the ago-PAM GAT107 and Ca²⁺ in the open and desensitized states, respectively. Our results from both structural comparisons and functional assays suggest an allosteric mechanism underlying GAT107 modulation and calcium potentiation of α7 nAChR, involving local conformational changes in the ECD-TMD coupling region and a global structural rearrangement in the transmembrane domain. This work provides a new mechanism of α7 nAChR gating distinct from that of conventional agonist binding. These findings would aid in drug design and enrich our biophysical understanding of pentameric ligand-gated ion channels.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"35"},"PeriodicalIF":13.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11977206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802603","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}