Cell Discovery最新文献

{"title":"The induced-fit and catalytic mechanisms of human G6PC1.","authors":"Qihao Chen, Yuhang Wang, Renjie Li, Qinru Bai, Yan Zhao","doi":"10.1038/s41421-025-00814-z","DOIUrl":"https://doi.org/10.1038/s41421-025-00814-z","url":null,"abstract":"<p><p>Human glucose-6-phosphatase catalytic subunit 1 (hG6PC1) is a key enzyme in glucose metabolism, governing the final common step of gluconeogenesis and glycogenolysis, and directly regulating energy homeostasis. Aberrant mutations in G6PC1 directly cause glycogen storage disease type 1a, which is characterized by chronic hypoglycemia and glycogen accumulation. Additionally, abnormal G6PC1 function leads to increased fasting blood glucose. Consequently, it is a critical target for treating glucose metabolism disorders. In this study, we determine the cryo-EM structures of G6PC1 in both the partially open and fully open states, in either the apo form or in complex with the substrates G6P or F6P and the product phosphate. These structures offer distinct insights into the mechanism of hydrolysis and induced-fit, providing a structural foundation for the diagnostic analysis of disease-causing mutations in G6PC1. Moreover, we propose a potential mechanism by which phosphatidylserine regulates G6PC1 activity, providing a novel perspective on its role and implications.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"62"},"PeriodicalIF":13.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641903","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":"Decoding and reprogramming of the biosynthetic networks of mushroom-derived bioactive type II ganoderic acids in yeast.","authors":"Qin Wang, Ye Li, Shunhan Zhang, Wei Yuan, Zeqian Du, Ting Shi, Zhao Chang, Xingye Zhai, Yinhua Lu, Meng Wang, Juan Guo, Jian-Jiang Zhong, Han Xiao","doi":"10.1038/s41421-025-00812-1","DOIUrl":"10.1038/s41421-025-00812-1","url":null,"abstract":"<p><p>Mushroom's specialized secondary metabolites possess important pharmacological activities, but their biosynthetic pathway elucidation is extremely challenging, not to mention reprogramming of their biosynthetic networks to target metabolites. By taking Ganoderma lucidum, a famous traditional medicinal mushroom, as a lead example, here we decoded the biosynthetic networks of type II ganoderic acids (TIIGAs), a group of its main bioactive metabolites by studying the coordinated gene expression in G. lucidum, identifying endogenous or heterologous enzymes capable of C22 hydroxylation, configuration conversion of C3 hydroxyl group, and acetylation on C3, C15 and C22 hydroxyl groups. Notably, we revealed the catalytic mechanism of the C22 hydroxylase CYP512W6, and an unexpected bifunctional acetyltransferase GlAT that is required to transfer acetyl groups to C15 and C22. Using a fluorescence-guided integration method, we achieved efficient biosynthesis of significant TIIGAs applicable to industrial fermentation. After introducing all the identified enzymes to baker's yeast, we observed that biosynthesis of downstream TIIGAs was severely impeded, and dredged the metabolic block by temporally regulating the expression of acetyltransferases. By reprogramming of the biosynthetic networks of TIIGAs, we were able to produce over 30 TIIGAs, exhibiting 1-4 orders of magnitude higher titers or efficiencies than those from farmed mushrooms. The work enables the access to valuable TIIGAs, facilitates their widespread application, and sheds light on research of other mushroom products.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"61"},"PeriodicalIF":13.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583199","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":"Spatially resolved C1QC⁺ macrophage-CD4⁺ T cell niche in colorectal cancer microenvironment: implications for immunotherapy response.","authors":"Hangyu Zhang, Libing Hong, Zhen Dong, Shan Xin, Bo Lin, Jinlin Cheng, Weihong Tian, Bin Li, Jing Wang, Xiaoyan Liu, Chuan Liu, Yuzhi Jin, Yanzhi Feng, Ge Su, Xuqi Sun, Qiqi Liu, Xiaomeng Dai, Yang Gao, Zhou Tong, Lulu Liu, Xudong Zhu, Yi Zheng, Peng Zhao, Tiannan Guo, Weijia Fang, Xuanwen Bao","doi":"10.1038/s41421-025-00811-2","DOIUrl":"10.1038/s41421-025-00811-2","url":null,"abstract":"<p><p>Colorectal cancer (CRC), including both microsatellite instability (MSI) and microsatellite stability (MSS) subtypes, frequently exhibits intrinsic resistance to immunotherapy. However, the spatial tumor microenvironment (TME) and its role in distinguishing immunotherapy responders from non-responders remain poorly understood. In this study, spatial multiomics, including imaging mass cytometry (n = 50 in-house), spatial proteomics (n = 50 in-house), and spatial transcriptomics (n = 9 in-house), were employed to elucidate the spatial TME of metastatic CRC (mCRC) patients receiving immunotherapy. These methodologies were integrated with single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and bulk proteomics for comprehensive analysis and validation. A spatial immune atlas containing 314,774 cells was constructed. We found that C1QC⁺ resident tissue macrophages (RTMs) were more abundant in responders regardless of microsatellite status. Co-localization of C1QC⁺ RTMs with CD4⁺ T cells was observed in responders, and MHC-II expression facilitated their interaction. In contrast, cancer-associated fibroblasts inhibited this interaction in non-responders. Moreover, whole genome screening identified key genes involved in antigen presentation in C1QC⁺ RTMs. Hence, our study highlights the importance of spatial immune mapping in revealing the complex spatial topology of CRC and corresponding immunotherapy response.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"60"},"PeriodicalIF":13.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12219098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539103","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":"Molecular mechanism of pH sensing and activation in GPR4 reveals proton-mediated GPCR signaling.","authors":"Chongzhao You, Shimeng Guo, Tianwei Zhang, Xinheng He, Tianyu Gao, Wenwen Xin, Zining Zhu, Yujie Lu, Youwei Xu, Zhen Li, Yumu Zhang, Xi Cheng, Yi Jiang, Xin Xie, H Eric Xu","doi":"10.1038/s41421-025-00807-y","DOIUrl":"10.1038/s41421-025-00807-y","url":null,"abstract":"<p><p>Maintaining pH homeostasis is critical for cellular function across all living organisms. Proton-sensing G protein-coupled receptors (GPCRs), particularly GPR4, play a pivotal role in cellular responses to pH changes. Yet, the molecular mechanisms underlying their proton sensing and activation remain incompletely understood. Here we present high-resolution cryo-electron microscopy structures of GPR4 in complex with G proteins under physiological and acidic pH conditions. Our structures reveal an intricate proton-sensing mechanism driven by a sophisticated histidine network in the receptor's extracellular domain. Upon protonation of key histidines under acidic conditions, a remarkable conformational cascade is initiated, propagating from the extracellular region to the intracellular G protein-coupling interface. This dynamic process involves precise transmembrane helix rearrangements and conformational shifts of conserved motifs, mediated by strategically positioned water molecules. Notably, we discovered a bound bioactive lipid, lysophosphatidylcholine, which has positive allosteric effects on GPR4 activation. These findings provide a comprehensive framework for understanding proton sensing in GPCRs and the interplay between pH sensing and lipid regulation, offering insights into cellular pH homeostasis and potential therapies for pH-related disorders.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"59"},"PeriodicalIF":13.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12187918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483265","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":"Sleep prevents brain phosphoproteome disruption to safeguard survival.","authors":"Jing Ma, Juhang Liu, Yu Li, Yikui Zhao, Yu Tian, Bing Hu, Kaiyue Yan, Ying Li, Kaihang Ding, Xiangyu Wang, Huiwen Tian, Wen Si, Ketong Liu, Huiran Zhang, Chongchong Zhao, Guangfu Wang, Zhiqiang Wang","doi":"10.1038/s41421-025-00809-w","DOIUrl":"10.1038/s41421-025-00809-w","url":null,"abstract":"<p><p>Prolonged sleep deprivation (Pr-SD) causes death in many species. While various mechanisms related to sleep regulation or this fatal consequence of sleep loss have been identified, the core molecular basis linking Pr-SD-induced lethality and sleep homeostasis remains unknown in mammals. A critical \"point of no return (PONE)\" status in Pr-SD subjects is highlighted in classic research, and characterizing PONE status could help uncover this mystery. Using a Pr-SD model and a reliable PONE status prediction method, we show that mice in PONE exhibit an inability to enter natural sleep, and significant disruptions in brain phosphoproteome, independent of deprivation time but closely linked to PONE status. Brain kinase or phosphatase dysfunction influences PONE status development and leads to corresponding sleep aberration concurrently. Daily 80-min recovery sleep significantly delays PONE onset and restores brain phosphoproteome. The harmful effects of excessive kinase activity on PONE development can be eliminated by combining recovery sleep and compensatory phosphatase expression. We conclude that sleep is crucial for maintaining brain phosphoproteome homeostasis, whose disruption may impact both Pr-SD-induced lethality and sleep regulation.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"58"},"PeriodicalIF":13.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12187926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483266","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 polymorphism of the antigenic loop in HBV surface antigen dictates binding of diverse neutralizing antibodies.","authors":"Xiao He, Weiyu Tao, Yunlu Kang, Jiaxuan Xu, Xiaoyu Liu, Lei Chen","doi":"10.1038/s41421-025-00803-2","DOIUrl":"10.1038/s41421-025-00803-2","url":null,"abstract":"<p><p>The Hepatitis B Virus (HBV) poses a significant health threat, causing millions of deaths each year. Hepatitis B surface antigen (HBsAg), the sole membrane protein on the HBV viral envelope, plays crucial roles in viral attachment to host cells and serves as the target for neutralizing antibodies (NAbs). Despite its functional and therapeutic significance, the mechanisms by which NAbs recognize HBsAg remain elusive. Here, we found that HBsAg proteins exist in distinct subtypes and are recognized by different groups of antibodies. Cryo-electron microscopy (Cryo-EM) structures of HBsAg dimers in complex with NAb Fab fragments reveal that the antigenic loop (AGL) of these distinct HBsAg types share a common structural core comprised of four β-strands. However, their surface structures exhibit unexpected polymorphism due to distinct disulfide bond linkages within the AGL region. This structural polymorphism determines the recognition of HBsAg by different groups of NAbs.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"57"},"PeriodicalIF":13.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309589","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":"Targeted depletion of dysfunctional hematopoietic stem cells mitigates myeloid-biased differentiation in aged mice.","authors":"Xiangle Ren, Yuting Wang, Yi Zhang","doi":"10.1038/s41421-025-00810-3","DOIUrl":"10.1038/s41421-025-00810-3","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"56"},"PeriodicalIF":13.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12149288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257435","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":"A potent and broad CD4 binding site neutralizing antibody with strong ADCC activity from a Chinese HIV-1 elite neutralizer.","authors":"Yingdan Wang, Ping Ji, Qianying Liu, Nannan Jia, Yunping Ma, Tianyi Yuan, Palizhati Rehati, Jiali Chen, Yumei Wen, Fan Wu, Jinghe Huang","doi":"10.1038/s41421-025-00808-x","DOIUrl":"10.1038/s41421-025-00808-x","url":null,"abstract":"<p><p>The discovery of broadly neutralizing antibodies (bNAbs) that target conserved epitopes on the HIV-1 envelope glycoprotein (Env) has garnered significant attention for its potential in the development of effective therapeutic and vaccine strategies. In this study, we isolated and characterized a CD4 binding site (CD4bs) antibody, FD22, from an elite neutralizer in China who had been infected with a clade B virus through contaminated blood plasma for 23 years. The heavy chain of FD22 was derived from a rarely reported IGHV3-30 germline gene and exhibited an exceptionally high degree of somatic hypermutation (SHM) (37%), along with a long and unique CDRH3 loop of 20-amino acids. FD22 exhibited potent and broad neutralizing activity, comparable to that of the well-known bNAb VRC01. It effectively neutralized 82% of a panel of 145 diverse HIV-1 pseudoviruses, including the two major circulating strains in China, CRF01_AE and CRF07_BC. FD22 bound strongly to HIV-1-infected cell lines, efficiently engaged FcγRIIIa receptors, triggered NK cell degranulation and the release of key cytokines such as IFN-γ and β-chemokines, and robustly induced antibody-dependent cellular cytotoxicity (ADCC) against HIV-1-infected target cells. Structural prediction for FD22 and the HIV Env SOSIP trimer performed by AlphaFold3, site-mutagenesis, and autologous virus reverse mutation assays revealed that the epitope of FD22 spans key CD4 binding site, including Loop D, the CD4 binding loop (CD4 BLP), and the V5 Loop. The unique long CDRH3 loop of FD22 interacts with the CD4 binding site through its negatively charged residue R102, distinguishing it from other CD4bs antibodies. Our findings provide valuable insights into the mechanisms of FD22 in viral neutralization and ADCC. The dual functionality of FD22 enhances its potential as a promising therapeutic antibody and offers new avenues for designing CD4bs-targeting vaccines with enhanced ADCC capabilities.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"55"},"PeriodicalIF":13.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12149299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257434","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 analysis of full-length human transmembrane protein 94 argues against its classification as a P-type Mg²⁺ ATPase.","authors":"Yuqi Li, Ye Cong, Xinyao Lou, Weiping Li, Runhao Wang, Mingyu Gong, Jiaxian Xiao, Dandan Qian, Chuangye Yan, Deshun Gong","doi":"10.1038/s41421-025-00806-z","DOIUrl":"10.1038/s41421-025-00806-z","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"54"},"PeriodicalIF":13.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215028","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":"Genomic locus of lncRNA-Gm26793 forms an inter-chromosomal interaction with Cubn to ensure proper stem cell differentiation in vitro and in vivo.","authors":"Zhiwen Liu, Xin Wan, Jiehui Chen, Yongjian Ma, Yonggao Fu, Yingying Chen, Mingzhu Wen, Yun Yang, Yun Qian, Yong Zhang, Dahai Zhu, Jinsong Li, Naihe Jing, Xianfa Yang","doi":"10.1038/s41421-025-00805-0","DOIUrl":"10.1038/s41421-025-00805-0","url":null,"abstract":"<p><p>Inter-chromosomal interactions play a crucial role in 3D genome organization, yet the organizational principles and functional significances remain elusive. In general, lncRNA loci and transcripts are frequently associated with transcriptional programs modulated by long-range chromatin interactions. Here, we identified a novel lncRNA named Gm26793, which is abundantly distributed in the primitive streak and mesodermal cells of embryonic day 7.5 mouse gastrula. Through genetic ablation of Gm26793, we observed a preferential responsiveness to primitive endoderm lineage during stem cell differentiation, as well as enhanced occurrence of transient and degenerative state cells in early mouse embryos when the cell fate segregates between epiblast and primitive endoderm. Mechanistically, we revealed that the genomic locus of Gm26793, rather than the lncRNA transcript or adjacent gene, governs the cell fate preference towards primitive endoderm. Concretely, Gm26793 locus (Chromosome 7) forms an inter-chromosomal molecular lock with Cubn (Chromosome 2) via CTCF, restraining the expression of Cubn and maintaining a natural epigenetic landscape, thus ensuring the proper lineage specification in vitro and in vivo. Overall, our study provides a clear paradigm that inter-chromosomal interaction collaborates with architectural factors to stabilize nuclear conformation and guarantee faithful gene expression during stem cell differentiation and mammalian embryogenesis.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"53"},"PeriodicalIF":13.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215027","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}