Cell Discovery最新文献

{"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}

{"title":"NUDT21 lactylation reprograms alternative polyadenylation to promote cuproptosis resistance.","authors":"Jinlong Lin, Yixin Yin, Jinghua Cao, Yiyang Zhang, Jiewei Chen, Rixin Chen, Bingxu Zou, Cijun Huang, Yongrui Lv, Shuidan Xu, Han Yang, Peng Lin, Dan Xie","doi":"10.1038/s41421-025-00804-1","DOIUrl":"10.1038/s41421-025-00804-1","url":null,"abstract":"<p><p>Alternative polyadenylation (APA) is critical for shaping transcriptome diversity and modulating cancer therapeutic resistance. While lactate is a well-established metabolic signal in cancer progression, its role in APA regulation remains unclear. Here, we demonstrate that L-lactate-induced lactylation of NUDT21 drives transcriptomic reprogramming through APA modulation. NUDT21 lactylation enhances its interaction with CPSF6, facilitating CFIm complex formation and inducing 3' untranslated region (UTR) lengthening of FDX1. Extension of the FDX1 3' UTR attenuates its protein output, thereby conferring resistance to cuproptosis in esophageal squamous cell carcinoma (ESCC). Furthermore, we identify AARS1 as the lactylation \"writer\" catalyzing NUDT21 K23 lactylation, and HDAC2 as its enzymatic \"eraser\". Clinically, elevated levels of both LDHA and NUDT21, as well as increased K23-lactylated NUDT21, are associated with reduced FDX1 expression and worse prognosis in ESCC patients. Notably, combined targeting of the lactate-NUDT21-FDX1-cuproptosis axis with the clinical LDHA inhibitor stiripentol and the copper ionophore elesclomol synergistically suppressed tumor growth. Collectively, our work identifies lactylated NUDT21 as a critical factor linking cellular metabolism to APA and proposes a promising therapeutic strategy for ESCC treatment.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"52"},"PeriodicalIF":13.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12116747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156528","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 insight into PIF6-mediated red light signal transduction of plant phytochrome B.","authors":"Hanli Jia, Zeyuan Guan, Junya Ding, Xiaoyu Wang, Dingfang Tian, Yan Zhu, Delin Zhang, Zhu Liu, Ling Ma, Ping Yin","doi":"10.1038/s41421-025-00802-3","DOIUrl":"10.1038/s41421-025-00802-3","url":null,"abstract":"<p><p>The red/far-red light receptor phytochrome B (phyB) plays essential roles in regulating various plant development processes. PhyB exists in two distinct photoreversible forms: the inactive Pr form and the active Pfr form. phyB-Pfr binds phytochrome-interacting factors (PIFs) to transduce red light signals. Here, we determined the cryo-electron microscopy (cryo-EM) structures of the photoactivated phyB-Pfr‒PIF6 complex, the constitutively active mutant phyB^Y276H‒PIF6 complex, and the truncated phyBN^Y276H‒PIF6 complex. In these structures, two parallel phyB-Pfr molecules interact with one PIF6 molecule. Red light-triggered rotation of the PΦB D-ring leads to the conversion of hairpin loops into α helices and the \"head-to-head\" reassembly of phyB-Pfr N-terminal photosensory modules. The interaction between phyB-Pfr and PIF6 influences the dimerization and transcriptional activation activity of PIF6, and PIF6 stabilizes the N-terminal extension of phyB-Pfr and increases the Pr→Pfr photoconversion efficiency of phyB. Our findings reveal the molecular mechanisms underlying Pr→Pfr photoconversion and PIF6-mediated red light signal transduction of phyB.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"51"},"PeriodicalIF":13.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126915","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":"Multiple infections with Omicron variants increase breadth and potency of Omicron-specific neutralizing antibodies.","authors":"Lei You, Luning Zhang, Shengqun Ouyang, Bo Gao, Yanan Li, Jialu Li, Ningbo Wu, Hong Wang, Shiqi Sun, Jinfeng Li, Zi Yin, Ziyang Xu, Yao Chen, Yiwen Zhu, Shuangyan Zhang, Zhan Xu, Tianyu Zhang, Zhaoyuan Liu, Chuanxin Huang, Bin Li, Jieming Qu, Bing Su, Leng-Siew Yeap","doi":"10.1038/s41421-025-00800-5","DOIUrl":"10.1038/s41421-025-00800-5","url":null,"abstract":"<p><p>Despite high vaccination rates, highly evolved Omicron variants have caused widespread infections and, in some cases, recurrent infections in the human population. As the population continues to be threatened by new variants, it is critical to understand how the dynamic cross-reactive antibody response evolves and affects protection. Here, we longitudinally profiled neutralizing antibodies in individuals who experienced three Omicron waves in China over an 18-month period following the lifting of the COVID restriction. We found that individuals with BA.5/BF.7 and XBB dual infections had increased breadth and neutralizing potency of Omicron-specific antibodies compared to those with a BA.5/BF.7 single infection, and were thus more resistant to JN.1/XDV.1 infection in the third wave. During the second infection, a new imprint based on the previously infected variant was established, and the antibodies developed high cross-reactivity against the Omicron variants and less against vaccine-derived WT SARS-CoV-2. Our results suggest that the high titer and breadth of cross-reactive antibodies from multiple infections may be protective against future infection with Omicron variants such as JN.1, but may still be vulnerable to antigenically advanced subvariants such as KP.3.1.1 and XEC.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"49"},"PeriodicalIF":13.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12089387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101504","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":"Spatiotemporal 3D chromatin organization across multiple brain regions during human fetal development.","authors":"Yaoyu Sun, Min Li, Chao Ning, Lei Gao, Zhenbo Liu, Suijuan Zhong, Junjie Lv, Yuwen Ke, Xinxin Wang, Qiang Ma, Zeyuan Liu, Shuaishuai Wu, Hao Yu, Fangqi Zhao, Jun Zhang, Qian Gong, Jiang Liu, Qian Wu, Xiaoqun Wang, Xuepeng Chen","doi":"10.1038/s41421-025-00798-w","DOIUrl":"10.1038/s41421-025-00798-w","url":null,"abstract":"<p><p>Elucidating the regulatory mechanisms underlying the development of different brain regions in humans is essential for understanding advanced cognition and neuropsychiatric disorders. However, the spatiotemporal organization of three-dimensional (3D) chromatin structure and its regulatory functions across different brain regions remain poorly understood. Here, we generated an atlas of high-resolution 3D chromatin structure across six developing human brain regions, including the prefrontal cortex (PFC), primary visual cortex (V1), cerebellum (CB), subcortical corpus striatum (CS), thalamus (TL), and hippocampus (HP), spanning gestational weeks 11-26. We found that the spatial and temporal dynamics of 3D chromatin organization play a key role in regulating brain region development. We also identified H3K27ac-marked super-enhancers as key contributors to shaping brain region-specific 3D chromatin structures and gene expression patterns. Finally, we uncovered hundreds of neuropsychiatric GWAS SNP-linked genes, shedding light on critical molecules in various neuropsychiatric disorders. In summary, our findings provide important insights into the 3D chromatin regulatory mechanisms governing brain region-specific development and can serve as a valuable resource for advancing our understanding of neuropsychiatric disorders.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"50"},"PeriodicalIF":13.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076222","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 insight into the self-activation and G-protein coupling of P2Y2 receptor.","authors":"Baoliang Lan, Shuhao Zhang, Kai Chen, Shengjie Dai, Jiaqi Fei, Kaixuan Gao, Xiaoou Sun, Bin Lin, Xiangyu Liu","doi":"10.1038/s41421-025-00797-x","DOIUrl":"10.1038/s41421-025-00797-x","url":null,"abstract":"<p><p>Purinergic P2Y2 receptor (P2Y2R) represents a typically extracellular ATP and UTP sensor for mediating purinergic signaling. Despite its importance as a pharmacological target, the molecular mechanisms underlying ligand recognition and G-protein coupling have remained elusive due to lack of structural information. In this study, we determined the cryo-electron microscopy (cryo-EM) structures of the apo P2Y2R in complex with G_q, ATP-bound P2Y2R in complex with G_q or G_o, and UTP-bound P2Y4R in complex with G_q. These structures reveal the similarities and distinctions of ligand recognition within the P2Y receptor family. Furthermore, a comprehensive analysis of G-protein coupling reveals that P2Y2R exhibits promiscuity in coupling with both G_q and G_o proteins. Combining molecular dynamics simulations and signaling assays, we elucidate the molecular mechanisms by which P2Y2R differentiates pathway-specific G_q or G_o coupling through distinct structural components on the intracellular side. Strikingly, we identify a helix-like segment within the N-terminus that occupies the orthosteric ligand-binding pocket of P2Y2R, accounting for its self-activation. Taken together, these findings provide a molecular framework for understanding the activation mechanism of P2Y2R, encompassing ligand recognition, G-protein coupling, and a novel N-terminus-mediated self-activation mechanism.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"47"},"PeriodicalIF":13.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12075631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984868","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}