Cell Discovery最新文献

{"title":"RhoA-mediated G₁₂-G₁₃ signaling maintains muscle stem cell quiescence and prevents stem cell loss.","authors":"Yundong Peng, Jingjing Du, Rui Li, Stefan Günther, Nina Wettschureck, Stefan Offermanns, Yan Wang, Andre Schneider, Thomas Braun","doi":"10.1038/s41421-024-00696-7","DOIUrl":"10.1038/s41421-024-00696-7","url":null,"abstract":"<p><p>Multiple processes control quiescence of muscle stem cells (MuSCs), which is instrumental to guarantee long-term replenishment of the stem cell pool. Here, we describe that the G-proteins G₁₂-G₁₃ integrate signals from different G-protein-coupled receptors (GPCRs) to control MuSC quiescence via activation of RhoA. Comprehensive screening of GPCR ligands identified two MuSC-niche-derived factors, endothelin-3 (ET-3) and neurotensin (NT), which activate G₁₂-G₁₃ signaling in MuSCs. Stimulation with ET-3 or NT prevented MuSC activation, whereas pharmacological inhibition of ET-3 or NT attenuated MuSC quiescence. Inactivation of Gna12-Gna13 or Rhoa but not of Gnaq-Gna11 completely abrogated MuSC quiescence, which depleted the MuSC pool and was associated with accelerated sarcopenia during aging. Expression of constitutively active RhoA prevented exit from quiescence in Gna12-Gna13 mutant MuSCs, inhibiting cell cycle entry and differentiation via Rock and formins without affecting Rac1-dependent MuSC projections, a hallmark of quiescent MuSCs. The study uncovers a critical role of G₁₂-G₁₃ and RhoA signaling for active regulation of MuSC quiescence.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"76"},"PeriodicalIF":13.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11251043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619444","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":"Synthetic macrolides overcoming MLS_BK-resistant pathogens.","authors":"Cong-Xuan Ma, Ye Li, Wen-Tian Liu, Yun Li, Fei Zhao, Xiao-Tian Lian, Jing Ding, Si-Meng Liu, Xie-Peng Liu, Bing-Zhi Fan, Li-Yong Liu, Feng Xue, Jian Li, Jue-Ru Zhang, Zhao Xue, Xiao-Tong Pei, Jin-Zhong Lin, Jian-Hua Liang","doi":"10.1038/s41421-024-00702-y","DOIUrl":"10.1038/s41421-024-00702-y","url":null,"abstract":"<p><p>Conventional macrolide-lincosamide-streptogramin B-ketolide (MLS_BK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLS_BK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLS_BK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLS_BK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"75"},"PeriodicalIF":13.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11239830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589679","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":"Simultaneous de novo calling and phasing of genetic variants at chromosome-scale using NanoStrand-seq.","authors":"Xiuzhen Bai, Zonggui Chen, Kexuan Chen, Zixin Wu, Rui Wang, Jun'e Liu, Liang Chang, Lu Wen, Fuchou Tang","doi":"10.1038/s41421-024-00694-9","DOIUrl":"10.1038/s41421-024-00694-9","url":null,"abstract":"<p><p>The successful accomplishment of the first telomere-to-telomere human genome assembly, T2T-CHM13, marked a milestone in achieving completeness of the human reference genome. The upcoming era of genome study will focus on fully phased diploid genome assembly, with an emphasis on genetic differences between individual haplotypes. Most existing sequencing approaches only achieved localized haplotype phasing and relied on additional pedigree information for further whole-chromosome scale phasing. The short-read-based Strand-seq method is able to directly phase single nucleotide polymorphisms (SNPs) at whole-chromosome scale but falls short when it comes to phasing structural variations (SVs). To shed light on this issue, we developed a Nanopore sequencing platform-based Strand-seq approach, which we named NanoStrand-seq. This method allowed for de novo SNP calling with high precision (99.52%) and acheived a superior phasing accuracy (0.02% Hamming error rate) at whole-chromosome scale, a level of performance comparable to Strand-seq for haplotype phasing of the GM12878 genome. Importantly, we demonstrated that NanoStrand-seq can efficiently resolve the MHC locus, a highly polymorphic genomic region. Moreover, NanoStrand-seq enabled independent direct calling and phasing of deletions and insertions at whole-chromosome level; when applied to long genomic regions of SNP homozygosity, it outperformed the strategy that combined Strand-seq with bulk long-read sequencing. Finally, we showed that, like Strand-seq, NanoStrand-seq was also applicable to primary cultured cells. Together, here we provided a novel methodology that enabled interrogation of a full spectrum of haplotype-resolved SNPs and SVs at whole-chromosome scale, with broad applications for species with diploid or even potentially polypoid genomes.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"74"},"PeriodicalIF":13.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11231365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558136","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":"Pig blastocyst-like structure models from embryonic stem cells.","authors":"Jinzhu Xiang, Hanning Wang, Bingbo Shi, Jiajun Li, Dong Liu, Kaipeng Wang, Zhuangfei Wang, Qiankun Min, Chengchen Zhao, Duanqing Pei","doi":"10.1038/s41421-024-00693-w","DOIUrl":"10.1038/s41421-024-00693-w","url":null,"abstract":"<p><p>Pluripotent stem cells have the potential to generate embryo models that can recapitulate developmental processes in vitro. Large animals such as pigs may also benefit from stem-cell-based embryo models for improving breeding. Here, we report the generation of blastoids from porcine embryonic stem cells (pESCs). We first develop a culture medium 4FIXY to derive pESCs. We develop a 3D two-step differentiation strategy to generate porcine blastoids from the pESCs. The resulting blastoids exhibit similar morphology, size, cell lineage composition, and single-cell transcriptome characteristics to blastocysts. These porcine blastoids survive and expand for more than two weeks in vitro under two different culture conditions. Large animal blastoids such as those derived from pESCs may enable in vitro modeling of early embryogenesis and improve livestock species' breeding practices.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"72"},"PeriodicalIF":13.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491019","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":"Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis.","authors":"Siyu Zhu, Wei Chen, Alasdair Masson, Yi-Ping Li","doi":"10.1038/s41421-024-00689-6","DOIUrl":"10.1038/s41421-024-00689-6","url":null,"abstract":"<p><p>The initiation of osteogenesis primarily occurs as mesenchymal stem cells undergo differentiation into osteoblasts. This differentiation process plays a crucial role in bone formation and homeostasis and is regulated by two intricate processes: cell signal transduction and transcriptional gene expression. Various essential cell signaling pathways, including Wnt, BMP, TGF-β, Hedgehog, PTH, FGF, Ephrin, Notch, Hippo, and Piezo1/2, play a critical role in facilitating osteoblast differentiation, bone formation, and bone homeostasis. Key transcriptional factors in this differentiation process include Runx2, Cbfβ, Runx1, Osterix, ATF4, SATB2, and TAZ/YAP. Furthermore, a diverse array of epigenetic factors also plays critical roles in osteoblast differentiation, bone formation, and homeostasis at the transcriptional level. This review provides an overview of the latest developments and current comprehension concerning the pathways of cell signaling, regulation of hormones, and transcriptional regulation of genes involved in the commitment and differentiation of osteoblast lineage, as well as in bone formation and maintenance of homeostasis. The paper also reviews epigenetic regulation of osteoblast differentiation via mechanisms, such as histone and DNA modifications. Additionally, we summarize the latest developments in osteoblast biology spurred by recent advancements in various modern technologies and bioinformatics. By synthesizing these insights into a comprehensive understanding of osteoblast differentiation, this review provides further clarification of the mechanisms underlying osteoblast lineage commitment, differentiation, and bone formation, and highlights potential new therapeutic applications for the treatment of bone diseases.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"71"},"PeriodicalIF":13.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491018","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 the inhibition mechanism of LAT1-4F2hc complex by JPH203.","authors":"Ziwei Hu, Renhong Yan","doi":"10.1038/s41421-024-00697-6","DOIUrl":"10.1038/s41421-024-00697-6","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"73"},"PeriodicalIF":13.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491020","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 pan-KRAS degrader for the treatment of KRAS-mutant cancers.","authors":"Jie Yang, Qiao-Li Wang, Guan-Nan Wang, Jia-Cong Ye, Zi-Qian Li, Jing-Yun Wang, Zhao-Hui Liang, Shu-Xin Li, Cong Sun, Wen-Ting Liao, Yi-Jun Gao, Jing Wang, Yong Mao, Chunjing Yu, Guo-Kai Feng, Mu-Sheng Zeng","doi":"10.1038/s41421-024-00699-4","DOIUrl":"https://doi.org/10.1038/s41421-024-00699-4","url":null,"abstract":"<p><p>KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting \"undruggable\" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"70"},"PeriodicalIF":13.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466371","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 and functional insights into the helicase protein E5 of Mpox virus.","authors":"Weizhen Zhang, Yusong Liu, Mengquan Yang, Jie Yang, Zhiwei Shao, Yanqing Gao, Xinran Jiang, Ruixue Cui, Yixi Zhang, Xin Zhao, Qiyuan Shao, Chulei Cao, Huili Li, Linxi Li, Hehua Liu, Haishan Gao, Jianhua Gan","doi":"10.1038/s41421-024-00680-1","DOIUrl":"10.1038/s41421-024-00680-1","url":null,"abstract":"<p><p>Mpox virus (MPXV) can cause mpox in humans. Due to its quick and wide spread in the past two years, mpox has turned into a significant public health concern. Helicase E5 is a multi-domain protein; its primer synthesis and DNA unwinding activity are required for genome uncoating and DNA replication of MPXV. However, the in vitro DNA unwinding activity has never been demonstrated. Here, we report the structural and biochemical studies of MPXV E5, showing that the full-length protein adopts an auto-inhibited conformation. Truncation of the N-terminus can recover the in vitro unwinding activity of E5 towards the forked DNA. Further structural analysis reveals that MPXV E5 shares a conserved mechanism in DNA unwinding and primer synthesis with the homologous proteins. These findings not only advance our understanding on the function of MPXV E5, but also provide a solid basis for the development of anti-poxvirus drugs.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"67"},"PeriodicalIF":13.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11196578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445708","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 recognition of the atypical chemokine-like peptide GPR15L by its cognate receptor GPR15.","authors":"Zhongyuan Zhang, You Zheng, Lu Xu, Yang Yue, Kexin Xu, Fei Li, Fei Xu","doi":"10.1038/s41421-024-00698-5","DOIUrl":"10.1038/s41421-024-00698-5","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"69"},"PeriodicalIF":13.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449779","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":"TMC6 functions as a GPCR-like receptor to sense noxious heat via Gαq signaling.","authors":"Chen Zhang, Fang Tong, Bin Zhou, Mingdong He, Shuai Liu, Xiaomeng Zhou, Qiang Ma, Tianyu Feng, Wan-Jie Du, Huan Yang, Hao Xu, Lei Xiao, Zhen-Zhong Xu, Cheng Zhu, Ruiqi Wu, Yan-Qing Wang, Qingjian Han","doi":"10.1038/s41421-024-00678-9","DOIUrl":"10.1038/s41421-024-00678-9","url":null,"abstract":"<p><p>Thermosensation is vital for the survival, propagation, and adaption of all organisms, but its mechanism is not fully understood yet. Here, we find that TMC6, a membrane protein of unknown function, is highly expressed in dorsal root ganglion (DRG) neurons and functions as a Gαq-coupled G protein-coupled receptor (GPCR)-like receptor to sense noxious heat. TMC6-deficient mice display a substantial impairment in noxious heat sensation while maintaining normal perception of cold, warmth, touch, and mechanical pain. Further studies show that TMC6 interacts with Gαq via its intracellular C-terminal region spanning Ser⁷⁸⁰ to Pro⁸¹⁰. Specifically disrupting such interaction using polypeptide in DRG neurons, genetically ablating Gαq, or pharmacologically blocking Gαq-coupled GPCR signaling can replicate the phenotype of TMC6 deficient mice regarding noxious heat sensation. Noxious heat stimulation triggers intracellular calcium release from the endoplasmic reticulum (ER) of TMC6- but not control vector-transfected HEK293T cell, which can be significantly inhibited by blocking PLC or IP3R. Consistently, noxious heat-induced intracellular Ca²⁺ release from ER and action potentials of DRG neurons largely reduced when ablating TMC6 or blocking Gαq/PLC/IP3R signaling pathway as well. In summary, our findings indicate that TMC6 can directly function as a Gαq-coupled GPCR-like receptor sensing noxious heat.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"66"},"PeriodicalIF":33.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11183229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417914","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}