Cell DiscoveryPub Date : 2024-09-17DOI: 10.1038/s41421-024-00715-7
Wenxiao Yang, Luo Hong, Linwei Guo, Yunjin Wang, Xiangchen Han, Boyue Han, Zheng Xing, Guoliang Zhang, Hongxia Zhou, Chao Chen, Hong Ling, Zhimin Shao, Xin Hu
{"title":"Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer","authors":"Wenxiao Yang, Luo Hong, Linwei Guo, Yunjin Wang, Xiangchen Han, Boyue Han, Zheng Xing, Guoliang Zhang, Hongxia Zhou, Chao Chen, Hong Ling, Zhimin Shao, Xin Hu","doi":"10.1038/s41421-024-00715-7","DOIUrl":"https://doi.org/10.1038/s41421-024-00715-7","url":null,"abstract":"<p>Metabolic dysregulation is prominent in triple-negative breast cancer (TNBC), yet therapeutic strategies targeting cancer metabolism are limited. Here, utilizing multiomics data from our TNBC cohort (<i>n</i> = 465), we demonstrated widespread splicing deregulation and increased spliceosome abundance in the glycolytic TNBC subtype. We identified SNRNP200 as a crucial mediator of glucose-driven metabolic reprogramming. Mechanistically, glucose induces acetylation at SNRNP200 K1610, preventing its proteasomal degradation. Augmented SNRNP200 then facilitates splicing key metabolic enzyme-encoding genes (<i>GAPDH</i>, <i>ALDOA</i>, and <i>GSS</i>), leading to increased lactic acid and glutathione production. Targeting SNRNP200 with antisense oligonucleotide therapy impedes tumor metabolism and enhances the efficacy of anti-PD-1 therapy by activating intratumoral CD8<sup>+</sup> T cells while suppressing regulatory T cells. Clinically, higher SNRNP200 levels indicate an inferior response to immunotherapy in glycolytic TNBCs. Overall, our study revealed the intricate interplay between RNA splicing and metabolic dysregulation, suggesting an innovative combination strategy for immunotherapy in glycolytic TNBCs.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"16 1","pages":""},"PeriodicalIF":33.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255888","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":"Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control","authors":"Qianying Zhang, Wanhong Han, Rimao Wu, Shixian Deng, Jiemiao Meng, Yuanping Yang, Lili Li, Mingwei Sun, Heng Ai, Yingxi Chen, Qinyao Liu, Tian Gao, Xingchen Niu, Haixia Liu, Li Zhang, Dan Zhang, Meihong Chen, Pengbin Yin, Licheng Zhang, Peifu Tang, Dahai Zhu, Yong Zhang, Hu Li","doi":"10.1038/s41421-024-00712-w","DOIUrl":"https://doi.org/10.1038/s41421-024-00712-w","url":null,"abstract":"<p>Adult skeletal muscle stem cells, also known satellite cells (SCs), are quiescent and activate in response to injury. However, the activation mechanisms of quiescent SCs (QSCs) remain largely unknown. Here, we investigated the metabolic regulation of SC activation by identifying regulatory metabolites that promote SC activation. Using targeted metabolomics, we found that spermidine acts as a regulatory metabolite to promote SC activation and muscle regeneration in mice. Mechanistically, spermidine activates SCs via generating hypusinated eIF5A. Using SC-specific <i>eIF5A</i>-knockout (KO) and <i>Myod</i>-KO mice, we further found that eIF5A is required for spermidine-mediated SC activation by controlling MyoD translation. More significantly, depletion of eIF5A in SCs results in impaired muscle regeneration in mice. Together, the findings of our study define a novel mechanism that is essential for SC activation and acts via spermidine-eIF5A-mediated MyoD translation. Our findings suggest that the spermidine-eIF5A axis represents a promising pharmacological target in efforts to activate endogenous SCs for the treatment of muscular disease.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"400 1","pages":""},"PeriodicalIF":33.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180176","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}
Cell DiscoveryPub Date : 2024-09-10DOI: 10.1038/s41421-024-00728-2
Bingxin Zhou, Lirong Zheng, Banghao Wu, Kai Yi, Bozitao Zhong, Yang Tan, Qian Liu, Pietro Liò, Liang Hong
{"title":"A conditional protein diffusion model generates artificial programmable endonuclease sequences with enhanced activity","authors":"Bingxin Zhou, Lirong Zheng, Banghao Wu, Kai Yi, Bozitao Zhong, Yang Tan, Qian Liu, Pietro Liò, Liang Hong","doi":"10.1038/s41421-024-00728-2","DOIUrl":"https://doi.org/10.1038/s41421-024-00728-2","url":null,"abstract":"<p>Deep learning-based methods for generating functional proteins address the growing need for novel biocatalysts, allowing for precise tailoring of functionalities to meet specific requirements. This advancement leads to the development of highly efficient and specialized proteins with diverse applications across scientific, technological, and biomedical fields. This study establishes a pipeline for protein sequence generation with a conditional protein diffusion model, namely CPDiffusion, to create diverse sequences of proteins with enhanced functions. CPDiffusion accommodates protein-specific conditions, such as secondary structures and highly conserved amino acids. Without relying on extensive training data, CPDiffusion effectively captures highly conserved residues and sequence features for specific protein families. We applied CPDiffusion to generate artificial sequences of Argonaute (Ago) proteins based on the backbone structures of wild-type (WT) <i>Kurthia massiliensis</i> Ago (KmAgo) and <i>Pyrococcus furiosus</i> Ago (PfAgo), which are complex multi-domain programmable endonucleases. The generated sequences deviate by up to nearly 400 amino acids from their WT templates. Experimental tests demonstrated that the majority of the generated proteins for both KmAgo and PfAgo show unambiguous activity in DNA cleavage, with many of them exhibiting superior activity as compared to the WT. These findings underscore CPDiffusion’s remarkable success rate in generating novel sequences for proteins with complex structures and functions in a single step, leading to enhanced activity. This approach facilitates the design of enzymes with multi-domain molecular structures and intricate functions through in silico generation and screening, all accomplished without the need for supervision from labeled data.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"77 1","pages":""},"PeriodicalIF":33.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180175","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}
Cell DiscoveryPub Date : 2024-09-04DOI: 10.1038/s41421-024-00703-x
Ying Jin, Yuefeng Wu, Alexandre Reuben, Liang Zhu, Carl M Gay, Qingzhe Wu, Xintong Zhou, Haomin Mo, Qi Zheng, Junyu Ren, Zhaoyuan Fang, Teng Peng, Nan Wang, Liang Ma, Yun Fan, Hai Song, Jianjun Zhang, Ming Chen
{"title":"Single-cell and spatial proteo-transcriptomic profiling reveals immune infiltration heterogeneity associated with neuroendocrine features in small cell lung cancer.","authors":"Ying Jin, Yuefeng Wu, Alexandre Reuben, Liang Zhu, Carl M Gay, Qingzhe Wu, Xintong Zhou, Haomin Mo, Qi Zheng, Junyu Ren, Zhaoyuan Fang, Teng Peng, Nan Wang, Liang Ma, Yun Fan, Hai Song, Jianjun Zhang, Ming Chen","doi":"10.1038/s41421-024-00703-x","DOIUrl":"10.1038/s41421-024-00703-x","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 pathologically defined spatial compartments (pan-CK-positive tumor nest; CD45/CD3-positive tumor stroma; para-tumor). Our study depicted the spatial transcriptomic and proteomic TIME architecture of SCLC, indicating clear intra-tumor heterogeneity dictated via canonical neuroendocrine subtyping markers; revealed the enrichment of innate immune cells and functionally impaired B cells in tumor nest and suggested potentially important immunoregulatory roles of monocytes/macrophages. We identified RE1 silencing factor (REST) as a potential biomarker for SCLC associated with low neuroendocrine features, more active anti-tumor immunity, and prolonged survival.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"93"},"PeriodicalIF":13.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11375181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131908","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 : 2024-09-03DOI: 10.1038/s41421-024-00722-8
Yang Li, Zhi-Peng Chen, Da Xu, Liang Wang, Meng-Ting Cheng, Cong-Zhao Zhou, Yuxing Chen, Wen-Tao Hou
{"title":"Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation.","authors":"Yang Li, Zhi-Peng Chen, Da Xu, Liang Wang, Meng-Ting Cheng, Cong-Zhao Zhou, Yuxing Chen, Wen-Tao Hou","doi":"10.1038/s41421-024-00722-8","DOIUrl":"10.1038/s41421-024-00722-8","url":null,"abstract":"<p><p>Human ABC transporters ABCD1-3 are all localized on the peroxisomal membrane and participate in the β-oxidation of fatty acyl-CoAs, but they differ from each other in substrate specificity. The transport of branched-chain fatty acids from cytosol to peroxisome is specifically driven by ABCD3, dysfunction of which causes severe liver diseases such as hepatosplenomegaly. Here we report two cryogenic electron microscopy (cryo-EM) structures of ABCD3 bound to phytanoyl-CoA and ATP at resolutions of 2.9 Å and 3.2 Å, respectively. A pair of phytanoyl-CoA molecules were observed in ABCD3, each binding to one transmembrane domain (TMD), which is distinct from our previously reported structure of ABCD1, where each fatty acyl-CoA molecule strongly crosslinks two TMDs. Upon ATP binding, ABCD3 exhibits a conformation that is open towards the peroxisomal matrix, leaving two extra densities corresponding to two CoA molecules deeply embedded in the translocation cavity. Structural analysis combined with substrate-stimulated ATPase activity assays indicated that the present structures might represent two states of ABCD3 in the transport cycle. These findings advance our understanding of fatty acid oxidation and the molecular pathology of related diseases.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"92"},"PeriodicalIF":13.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119104","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 : 2024-09-03DOI: 10.1038/s41421-024-00724-6
Yang Li, Qingning Yuan, Xinheng He, Yumu Zhang, Chongzhao You, Canrong Wu, Jingru Li, H Eric Xu, Li-Hua Zhao
{"title":"Molecular mechanism of prolactin-releasing peptide recognition and signaling via its G protein-coupled receptor.","authors":"Yang Li, Qingning Yuan, Xinheng He, Yumu Zhang, Chongzhao You, Canrong Wu, Jingru Li, H Eric Xu, Li-Hua Zhao","doi":"10.1038/s41421-024-00724-6","DOIUrl":"10.1038/s41421-024-00724-6","url":null,"abstract":"<p><p>Prolactin-releasing peptide (PrRP) is an RF-amide neuropeptide that binds and activates its cognate G protein-coupled receptor, prolactin-releasing peptide receptor (PrRPR), also known as GPR10. PrRP and PrRPR are highly conserved across mammals and involved in regulating a range of physiological processes, including stress response, appetite regulation, pain modulation, cardiovascular function, and potentially reproductive functions. Here we present cryo-electron microscopy structures of PrRP-bound PrRPR coupled to G<sub>q</sub> or G<sub>i</sub> heterotrimer, unveiling distinct molecular determinants underlying the specific recognition of the ligand's C-terminal RF-amide motif. We identify a conserved polar pocket that accommodates the C-terminal amide shared by RF-amide peptides. Structural comparison with neuropeptide Y receptors reveals both similarities and differences in engaging the essential RF/RY-amide motifs. Our findings demonstrate the general mechanism governing RF-amide motif recognition by PrRPR and RF-amide peptide receptors, and provide a foundation for elucidating activation mechanisms and developing selective drugs targeting this important peptide-receptor system.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"91"},"PeriodicalIF":13.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119102","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 : 2024-08-27DOI: 10.1038/s41421-024-00709-5
Hao Li, Yu Du, Kaiwen Cheng, Yuxi Chen, Ling Wei, Yujun Pei, Xiaoyu Wang, Lan Wang, Ye Zhang, Xiaoxin Hu, Yi Lu, Xiangjia Zhu
{"title":"Gut microbiota-derived indole-3-acetic acid suppresses high myopia progression by promoting type I collagen synthesis.","authors":"Hao Li, Yu Du, Kaiwen Cheng, Yuxi Chen, Ling Wei, Yujun Pei, Xiaoyu Wang, Lan Wang, Ye Zhang, Xiaoxin Hu, Yi Lu, Xiangjia Zhu","doi":"10.1038/s41421-024-00709-5","DOIUrl":"10.1038/s41421-024-00709-5","url":null,"abstract":"<p><p>High myopia (HM) is a leading cause of blindness worldwide with currently no effective interventions available. A major hurdle lies in its often isolated perception as a purely ocular morbidity, disregarding potential systemic implications. Recent evidence suggests the existence of a gut-eye axis; however, the role of gut microbiota in the pathogenesis of HM remains largely unexplored. Herein, we provide a potential crosstalk among HM's gut dysbiosis, microbial metabolites, and scleral remodeling. Utilizing 16S rRNA gene sequencing, we observed an altered gut microbiota profile in HM patients with a significant reduction in probiotic abundance compared with healthy controls. Subsequent targeted metabolic profiling revealed a notable decrease in plasma levels of the gut microbiota-derived metabolite indole-3-acetic acid (3-IAA) among HM patients, which is closely associated with the reduced probiotics, both negatively correlated with HM severity. Genetic analyses determined that gut microbiota are causally associated with myopia risk. Importantly, when mice subjected to HM modeling receive fecal microbiota transplantation from healthy donors, there is an increase in 3-IAA plasma levels and simultaneous retardation of HM progression along with better maintenance of collagen type I alpha 1 (COL1A1) expression in the sclera. Furthermore, 3-IAA gavage achieves similar effects. Mechanistic investigations confirm the transcriptional activation of COL1A1 by 3-IAA via promoting the enrichment of SP1 to its promoter. Together, our findings provide novel insights into the gut microbiota-eye axis in the pathogenesis of HM and propose new strategies for HM intervention by remodeling the gut microbiota and indole supplementation.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"89"},"PeriodicalIF":13.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11347609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072138","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 : 2024-08-20DOI: 10.1038/s41421-024-00706-8
Ling-Shuang Zhu, Chuan Lai, Chao-Wen Zhou, Hui-Yang Chen, Zhi-Qiang Liu, Ziyuan Guo, Hengye Man, Hui-Yun Du, Youming Lu, Feng Hu, Zhiye Chen, Kai Shu, Ling-Qiang Zhu, Dan Liu
{"title":"Postsynaptic lncRNA Sera/Pkm2 pathway orchestrates the transition from social competition to rank by remodeling the neural ensemble in mPFC.","authors":"Ling-Shuang Zhu, Chuan Lai, Chao-Wen Zhou, Hui-Yang Chen, Zhi-Qiang Liu, Ziyuan Guo, Hengye Man, Hui-Yun Du, Youming Lu, Feng Hu, Zhiye Chen, Kai Shu, Ling-Qiang Zhu, Dan Liu","doi":"10.1038/s41421-024-00706-8","DOIUrl":"10.1038/s41421-024-00706-8","url":null,"abstract":"<p><p>Individuals' continuous success in competitive interactions with conspecifics strongly affects their social hierarchy. Medial prefrontal cortex (mPFC) is the key brain region mediating both social competition and hierarchy. However, the molecular regulatory mechanisms underlying the neural ensemble in the mPFC remains unclear. Here, we demonstrate that in excitatory neurons of prelimbic cortex (PL), lncRNA Sera remodels the utilization of Pkm Exon9 and Exon10, resulting in a decrease in the Pkm1/2 ratio in highly competitive mice. By employing a tet-on/off system, we disrupt or rebuild the normal Pkm1/2 ratio by controlling the expression of Pkm2 in PL excitatory neurons. We find that long-term Pkm2 modulation induces timely competition alteration and hysteretic rank change, through phosphorylating the Ser845 site of GluA1. Together, this study uncovers a crucial role of lncRNA Sera/Pkm2 pathway in the transition of social competition to rank by remodeling neural ensemble in mPFC.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"87"},"PeriodicalIF":13.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11333582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003714","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}
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