Cell DiscoveryPub Date : 2026-08-25DOI: 10.1038/s41421-026-00909-1
Qian He, Li-Hua Zhao, H Eric Xu
{"title":"Arrestins as programmable integrators of GPCR signaling: structural microstates, spatiotemporal logic, and therapeutic control.","authors":"Qian He, Li-Hua Zhao, H Eric Xu","doi":"10.1038/s41421-026-00909-1","DOIUrl":"10.1038/s41421-026-00909-1","url":null,"abstract":"<p><p>Arrestins were originally defined as terminators of G protein-coupled receptor (GPCR) signaling, yet structural and mechanistic advances now reveal them as programmable, spatiotemporal integrators of cellular signaling. Recent cryo-electron microscopy studies have revealed a diverse spectrum of GPCR-arrestin engagement modes, including core-, tail-, loop-, side-engaged, and membrane-anchored conformations, across GPCR classes and arrestin isoforms. These structures reveal that arrestin recruitment operates as a conditional, allosterically regulated process rather than a binary on-off switch. The selection of the arrestin microstate is governed by layered regulatory inputs, including GPCR kinase-dependent phosphorylation barcodes, membrane and lipid cofactors, and isoform-specific mechanics, which together define the signaling geometry, duration, and subcellular localization. This structural logic provides a mechanistic foundation for biased signaling, noncanonical endosomal signaling, and GPCR-independent arrestin functions. Importantly, emerging therapeutic strategies, including intracellular allosteric modulators and molecular glues, demonstrate that arrestin signaling can be reprogrammed by directly sculpting transducer assemblies rather than ligand efficacy alone. Here, we synthesize recent structural, biochemical, and physiological insights to outline how arrestins decode regulatory inputs into signaling outcomes and how this knowledge enables the development of next-generation, structure-guided GPCR therapeutics.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13503860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811999","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":"Asymmetric RBBP7 regulates the first cell fate decision of early mammalian embryos.","authors":"Lin-Fang Ju, Xiao Han, Danru Zhang, Heng-Ji Xu, Shaokang Jia, Meng-Xia Liu, Yanchen Liu, Yu-Ting Cai, Yu-Sheng Chen, Chun-Chun Gao, Yong-Liang Zhao, Yajing Hao, Xiu-Jie Wang, Dangsheng Li, Xiang Zhou, Ying Yang, Jianyong Han, Yun-Gui Yang","doi":"10.1038/s41421-026-00912-6","DOIUrl":"https://doi.org/10.1038/s41421-026-00912-6","url":null,"abstract":"<p><p>Asymmetric transcription of noncoding RNA LincGET is currently recognized as the earliest event regulating the first cell fate decision in mammalian embryogenesis. However, whether key protein factors modulate this process remains elusive. Here, we identify RBBP7 as the earliest protein factor regulating developmental cell fate in mammals. Loss of RBBP7 drives cells towards ICM lineage. In mouse late 2-cell embryos, unequal translation of Rbbp7 contributes to its asymmetric protein distribution, which subsequently induces inversed asymmetric histone acetylation H3K9ac by interaction with HDAC1, thereby promoting cell differentiation. Interestingly, RBBP7 and LincGET exhibit a consistent asymmetric tendency but direct different cell fates; depletion or overexpression of both Rbbp7 and LincGET restored the cell fate bias, suggesting a coordinated regulatory mechanism during initial lineage specification. In summary, our study reveals RBBP7 as a new protein factor and elucidates its role in the first cell fate decision.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13482399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788627","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":"Phosphoantigen-driven dissociation of butyrophilin oligomers activates γδ T cells.","authors":"Weizhi Xin, Bangdong Huang, Weijie Gao, Wenjia Zhang, Yundi Hu, Yuehua Liu, Enyuan Liang, Jin Chen, Yigong Shi, Qiang Su, Qiang Zhou","doi":"10.1038/s41421-026-00911-7","DOIUrl":"10.1038/s41421-026-00911-7","url":null,"abstract":"<p><p>γδ T cells represent a promising avenue for cancer immunotherapy. The Vγ9Vδ2 T-cell receptor (TCR), which is expressed by the predominant subset of γδ T cells, responds to phosphoantigen (pAg)-engaged butyrophilins (BTNs) on various cancer cells. However, the molecular mechanism underlying the pAg-mediated activation of Vγ9Vδ2 TCRs remains a subject of debate. Here, we employed an integrative approach to elucidate the mechanism of pAg reactivity in Vγ9Vδ2 T cells. Our results demonstrate that BTNs form higher-order oligomers in the absence of pAg. Upon pAg binding, these higher-order oligomers dissociate into separate tetramers, enabling Vγ9Vδ2 TCR engagement. This pAg-induced dissociation of higher-order BTN oligomers is critical for pAg-mediated activation of γδ T cells. Our findings reveal a mechanism of BTN higher-order oligomer dissociation-driven pAg sensing, providing valuable insight for future immunotherapeutic strategies.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13457854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705193","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 : 2026-08-04DOI: 10.1038/s41421-026-00908-2
Zheng-Hui Zhao, Ning Xu, Xue-Ying Chen, Cheng-Yan Zhuo, Yong Lu, Ang Li, Qiang Sun, Xiang-Hong Ou, Qing-Yuan Sun
{"title":"Single-cell atlas of reproductive endocrine organs reveals transcriptomic responses to type 1 diabetes mellitus in nonhuman primates.","authors":"Zheng-Hui Zhao, Ning Xu, Xue-Ying Chen, Cheng-Yan Zhuo, Yong Lu, Ang Li, Qiang Sun, Xiang-Hong Ou, Qing-Yuan Sun","doi":"10.1038/s41421-026-00908-2","DOIUrl":"10.1038/s41421-026-00908-2","url":null,"abstract":"<p><p>Type 1 diabetes mellitus characterized by insulin deficiency and hyperglycemia is associated with female subfertility. However, how hyperglycemia affects the hypothalamic-pituitary-ovarian-uterine axis remains poorly understood. In this study, we performed single-cell transcriptomic profiling of the hypothalamus, pituitary, ovary and uterus during the proliferative phase of the menstrual cycle in type 1 diabetic macaques to systematically characterize changes in tissue-specific cellular heterogeneity, gene expression, and intercellular communication networks under diabetic conditions. Our analysis revealed significant upregulation of the TNF signaling pathway across multiple tissues, concomitant with marked activation of inflammation-related pathways. Notably, the macrophage migration inhibitory factor signaling pathway exhibited a tissue-specific regulatory pattern, being significantly upregulated in the hypothalamus and pituitary but downregulated in the ovary and uterus, suggesting divergent inflammatory modulation along the reproductive endocrine axis in response to diabetes. Moreover, we observed that diabetes leads to reduced FSHR expression during granulosa cell differentiation, and this process is further exacerbated by the upregulated expression of SFRP4, a known antagonist of follicle-stimulating hormone signaling, resulting in diminished granulosa cell responsiveness to follicle-stimulating hormone. Consequently, this dysregulation is correlated with increased FSHB expression in pituitary gonadotropes, likely due to disrupted ovarian feedback signaling. Collectively, our findings provide a comprehensive landscape of cellular and molecular alterations in immune and endocrine compartments in the female reproductive system in diabetic states, advancing our understanding of immune‒endocrine cell crosstalk in the context of metabolic disease.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677304","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 : 2026-07-28DOI: 10.1038/s41421-026-00907-3
Zhe Zhang, Na Kong, Jie Mei, Xiaoqiang Sheng, Jidong Zhou, Haiquan Wang, Nannan Kang, Yang Zhang, Lina Yu, Pengfei Xu, Xin Zhen, Min Wu, Lijun Ding, Guangyi Cao, Dake Li, Chaojun Li, Guijun Yan, Haixiang Sun
{"title":"Perifollicular stromal cells sustain folliculogenesis via MDK-NCL signaling in mice and humans.","authors":"Zhe Zhang, Na Kong, Jie Mei, Xiaoqiang Sheng, Jidong Zhou, Haiquan Wang, Nannan Kang, Yang Zhang, Lina Yu, Pengfei Xu, Xin Zhen, Min Wu, Lijun Ding, Guangyi Cao, Dake Li, Chaojun Li, Guijun Yan, Haixiang Sun","doi":"10.1038/s41421-026-00907-3","DOIUrl":"10.1038/s41421-026-00907-3","url":null,"abstract":"<p><p>Oocyte development requires coordinated metabolic and signaling support from granulosa and theca cells. By performing integrated single-cell RNA sequencing and spatial transcriptomic analyses of murine and human ovaries, we discovered a functionally specialized stromal subtype essential for folliculogenesis. These stromal cells (SCs) with glutamyl aminopeptidase (ENPEP) function, designated perifollicular SCs based on their circumferential follicle localization, exhibit two hallmark features: (1) dynamic proliferation synchronized with follicular maturation from primary to secondary to antral stages, and (2) secretion of midkine (MDK), which activates nucleolin (NCL) receptor signaling to drive granulosa cell (GC) expansion. Furthermore, analyses of ovarian aging revealed the concurrent depletion of perifollicular SCs and the attenuation of MDK-NCL signaling between perifollicular SCs and GCs. The unique spatial confinement and regulatory capacity of perifollicular SCs endow them with the potential to become important components of the follicular functional unit, providing new theoretical support for understanding the molecular regulatory mechanisms of ovarian aging from the perspective of the follicular microenvironment.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13408105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599378","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 : 2026-07-21DOI: 10.1038/s41421-026-00904-6
Na Zhang, Xinyu Ye, Kai Wang, Yameng Hu, Zixi Wang, Lichun Huang, Xi Chen, Ding Yan, Wen Fu, Qian Xue, Shihao Sun, Yihan Xu, Daolin Tang, Xin Chen, Li Zhou, Jinbao Liu
{"title":"GV-971 remodels the gut microbiota-bile acid-FXR axis to ameliorate obesity and metabolic dysfunction.","authors":"Na Zhang, Xinyu Ye, Kai Wang, Yameng Hu, Zixi Wang, Lichun Huang, Xi Chen, Ding Yan, Wen Fu, Qian Xue, Shihao Sun, Yihan Xu, Daolin Tang, Xin Chen, Li Zhou, Jinbao Liu","doi":"10.1038/s41421-026-00904-6","DOIUrl":"10.1038/s41421-026-00904-6","url":null,"abstract":"<p><p>Obesity and its associated metabolic complications represent a global health crisis, yet effective microbiota-targeted pharmacotherapies remain limited. Here, we report that GV-971 (sodium oligomannate), a marine-derived oligosaccharide originally developed for Alzheimer's disease, exerts potent anti-obesity and metabolic benefits by reprogramming gut microbial and host signaling networks. In high-fat diet-induced obese mice, GV-971 reduced adiposity, improved glucose homeostasis, and alleviated hepatic steatosis without affecting food intake. Multi-omics and causal intervention experiments revealed that GV-971 selectively decreased the abundance of Clostridium scindens, a keystone bacterium responsible for secondary bile acid synthesis. This decrease downregulated the expression of the baiF gene encoding 7α-hydroxysteroid dehydrogenase, leading to reduced intestinal deoxycholic acid (DCA) levels and inhibition of intestinal farnesoid X receptor (FXR) signaling. Restoration of C. scindens abundance, baiF expression, or DCA supplementation abrogated the metabolic benefits of GV-971, confirming the causal role of the C. scindens-DCA-FXR axis. Mechanistically, inhibition of intestinal FXR promoted thermogenic gene expression and white adipose tissue browning, thus enhancing systemic energy expenditure. These findings uncover a bacterium-metabolite-host signaling pathway underlying the effects of GV-971 and establish microbiota-directed FXR modulation as a promising therapeutic approach for obesity and metabolic disease.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535395","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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