Cell Research最新文献

{"title":"Myeloperoxidase: one enzyme, two jobs","authors":"Sara Marchese, Andrea Mattevi","doi":"10.1038/s41422-025-01192-7","DOIUrl":"10.1038/s41422-025-01192-7","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 4","pages":"247-248"},"PeriodicalIF":25.9,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13013829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145494753","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":"The molecular basis of μ-opioid receptor signaling plasticity","authors":"Huibing Zhang, Xueting Wang, Kun Xi, Qingya Shen, Jianheng Xue, Yanqing Zhu, Shao-Kun Zang, Tianqiang Yu, Dan-Dan Shen, Jia Guo, Li-Nan Chen, Su-Yu Ji, Jiao Qin, Yingjun Dong, Mingming Zhao, Ming Yang, Haijing Wu, Guoli Yang, Yan Zhang","doi":"10.1038/s41422-025-01191-8","DOIUrl":"10.1038/s41422-025-01191-8","url":null,"abstract":"Activation of the μ-opioid receptor (μOR) alleviates pain but also elicits adverse effects through diverse G proteins and β-arrestins. The structural details of μOR complexes with Gz and β-arrestins have not been determined, impeding a comprehensive understanding of μOR signaling plasticity. Here, we present the cryo-EM structures of the μOR–Gz and μOR–βarr1 complexes, revealing selective conformational preferences of μOR when engaged with specific downstream signaling transducers. Integrated receptor pharmacology, including high-resolution structural analysis, cell signaling assays, and molecular dynamics simulations, demonstrated that transmembrane helix 1 (TM1) acts as an allosteric regulator of μOR signaling bias through differential stabilization of the Gi-, Gz-, and βarr1-bound states. Mechanistically, outward TM1 displacement confers structural flexibility that promotes G protein recruitment, whereas inward TM1 retraction facilitates βarr1 recruitment by stabilizing the intracellular binding pocket through coordinated interactions with TM2, TM7, and helix8. Structural comparisons between the Gi-, Gz-, and βarr1-bound complexes identified a TM1-fusion pocket with significant implications for downstream signaling regulation. Overall, we demonstrate that the conformational and thermodynamic heterogeneity of TM1 allosterically drives the downstream signaling specificity and plasticity of μOR, thereby expanding the understanding of μOR signal transduction mechanisms and providing new avenues for the rational design of analgesics.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"1021-1036"},"PeriodicalIF":25.9,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01191-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457272","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":"Nearly complete redirection of insertion-type indel into recombination enhances knock-in and facilitates endogenous biomolecular condensate analysis","authors":"Minglei Huang, Jingjing Fu, Peizhe Wang, Boyi Chen, Qichen Yuan, Jiawei Yu, Huimin Wang, Yiting Liu, Zhiyi Li, Yanling Wu, Tianlei Ying, Qingfeng Wu, Ming Zhu, Wei Qin, Yinqing Li","doi":"10.1038/s41422-025-01190-9","DOIUrl":"10.1038/s41422-025-01190-9","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"1079-1082"},"PeriodicalIF":25.9,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145380880","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":"KCNQ1 and PIP2: it takes two to tango","authors":"Alicia De La Cruz, H. Peter Larsson","doi":"10.1038/s41422-025-01189-2","DOIUrl":"10.1038/s41422-025-01189-2","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"922-923"},"PeriodicalIF":25.9,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01189-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351546","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":"Intestinal GAPs: neuro–epithelial–immune modules for liver protection","authors":"Manuel O. Jakob, Andreas Diefenbach","doi":"10.1038/s41422-025-01188-3","DOIUrl":"10.1038/s41422-025-01188-3","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 3","pages":"179-180"},"PeriodicalIF":25.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01188-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305470","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":"LGP2 stops MDA5 translocation to start antiviral signaling","authors":"Jiyoung Jang, Myung Hyun Jo","doi":"10.1038/s41422-025-01187-4","DOIUrl":"10.1038/s41422-025-01187-4","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 11","pages":"785-786"},"PeriodicalIF":25.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01187-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296067","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":"Trained immunity: induction of an inflammatory memory in disease","authors":"Titus Schlüter, Yuri van Elsas, Bram Priem, Athanasios Ziogas, Mihai G. Netea","doi":"10.1038/s41422-025-01171-y","DOIUrl":"10.1038/s41422-025-01171-y","url":null,"abstract":"The innate immune system adapts its behavior based on previous insults, mounting an enhanced response upon re-exposure. Hematopoietic progenitors in the bone marrow and peripheral innate immune cells can undergo epigenetic and metabolic reprogramming, establishing an innate immune memory known as trained immunity. The concept of trained immunity recently gained relevance in our understanding of how innate immunity is regulated in various diseases. This review explores the role of trained immunity in infections, autoimmune disease, cardiovascular disease, cancer, and neurodegenerative disease. We discuss how trained immunity can provide heterologous protection against infections, as it has been induced for decades by the Bacillus Calmette Guérin vaccine, how it can help counteract immunosuppression, and how it can be inappropriately induced leading to chronic inflammation. By understanding how trained immunity is involved in processes leading to health and disease, novel therapeutic strategies can be developed.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 11","pages":"792-802"},"PeriodicalIF":25.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01171-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283189","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":"Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating","authors":"Ling Zhong, Xiaoqing Lin, Xinyu Cheng, Shuangyan Wan, Yaoguang Hua, Weiwei Nan, Bin Hu, Xiangjun Peng, Zihan Zhou, Qiansen Zhang, Huaiyu Yang, Frank Noé, Zhenzhen Yan, Dexiang Jiang, Hangyu Zhang, Fengjiao Liu, Chenxin Xiao, Zhuo Zhou, Yimin Mou, Haijie Yu, Lijuan Ma, Chen Huang, Vincent Kam Wai Wong, Sookja Kim Chung, Bing Shen, Zhi-Hong Jiang, Erwin Neher, Wandi Zhu, Jin Zhang, Panpan Hou","doi":"10.1038/s41422-025-01182-9","DOIUrl":"10.1038/s41422-025-01182-9","url":null,"abstract":"The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (IKs) critical for cardiac repolarization. Loss-of-function mutations in KCNQ1 and KCNE1 cause long QT syndrome (LQTS) types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1 + KCNE3, the structural basis of KCNQ1 + KCNE1 remains unresolved. Using cryo-electron microscopy and electrophysiology, we determined high-resolution (2.5–3.4 Å) structures of human KCNQ1APO, and KCNQ1 + KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing six helix-to-loop transitions in KCNQ1 transmembrane segments. Three of them occur at both ends of the S4–S5 linker, maintaining a loop conformation during IKs gating, while the other three, in S6 and helix A, undergo dynamic helix-loop transitions during IKs gating. These structural rearrangements: (1) stabilize the closed pore and the conformation of the intermediate state voltage-sensing domain, thereby determining channel gating, ion permeation, and single-channel conductance; (2) enable a dual-PIP2 modulation mechanism, where one PIP2 occupies the canonical site, while the second PIP2 bridges the S4–S5 linker, KCNE1, and the adjacent S6’, stabilizing channel opening; (3) create a fenestration capable of binding compounds specific for KCNQ1 + KCNE1 (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes IKs function and provides a foundation for developing targeted LQTS therapy.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 11","pages":"887-899"},"PeriodicalIF":25.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01182-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205680","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":"Lineage plasticity and histological transformation: tumor histology as a spectrum","authors":"Xiaoling Li, Eric E. Gardner, Sonia Molina-Pinelo, Clare Wilhelm, Ping Mu, Álvaro Quintanal-Villalonga","doi":"10.1038/s41422-025-01180-x","DOIUrl":"10.1038/s41422-025-01180-x","url":null,"abstract":"Lineage plasticity, the ability of cells to transition to an alternative phenotype as a means for adaptation, is an increasingly recognized mechanism of tumor evolution and a driver of resistance to anticancer therapies. The most extensively described clinical settings impacted by such molecular phenomena include neuroendocrine transformation in androgen receptor-dependent prostate adenocarcinoma, and adenocarcinoma-to-neuroendocrine and adenocarcinoma-to-squamous transdifferentiation in epidermal growth factor receptor-driven lung adenocarcinoma, affecting 10%–20% of patients treated with targeted therapy. Recent analyses of human tumor samples and in vivo models of histological transformation have led to insights into the biology of lineage plasticity, including biomarkers predictive of high risk of transformation. However, no clinically available therapies aimed to prevent or revert plasticity are currently available. In the present review, we will provide a biological and therapeutic overview of the current understanding of common and divergent molecular drivers of neuroendocrine and squamous transdifferentiation in tumors from different origins, including descriptive analysis of previously known and recently described molecular events associated with histological transformation, and propose evidence-based alternative models of transdifferentiation. A clear definition of the commonalities and differences of transforming tumors in different organs and to different histological fates will be important to translate molecular findings to the clinical setting.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 11","pages":"803-823"},"PeriodicalIF":25.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01180-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189203","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 basis of vitamin K-dependent protein γ-glutamyl carboxylation","authors":"Qihang Zhong, Dandan Chen, Jinkun Xu, Yao Li, Wanqiong Yuan, Yan Meng, Qi Wen, Qiwei Ye, Guopeng Wang, Kexin Pan, Chunli Song, Lin Tao, Jie Qiao, Jing Hang","doi":"10.1038/s41422-025-01185-6","DOIUrl":"10.1038/s41422-025-01185-6","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 11","pages":"917-920"},"PeriodicalIF":25.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01185-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184691","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}