Cell Research最新文献_第4页

Selective CDK4 inhibition holds promise for breast cancer 选择性CDK4抑制有望治疗乳腺癌

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-14 DOI: 10.1038/s41422-025-01117-4

Manuel Beltrán-Visiedo, Rebecca M. Shulman, Lorenzo Galluzzi

引用次数: 0

Phase separation paints Xi with Xist 相分离把Xi和Xist画在一起

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-14 DOI: 10.1038/s41422-025-01116-5

Thomas C. T. Michaels, Anton Wutz

引用次数: 0

Structural basis of stepwise proton sensing-mediated GPCR activation. 质子感应介导的GPCR逐步激活的结构基础。

IF 28.1 1区生物学

Cell Research Pub Date : 2025-04-11 DOI: 10.1038/s41422-025-01092-w

Xiaolei Yue, Li Peng, Shenhui Liu, Bingjie Zhang, Xiaodan Zhang, Hao Chang, Yuan Pei, Xiaoting Li, Junlin Liu, Wenqing Shui, Lijie Wu, Huji Xu, Zhi-Jie Liu, Tian Hua

{"title":"Structural basis of stepwise proton sensing-mediated GPCR activation.","authors":"Xiaolei Yue, Li Peng, Shenhui Liu, Bingjie Zhang, Xiaodan Zhang, Hao Chang, Yuan Pei, Xiaoting Li, Junlin Liu, Wenqing Shui, Lijie Wu, Huji Xu, Zhi-Jie Liu, Tian Hua","doi":"10.1038/s41422-025-01092-w","DOIUrl":"https://doi.org/10.1038/s41422-025-01092-w","url":null,"abstract":"The regulation of pH homeostasis is crucial in many biological processes vital for survival, growth, and function of life. The pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 and GPR68, play a pivotal role in detecting changes in extracellular proton concentrations, impacting both physiological and pathological states. However, comprehensive understanding of the proton sensing mechanism is still elusive. Here, we determined the cryo-electron microscopy structures of GPR4 and GPR65 in various activation states across different pH levels, coupled with Gs, Gq or G13 proteins, as well as a small molecule NE52-QQ57-bound inactive GPR4 structure. These structures reveal the dynamic nature of the extracellular loop 2 and its signature conformations in different receptor states, and disclose the proton sensing mechanism mediated by networks of extracellular histidine and carboxylic acid residues. Notably, we unexpectedly captured partially active intermediate states of both GPR4-Gs and GPR4-Gq complexes, and identified a unique allosteric binding site for NE52-QQ57 in GPR4. By integrating prior investigations with our structural analysis and mutagenesis data, we propose a detailed atomic model for stepwise proton sensation and GPCR activation. These insights may pave the way for the development of selective ligands and targeted therapeutic interventions for pH sensing-relevant diseases.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979144","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}

引用次数: 0

Mechanisms of chromatin remodeling by the human Snf2-type ATPase SNF2H. 人类snf2型atp酶SNF2H的染色质重塑机制。

IF 28.1 1区生物学

Cell Research Pub Date : 2025-04-03 DOI: 10.1038/s41422-025-01103-w

Deepshikha Malik, Ashish Deshmukh, Silvija Bilokapic, Mario Halic

引用次数: 0

Signal-induced NLRP3 phase separation initiates inflammasome activation 信号诱导的NLRP3相分离启动炎性小体激活

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-01 DOI: 10.1038/s41422-025-01096-6

Gonglu Zou, Yuluan Tang, Jie Yang, Shuo Fu, Yuheng Li, Xuanyao Ren, Nanhai Zhou, Wenlong Zhao, Juyi Gao, Ziran Ruan, Zhengfan Jiang

{"title":"Signal-induced NLRP3 phase separation initiates inflammasome activation","authors":"Gonglu Zou, Yuluan Tang, Jie Yang, Shuo Fu, Yuheng Li, Xuanyao Ren, Nanhai Zhou, Wenlong Zhao, Juyi Gao, Ziran Ruan, Zhengfan Jiang","doi":"10.1038/s41422-025-01096-6","DOIUrl":"https://doi.org/10.1038/s41422-025-01096-6","url":null,"abstract":"NLRP3 inflammasome is activated by diverse stimuli including infections, intracellular and environmental irritants. How NLRP3 senses these unrelated stimuli and what activates NLRP3 remain unknown. Here we report that signal-dependent NLRP3 phase separation initiated its activation, in which the palmitoyltransferase ZDHHC7-mediated tonic NLRP3 palmitoylation and an IDR region in the FISNA domain of NLRP3 play important roles. Moreover, three conserved hydrophobic residues in the IDR critically mediate multivalent weak interactions. NLRP3-activating stimuli including K+ efflux and NLRP3-interacting molecules imiquimod, palmitate, and cardiolipin all cause NLRP3 conformational change and induce its phase separation and activation in cells and/or in vitro. Surprisingly, amphiphilic molecules like di-alcohols used to inhibit biomolecular phase separation and chemotherapeutic drugs doxorubicin and paclitaxel activate NLRP3 independently of ZDHHC7 by directly inducing NLRP3 phase separation. Mechanistically, amphiphilic molecules decrease the solubility of both palmitoylated and non-palmitoylated NLRP3 to directly induce its phase separation and activation while NLRP3 palmitoylation reduces its solubility to some extent without activation. Therefore, ZDHHC7-mediated NLRP3 palmitoylation in resting cells licenses its activation by lowering the threshold for NLRP3 phase separation in response to any of the diverse stimuli whereas NLRP3 solubility-reducing molecules like di-alcohols and chemotherapeutic drugs activate NLRP3 directly. The signal-induced NLRP3 phase separation likely provides the simplest and most direct mechanistic basis for NLRP3 activation.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"1 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744701","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}

引用次数: 0

A phytoalexin dismantles bacterial type III injectisome 一种植物抗菌素可以分解细菌III型注射体

IF 44.1 1区生物学

Cell Research Pub Date : 2025-03-31 DOI: 10.1038/s41422-025-01111-w

Manman Zhang, Cheng Li, Zheng Qing Fu

引用次数: 0

Author Correction: Improved survival of porcine acute liver failure by a bioartificial liver device implanted with induced human functional hepatocytes. 作者更正：通过植入诱导的人类功能性肝细胞的生物人工肝装置提高猪急性肝衰竭的存活率。

IF 28.1 1区生物学

Cell Research Pub Date : 2025-03-27 DOI: 10.1038/s41422-025-01108-5

Xiao-Lei Shi, Yimeng Gao, Yupeng Yan, Hucheng Ma, Lulu Sun, Pengyu Huang, Xuan Ni, Ludi Zhang, Xin Zhao, Haozhen Ren, Dan Hu, Yan Zhou, Feng Tian, Yuan Ji, Xin Cheng, Guoyu Pan, Yi-Tao Ding, Lijian Hui

引用次数: 0

The night shift: norepinephrine drives glymphatics. 夜班：去甲肾上腺素驱动淋巴细胞。

IF 28.1 1区生物学

Cell Research Pub Date : 2025-03-25 DOI: 10.1038/s41422-025-01106-7

Benjamin A Plog, Leon C D Smyth, Jonathan Kipnis

引用次数: 0

Nociceptor neurons promote PDAC progression and cancer pain by interaction with cancer-associated fibroblasts and suppression of natural killer cells 痛觉感受器神经元通过与癌症相关成纤维细胞和抑制自然杀伤细胞的相互作用促进PDAC的进展和癌症疼痛

IF 44.1 1区生物学

Cell Research Pub Date : 2025-03-24 DOI: 10.1038/s41422-025-01098-4

Kaiyuan Wang, Bo Ni, Yongjie Xie, Zekun Li, Limei Yuan, Chenyang Meng, Tiansuo Zhao, Song Gao, Chongbiao Huang, Hongwei Wang, Ying Ma, Tianxing Zhou, Yukuan Feng, Antao Chang, Chao Yang, Jun Yu, Wenwen Yu, Fenglin Zang, Yanhui Zhang, Ru-Rong Ji, Xiuchao Wang, Jihui Hao

{"title":"Nociceptor neurons promote PDAC progression and cancer pain by interaction with cancer-associated fibroblasts and suppression of natural killer cells","authors":"Kaiyuan Wang, Bo Ni, Yongjie Xie, Zekun Li, Limei Yuan, Chenyang Meng, Tiansuo Zhao, Song Gao, Chongbiao Huang, Hongwei Wang, Ying Ma, Tianxing Zhou, Yukuan Feng, Antao Chang, Chao Yang, Jun Yu, Wenwen Yu, Fenglin Zang, Yanhui Zhang, Ru-Rong Ji, Xiuchao Wang, Jihui Hao","doi":"10.1038/s41422-025-01098-4","DOIUrl":"https://doi.org/10.1038/s41422-025-01098-4","url":null,"abstract":"The emerging field of cancer neuroscience has demonstrated great progress in revealing the crucial role of the nervous system in cancer initiation and progression. Pancreatic ductal adenocarcinoma (PDAC) is characterized by perineural invasion and modulated by autonomic (sympathetic and parasympathetic) and sensory innervations. Here, we further demonstrated that within the tumor microenvironment of PDAC, nociceptor neurons interacted with cancer-associated fibroblasts (CAFs) through calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF). This interaction led to the inhibition of interleukin-15 expression in CAFs, suppressing the infiltration and cytotoxic function of natural killer (NK) cells and thereby promoting PDAC progression and cancer pain. In PDAC patients, nociceptive innervation of tumor tissue is negatively correlated with the infiltration of NK cells while positively correlated with pain intensity. This association serves as an independent prognostic factor for both overall survival and relapse-free survival for PDAC patients. Our findings highlight the crucial regulation of NK cells by nociceptor neurons through interaction with CAFs in the development of PDAC. We also propose that targeting nociceptor neurons or CGRP signaling may offer a promising therapy for PDAC and cancer pain.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"123 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677992","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}

引用次数: 0

Target DNA-induced filament formation and nuclease activation of SPARDA complex 靶dna诱导丝的形成和SPARDA复合体的核酸酶激活

IF 44.1 1区生物学

Cell Research Pub Date : 2025-03-24 DOI: 10.1038/s41422-025-01100-z

Feng Wang, Haijiang Xu, Chendi Zhang, Jialin Xue, Zhuang Li

{"title":"Target DNA-induced filament formation and nuclease activation of SPARDA complex","authors":"Feng Wang, Haijiang Xu, Chendi Zhang, Jialin Xue, Zhuang Li","doi":"10.1038/s41422-025-01100-z","DOIUrl":"https://doi.org/10.1038/s41422-025-01100-z","url":null,"abstract":"The short Argonaute-based bacterial defense system, SPARDA (Short Prokaryotic Argonaute and DNase/RNase-APAZ), utilizes guide RNA to target invading complementary DNA and exhibits collateral nuclease activity, leading to cell death or dormancy. However, its detailed mechanisms remain poorly understood. In this study, we investigated the SPARDA system from Novosphingopyxis baekryungensis (NbaSPARDA) and discovered an unexpected filament configuration upon target DNA binding, which strongly correlated with collateral nuclease activity. Filament formation and nuclease activation require a guide–target heteroduplex of sufficient length with perfect complementarity at the central region. A series of cryo-EM structures of NbaSPARDA complexes, loaded with guide RNA, target DNA of varying lengths, and substrate ssDNA, were determined at ~3.0 Å resolution. Structural analyses indicated that guide RNA binding induces dimerization of the NbaSPARDA complex, while target DNA engagement disrupts this dimerization. Further propagation of the guide–target heteroduplex triggers filament formation through a checkpoint mechanism. The NbaSPARDA filament consists of a backbone formed by interlocking short Argonaute proteins, with an inner layer composed of DREN nuclease domains. Filament formation leads to tetramerization of the monomeric DREN nuclease domain, activating its collateral nuclease activity against environmental nucleic acids — a feature leveraged for molecular diagnostics. For bacteria heterologously expressing the NbaSPARDA system, defense against invading bacteriophages and plasmids relies on filament formation. Collectively, these findings illustrate the detailed working mechanism of the NbaSPARDA complex and highlight the importance of its filament formation in host defense.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"97 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143678022","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}

引用次数: 0