Cell Research最新文献_第8页

Mechanistic insights into RNA cleavage by human Argonaute2–siRNA complex 人类Argonaute2-siRNA复合物裂解RNA的机制

IF 25.9 1区生物学

Cell Research Pub Date : 2025-04-16 DOI: 10.1038/s41422-025-01114-7

Zhenzhen Li, Qikui Xu, Yan Zhang, Jing Zhong, Tianxiang Zhang, Junchao Xue, Shuxian Liu, Haishan Gao, Z. Z. Zhao Zhang, Jianping Wu, En-Zhi Shen

{"title":"Mechanistic insights into RNA cleavage by human Argonaute2–siRNA complex","authors":"Zhenzhen Li, Qikui Xu, Yan Zhang, Jing Zhong, Tianxiang Zhang, Junchao Xue, Shuxian Liu, Haishan Gao, Z. Z. Zhao Zhang, Jianping Wu, En-Zhi Shen","doi":"10.1038/s41422-025-01114-7","DOIUrl":"10.1038/s41422-025-01114-7","url":null,"abstract":"In animals, AGO-clade Argonaute proteins utilize small interfering RNAs (siRNAs) as guides to recognize target with complete complementarity, resulting in target RNA cleavage that is a critical step for target silencing. These proteins feature a constricted nucleic acid-binding channel that limits base pairing between the guide and target beyond the seed region. How the AGO–siRNA complexes overcome this structural limitation and achieve efficient target cleavage remains unclear. We performed cryo-electron microscopy of human AGO–siRNA complexes bound to target RNAs of increasing lengths to examine the conformational changes associated with target recognition and cleavage. Initially, conformational transition propagates from the opening of the PAZ domain and extends through a repositioning of the PIWI–L1–N domain toward the binding channel, facilitating the capture of siRNA–target duplex. Subsequent extension of base pairing drives the downward movement of the PIWI–L1–N domain to enable catalytic activation. Finally, further base pairing toward the 3′ end of siRNA destabilizes the PAZ–N domain, resulting in a “uni-lobed” architecture, which might facilitate the multi-turnover action of the AGO–siRNA enzyme complex. In contrast to PIWI-clade Argonautes, the “uni-lobed” structure of the AGO complex makes multiple contacts with the target in the central region of the siRNA–target duplex, positioning it within the catalytic site. Our findings shed light on the stepwise mechanisms by which the AGO–siRNA complex executes target RNA cleavage and offer insights into the distinct operational modalities of AGO and PIWI proteins in achieving such cleavage.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 6","pages":"453-464"},"PeriodicalIF":25.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836746","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

Why resident microglial-like cells were missed in the peripheral nervous system. 为什么周围神经系统中缺少常驻小胶质样细胞。

IF 28.1 1区生物学

Cell Research Pub Date : 2025-04-15 DOI: 10.1038/s41422-025-01119-2

Michal Schwartz

引用次数: 0

Beyond peptide targeting sequences: machine learning of cellular condensate localization 超越肽靶向序列：细胞凝聚物定位的机器学习

IF 25.9 1区生物学

Cell Research Pub Date : 2025-04-14 DOI: 10.1038/s41422-025-01115-6

Jonathon A. Ditlev, Julie D. Forman-Kay

引用次数: 0

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 25.9 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 25.9 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":"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":"35 6","pages":"423-436"},"PeriodicalIF":25.9,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134361/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pyroptosis: molecular mechanisms and roles in disease 焦亡：分子机制及其在疾病中的作用。

IF 25.9 1区生物学

Cell Research Pub Date : 2025-04-03 DOI: 10.1038/s41422-025-01107-6

Petr Broz

{"title":"Pyroptosis: molecular mechanisms and roles in disease","authors":"Petr Broz","doi":"10.1038/s41422-025-01107-6","DOIUrl":"10.1038/s41422-025-01107-6","url":null,"abstract":"Pyroptosis is a type of programmed necrosis triggered by the detection of pathogens or endogenous danger signals in the cytosol. Pyroptotic cells exhibit a swollen, enlarged morphology and ultimately undergo lysis, releasing their cytosolic contents — such as proteins, metabolites, and nucleic acids — into the extracellular space. These molecules can function as danger-associated molecular patterns (DAMPs), triggering inflammation when detected by neighboring cells. Mechanistically, pyroptosis is initiated by members of the gasdermin protein family, which were identified a decade ago as pore-forming executors of cell death. Mammalian gasdermins consist of a cytotoxic N-terminal domain, a flexible linker, and a C-terminal regulatory domain that binds to and inhibits the N-terminus. Proteolytic cleavage within the linker releases the N-terminal domain, enabling it to target various cellular membranes, including nuclear, mitochondrial, and plasma membranes, where it forms large transmembrane pores. Gasdermin pores in the plasma membrane disrupt the electrochemical gradient, leading to water influx and cell swelling. Their formation also activates the membrane protein ninjurin-1 (NINJ1), which oligomerizes to drive complete plasma membrane rupture and the release of large DAMPs. Since their discovery as pore-forming proteins, gasdermins have been linked to pyroptosis not only in host defense but also in various pathological conditions. This review explores the history of pyroptosis, recent insights into gasdermin activation, the cellular consequences of pore formation, and the physiological roles of pyroptosis.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 5","pages":"334-344"},"PeriodicalIF":25.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779207","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}

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 25.9 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 25.9 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":"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":"35 6","pages":"437-452"},"PeriodicalIF":25.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01096-6.pdf","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":"OA","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 25.9 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