Cell Research最新文献_第5页

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

IF 28.1 1区生物学

Cell Research Pub Date : 2025-05-01 Epub 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":" ","pages":"334-344"},"PeriodicalIF":28.1,"publicationDate":"2025-05-01","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

Mechano-pharmacology of T cell receptor specificity. T细胞受体特异性的机械药理学。

IF 28.1 1区生物学

Cell Research Pub Date : 2025-05-01 DOI: 10.1038/s41422-025-01105-8

Panyu Fei, Michael L Dustin

引用次数: 0

Broad H3K4me3 domains orchestrate temporal control of gene expression. 广泛的H3K4me3结构域协调基因表达的时间控制。

IF 28.1 1区生物学

Cell Research Pub Date : 2025-05-01 DOI: 10.1038/s41422-025-01104-9

Yuka Kitamura, Mengwen Hu, Satoshi H Namekawa

引用次数: 0

Identification of a GPCR as a tip link-independent equilibrioceptor. 鉴定一个GPCR作为尖端连接无关的平衡受体。

IF 28.1 1区生物学

Cell Research Pub Date : 2025-05-01 DOI: 10.1038/s41422-025-01102-x

Biyun Zhu, Shao Wei Hu, Yilai Shu

引用次数: 0

Lysosomal EGFR acts as a Rheb-GEF independent of its kinase activity to activate mTORC1 溶酶体表皮生长因子受体作为独立于其激酶活性的 Rheb-GEF 激活 mTORC1

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-21 DOI: 10.1038/s41422-025-01110-x

Xiaobo He, Qiu-Xia Wang, Denghui Wei, Yujie Lin, Xia Zhang, Yuanzhong Wu, Xuexia Qian, Zhihao Lin, Beibei Xiao, Qinxue Wu, Zhen Wang, Fengtao Zhou, Zhihao Wei, Jingxuan Wang, Run Gong, Ruhua Zhang, Qingling Zhang, Ke Ding, Song Gao, Tiebang Kang

{"title":"Lysosomal EGFR acts as a Rheb-GEF independent of its kinase activity to activate mTORC1","authors":"Xiaobo He, Qiu-Xia Wang, Denghui Wei, Yujie Lin, Xia Zhang, Yuanzhong Wu, Xuexia Qian, Zhihao Lin, Beibei Xiao, Qinxue Wu, Zhen Wang, Fengtao Zhou, Zhihao Wei, Jingxuan Wang, Run Gong, Ruhua Zhang, Qingling Zhang, Ke Ding, Song Gao, Tiebang Kang","doi":"10.1038/s41422-025-01110-x","DOIUrl":"https://doi.org/10.1038/s41422-025-01110-x","url":null,"abstract":"Oncogenic mutations in EGFR often result in EGF-independent constitutive activation and aberrant trafficking and are associated with several human malignancies, including non-small cell lung cancer. A major consequence of EGFR mutations is the activation of the mechanistic target of rapamycin complex 1 (mTORC1), which requires EGFR kinase activity and downstream PI3K/AKT signaling, resulting in increased cell proliferation. However, recent studies have elucidated kinase-independent roles of EGFR in cell survival and cancer progression. Here, we report a cis mTORC1 activation function of EGFR that is independent of its kinase activity. Our results reveal that lysosomal localization of EGFR is critical to mTORC1 activation, where EGFR physically binds Rheb, acting as a guanine exchange factor (GEF) for Rheb, with its Glu804 serving as a potential glutamic finger. Genetic knock-in of EGFR-E804K in cells reduces the level of GTP-bound Rheb, and significantly suppresses mTORC1 activation, cell proliferation and tumor growth. Different tyrosine kinase inhibitors exhibit distinct effects on EGFR-induced mTORC1 activation, with afatinib, which additionally blocks EGFR’s GEF activity, causing a much greater suppression of mTORC1 activation and cell growth, and erlotinib, which targets only kinase activity, resulting in only a slight decrease. Moreover, a novel small molecule, BIEGi-1, was designed to target both the Rheb-GEF and kinase activities of EGFR, and shows a strong inhibitory effect on the viability of cells harboring EGFR mutants. These findings unveil a fundamental event in cell growth and suggest a promising strategy against cancers with EGFR mutations.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"47 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853179","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

Decoding NLRP3: Phase separation enters the scene 解码NLRP3：相位分离进入场景

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-21 DOI: 10.1038/s41422-025-01120-9

Niklas A. Schmacke, Veit Hornung

引用次数: 0

Gasdermin D pores hitch a ride: extracellular vesicles spread pyroptosis 气真皮蛋白D毛孔搭便车：细胞外囊泡扩散热亡

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-21 DOI: 10.1038/s41422-025-01109-4

Gang Du, Hao Wu

引用次数: 0

Orchestrating NTSR1 signaling from the interface 编排来自接口的NTSR1信令

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-21 DOI: 10.1038/s41422-025-01121-8

Xianglin Huang, Brian E. Krumm, Bryan L. Roth

引用次数: 0

Spliceosome-associated quality control 剪接体相关质量控制

IF 44.1 1区生物学

Cell Research Pub Date : 2025-04-21 DOI: 10.1038/s41422-025-01118-3

Nikita Sharaev, Jiangfeng Zhao, Wojciech P. Galej

引用次数: 0

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

IF 44.1 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":"https://doi.org/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":"16 1","pages":""},"PeriodicalIF":44.1,"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