Cell Research最新文献_第2页

APOL proteins tune gut immunity via commensal lipid recognition APOL蛋白通过共生脂质识别调节肠道免疫

IF 44.1 1区生物学

Cell Research Pub Date : 2025-09-08 DOI: 10.1038/s41422-025-01166-9

Shohei Asami, Hiroshi Ohno

引用次数: 0

Molecular characterization of endosomal self RNA Rmrp-engaged TLR3 dimerization to prime innate activation. 内体自身RNA rmrp参与TLR3二聚化以启动先天激活的分子特征。

IF 44.1 1区生物学

Cell Research Pub Date : 2025-09-08 DOI: 10.1038/s41422-025-01178-5

Shikun Zhang,Bo Li,Lun Liu,Dongsheng Gong,Deyu Zhang,Fengjiang Liu,Xiuna Yang,Hua Qin,Deling Kong,Shuyang Zhang,Zihe Rao,Xuetao Cao

{"title":"Molecular characterization of endosomal self RNA Rmrp-engaged TLR3 dimerization to prime innate activation.","authors":"Shikun Zhang,Bo Li,Lun Liu,Dongsheng Gong,Deyu Zhang,Fengjiang Liu,Xiuna Yang,Hua Qin,Deling Kong,Shuyang Zhang,Zihe Rao,Xuetao Cao","doi":"10.1038/s41422-025-01178-5","DOIUrl":"https://doi.org/10.1038/s41422-025-01178-5","url":null,"abstract":"The pre-dimerization of endosome-localized RNA sensor Toll-like receptor 3 (TLR3) is required for its innate recognition, yet how TLR3 pre-dimers are formed and precisely primed for innate activation remains unclear. Here, we demonstrate that endosome-localized self RNA Rmrp directly binds to TLR3 and induces TLR3 dimerization in the early endosome but does not interact with endosome-localized TLR7, TLR8, TLR9 or cytoplasmic RNA sensor RIG-I under homeostatic conditions. Cryo-EM structure of Rmrp-TLR3 complex reveals a novel lapped conformation of TLR3 dimer engaged by Rmrp, which is distinct from the activation mechanism by dsRNA and the specific structural feature at the 3'-end of Rmrp is critical for its functional interaction with TLR3. Furthermore, K42 residue of TLR3 is essential for binding to Rmrp and subsequent dimerization. Rmrp dissociates from TLR3 following endosomal acidification, generating a matured TLR3 dimer which is primed for innate recognition and activation. Myeloid-cell deficiency of Rmrp reduces TLR3 dimerization and attenuates TLR3-mediated antiviral responses against influenza A both in vitro and in vivo. These findings elucidate the structural mode of self RNA Rmrp-primed TLR3 dimerization and ready for efficient innate recognition on endosomal membrane, extending our knowledge of how membrane-associated TLRs pre-dimerize and suggesting a new function of subcellular localized self RNAs in empowering innate activation.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"11 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008738","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

Osteocalcin has many tricks to get γ-carboxylated 骨钙素有很多方法来使γ-羧化

IF 25.9 1区生物学

Cell Research Pub Date : 2025-09-05 DOI: 10.1038/s41422-025-01177-6

Mathieu Ferron

引用次数: 0

Targeting necrotic lipid release in tumors enhances immunosurveillance and cancer immunotherapy of glioblastoma 靶向肿瘤坏死脂质释放增强胶质母细胞瘤的免疫监测和肿瘤免疫治疗

IF 44.1 1区生物学

Cell Research Pub Date : 2025-09-03 DOI: 10.1038/s41422-025-01155-y

Yapeng Ji, Junyao Jiang, Lei Hu, Peng Lin, Mingshan Zhou, Song Hu, Minkai Wang, Yuchen Ji, Xianzhi Liu, Dongming Yan, Yang Guo, Adwait Amod Sathe, Bret M. Evers, Chao Xing, Xuelian Luo, Qi Xie, Weike Pei, Zhenyu Zhang, Hongtao Yu

{"title":"Targeting necrotic lipid release in tumors enhances immunosurveillance and cancer immunotherapy of glioblastoma","authors":"Yapeng Ji, Junyao Jiang, Lei Hu, Peng Lin, Mingshan Zhou, Song Hu, Minkai Wang, Yuchen Ji, Xianzhi Liu, Dongming Yan, Yang Guo, Adwait Amod Sathe, Bret M. Evers, Chao Xing, Xuelian Luo, Qi Xie, Weike Pei, Zhenyu Zhang, Hongtao Yu","doi":"10.1038/s41422-025-01155-y","DOIUrl":"https://doi.org/10.1038/s41422-025-01155-y","url":null,"abstract":"Tumors evolve to avoid immune destruction and establish an immunosuppressive microenvironment. Syngeneic mouse tumor models are critical for understanding tumor immune evasion and testing cancer immunotherapy. Derived from established mouse tumor cell lines that can already evade the immune system, these models cannot simulate early phases of immunoediting during initial tumorigenesis. We developed a syngeneic mouse teratoma model derived from noncancerous mouse embryonic stem cells and conducted a genome-wide CRISPR screen to identify genes that impact early phases of cancer immunoediting. We found that loss of pro-apoptotic tumor suppressor genes, including Trp53, increased necrosis in teratomas, releasing APOE lipid particles into the extracellular milieu. Infiltrating T cells drawn to tumor necrotic regions accumulated lipids and became dysfunctional. Blocking lipid uptake in T cells or reducing necrosis in teratomas by inactivating the mitochondrial permeability transition pore (mPTP) restored immunosurveillance. Because mouse teratomas were highly enriched for brain tissues, we next examined the tumor-immune interaction in human glioblastoma (GBM). Indeed, infiltrating T cells in TP53-mutated human GBM accumulated APOE and were dysfunctional. Anti-APOE and anti-PDCD1 antibodies synergistically boosted anti-GBM immunity and prolonged survival in mice. Our results link mPTP-mediated tumor necrosis to immune evasion and suggest that targeting the uptake of lipids released by necrotic tumor cells by infiltrating immune cells can enhance cancer immunotherapy.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"2 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930208","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

IF 25.9 1区生物学

Cell Research Pub Date : 2025-09-02 DOI: 10.1038/s41422-025-01174-9

Yisheng Jiang, Feipeng Zhu, Jie Zhong, Xiaomei Sun, Yuting Yuan, Shuo Wang, Haiyang Chen, Zhiheng Xu

{"title":"Autism-related proteins form a complex to maintain the striatal asymmetry in mice","authors":"Yisheng Jiang, Feipeng Zhu, Jie Zhong, Xiaomei Sun, Yuting Yuan, Shuo Wang, Haiyang Chen, Zhiheng Xu","doi":"10.1038/s41422-025-01174-9","DOIUrl":"10.1038/s41422-025-01174-9","url":null,"abstract":"The brain’s hemispheres exhibit profound lateralization, yet the underlying mechanisms remain elusive. Using proteomic and phosphoproteomic analyses of the bilateral striatum — a hub for important brain functions and a common node of autism pathophysiology — we identified significant phosphorylation asymmetries. Particularly, the phosphorylation processes in the left striatum appear more prone to disturbance. Notably, SH3RF2, whose single-copy knockout leads to autism spectrum disorder (ASD)-like behaviors in mice, is uniquely expressed in the striatum, forming a complex with CaMKII (an ASD-associated protein) and PPP1CC. Loss of SH3RF2 disturbs the CaMKII/PP1 “switch”, resulting in hyperactivity of CaMKII and increased phosphorylation of its substrate GluR1. In Sh3rf2-deficient mice, heightened GluR1-Ser831 phosphorylation and its aberrant postsynaptic membrane localization in the left striatum may impair the functional lateralization of striatal neurons and contribute to autism-like behaviors. This study unveils the first molecular mechanism governing brain lateralization in mammals, linking its impairment to autism development and treatment strategies.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 10","pages":"762-774"},"PeriodicalIF":25.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01174-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928211","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

Structural insights into the vitamin K-dependent γ-carboxylation of osteocalcin 对维生素k依赖性骨钙素γ-羧化的结构见解

IF 25.9 1区生物学

Cell Research Pub Date : 2025-09-02 DOI: 10.1038/s41422-025-01161-0

Qing Cao, Jianjun Fan, Aaron Ammerman, Samjhana Awasthi, Zongtao Lin, Saimi Mierxiati, Huaping Chen, Jinbin Xu, Benjamin A. Garcia, Bin Liu, Weikai Li

{"title":"Structural insights into the vitamin K-dependent γ-carboxylation of osteocalcin","authors":"Qing Cao, Jianjun Fan, Aaron Ammerman, Samjhana Awasthi, Zongtao Lin, Saimi Mierxiati, Huaping Chen, Jinbin Xu, Benjamin A. Garcia, Bin Liu, Weikai Li","doi":"10.1038/s41422-025-01161-0","DOIUrl":"10.1038/s41422-025-01161-0","url":null,"abstract":"The γ-carboxylation state of osteocalcin determines its essential functions in bone mineralization or systemic metabolism and serves as a prominent biomarker for bone health and vitamin K nutrition. This post-translational modification of glutamate residues is catalyzed by the membrane-embedded vitamin K-dependent γ-carboxylase (VKGC), which typically recognizes protein substrates through their tightly bound propeptide that triggers γ-carboxylation. However, the osteocalcin propeptide exhibits negligible affinity for VKGC. To understand the underlying molecular mechanism, we determined the cryo-electron microscopy structures of VKGC with osteocalcin carrying a native propeptide or a high-affinity variant at different carboxylation states. The structures reveal a large chamber in VKGC that maintains uncarboxylated and partially carboxylated osteocalcin in partially unfolded conformations, allowing their glutamate-rich region and C-terminal helices to engage with VKGC at multiple sites. Binding of this mature region together with the low-affinity propeptide effectively stimulates VKGC activity, similar to high-affinity propeptides that differ only in closely fitting interactions. However, the low-affinity propeptide renders osteocalcin prone to undercarboxylation at low vitamin K levels, thereby serving as a discernible biomarker. Overall, our studies reveal the unique interaction of osteocalcin with VKGC and provide a framework for designing therapeutic strategies targeting osteocalcin-related bone and metabolic disorders.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 10","pages":"735-749"},"PeriodicalIF":25.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928541","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

Modeling post-gastrula development via bidirectional pluripotent stem cells. 通过双向多能干细胞模拟原肠胚后发育。

IF 25.9 1区生物学

Cell Research Pub Date : 2025-08-29 DOI: 10.1038/s41422-025-01172-x

Kuisheng Liu, Zihui Yan, Dandan Bai, Rui Jiang, Yan Bi, Xiangjun Ma, Jiani Xiang, Yifan Sheng, Baoxing Dong, Zhiyuan Ning, Shanru Yi, Yingdong Liu, Xinyi Lei, Yanping Jia, Yan Zhang, Yalin Zhang, Yanhe Li, Tao Wu, Chenxiang Xi, Shanyao Liu, Shuyi Liu, Jiayu Chen, Jiqing Yin, Xiaochen Kou, Yanhong Zhao, Hong Wang, Yixuan Wang, Ke Wei, Shaorong Gao, Wenqiang Liu

{"title":"Modeling post-gastrula development via bidirectional pluripotent stem cells.","authors":"Kuisheng Liu, Zihui Yan, Dandan Bai, Rui Jiang, Yan Bi, Xiangjun Ma, Jiani Xiang, Yifan Sheng, Baoxing Dong, Zhiyuan Ning, Shanru Yi, Yingdong Liu, Xinyi Lei, Yanping Jia, Yan Zhang, Yalin Zhang, Yanhe Li, Tao Wu, Chenxiang Xi, Shanyao Liu, Shuyi Liu, Jiayu Chen, Jiqing Yin, Xiaochen Kou, Yanhong Zhao, Hong Wang, Yixuan Wang, Ke Wei, Shaorong Gao, Wenqiang Liu","doi":"10.1038/s41422-025-01172-x","DOIUrl":"https://doi.org/10.1038/s41422-025-01172-x","url":null,"abstract":"The absence of stem cells capable of efficiently generating both trophoblast and epiblast lineages has hindered precise recapitulation of embryonic development. Through high-content chemical screening, we established an (AS and LY) AL medium to generate mouse bidirectional pluripotent stem cells (BPSCs) characterized by concurrent expression of OCT4 and CDX2. Mouse BPSCs demonstrated highly plastic differentiation into trophoblast, epiblast and primitive endoderm (PrE) lineages in vitro within 48 h without exogenous inducing factors and efficiently contributed to embryonic and extraembryonic tissues in vivo. Mechanistically, hyperactivation of the Wnt signaling pathway breaks the early lineage differentiation barrier by initiating a Lef1-dependent bypass. Remarkably, integration of BPSCs with PrE induction system enables high-efficiency generation of E8.5-stage embryo models. These advanced models complete gastrulation and recapitulate definitive developmental milestones including brain morphogenesis, neural tube closure, cardiac contraction, somite patterning, and primordial germ cell specification. Moreover, human cells cultured under AL conditions acquire an OCT4 and CDX2 double-positive state and corresponding gene expression profiles, revealing conserved functionality of this culturing platform across species. These findings highlight BPSCs as a powerful tool for investigating early lineage specification and post-gastrulation embryonic development.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":25.9,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944816","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

Novel organoid culture condition: modeling fetal-like plasticity in colorectal cancer 新型类器官培养条件：模拟结直肠癌胎儿样可塑性。

IF 25.9 1区生物学

Cell Research Pub Date : 2025-08-29 DOI: 10.1038/s41422-025-01170-z

Chao Wu, Min Jung Kim, J. Joshua Smith

引用次数: 0

Sabotaging TCR signaling-LAG3 interferes with the CD3ε-LCK interaction. 破坏TCR信号- lag3干扰CD3ε-LCK相互作用。

IF 25.9 1区生物学

Cell Research Pub Date : 2025-08-22 DOI: 10.1038/s41422-025-01168-7

Gina J Fiala, Wolfgang W Schamel

引用次数: 0

A decade of migrasome research: biogenesis, physiological functions, and disease implications 十年来偏头痛研究：生物发生、生理功能和疾病影响。