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ENKD1 modulates innate immune responses through enhanced geranylgeranyl pyrophosphate synthase activity

cell Reports 2025年第3期44卷 115397页

作者： Zhang, Tianyu Wang, Yixuan Nie, Xiaotong Chen, Xiangrong Jin, Yueyi Sun, Lulu Yang, Ruqian Wang, Jie Xu, Wenqing Song, Ting Xie, Wei Chen, Xiangfeng Li, Chaojun Zhou, Jun Wu, Sijin Li, Yan Li, Tianliang Center for Cell Structure and Function Shandong Provincial Key Laboratory of Animal Resistance Biology Collaborative Innovation Center of Cell Biology in Universities of Shandong College of Life Sciences Shandong Normal University Jinan 250358 China Key Laboratory for Applied Technology of Sophisticated Analytical Instruments Shandong Analysis and Test Center Qilu University of Technology (Shandong Academy of Science) Shandong Jinan China Academy of Pharmacy Xi'an Jiaotong-Liverpool University Suzhou 215123 China Medical Science and Technology Innovation Center Shandong First Medical University & Shandong Academy of Medical Sciences Jinan 250117 China State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine and School of Medicine Nanjing University Jiangsu Nanjing 210093 China State Key Laboratory of Medicinal Chemical Biology Haihe Laboratory of Cell Ecosystem College of Life Sciences Nankai University Tianjin 300071 China

Inflammation is a crucial element of immune responses, with pivotal roles in host defenses against pathogens. Comprehensive understanding of the molecular mechanisms underlying inflammation is imperative for developing effective strategies to combat infectious diseases. Here, we conducted a screening analysis and identified enkurin domain-containing protein 1 (ENKD1) as a promising regulator of inflammation. We observed that ENKD1 expression was significantly reduced on activation of multiple Toll-like receptor (TLR) molecules. Deletion of ENKD1 resulted in enhanced innate immune system activation and exacerbation of septic inflammation. Mechanistically, ENKD1 interacted with geranylgeranyl diphosphate synthase 1 (GGPS1) and modulated its enzymatic activity, thereby influencing geranylgeranyl diphosphate production. This interaction ultimately led to Ras-related C3 botulinum toxin substrate 1 (RAC1) inactivation and suppression of pro-inflammatory signaling pathways. Our findings establish ENKD1 as a critical regulator of innate immune cell activation, underscoring its significant role in septic inflammation. © 2025 The Author(s)

关键词： CP: Immunology ENKD1 GGPS1 inflammation RAC1 sepsis Toll-like receptor

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A fixed site of DNA replication in eucaryotic cells

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cell 1980年第2期19卷 527-536页

作者： Pardoll, Drew M. Vogelstein, Bert Coffey, Donald S. Cell Structure and Function Laboratory The Oncology Center Johns Hopkins Univ. School of Medicine Ba MD 21205 United States

We studied the role of the nuclear matrix (the skeletal framework of the nucleus) in DNA replication both in vivo and in a cell culture system. When regenerating rat liver or exponentially growing 3T3 fibroblasts are pulse-labeled with ³H-thymidine and nuclear matrix is subsequently isolated, the fraction of DNA remaining tightly attached to the matrix is highly enriched in newly synthesized DNA. After a 30 sec pulse labeling period and limited DNAase I digestion, the matrix DNA of 3T3 fibroblasts, which constitutes 15% of the total DNA, contains approximately 90% of the labeled newly synthesized DNA. Over 80% of this label can be chased out of the matrix DNA if the pulse is followed by a 45 min incubation with excess unlabeled thymidine. These and other kinetic studies suggest that the growing point of DNA replication is attached to the nuclear matrix. Studies measuring the size distribution of the matrix DNA also support this conclusion. Reconstitution controls and autoradiographic studies indicate that these results are not due to preferential, nonspecific binding of nascent DNA to the matrix during the extraction procedures. Electron microscopic autoradiography shows that, as with intact nuclei, sites of DNA replication are distributed throughout the nuclear matrix. A fixed site of DNA synthesis is proposed in which DNA replication complexes are anchored to the nuclear matrix and the DNA is reeled through these complexes as it is replicated. © 1980.

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Cryo-EM structures of Native Chromatin Units From Human cells

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Genes to cells 2025年第3期30卷 e70019页

作者： Hatazawa, Suguru Fukuda, Yoshiyuki Kobayashi, Yuki Negishi, Lumi Kikkawa, Masahide Takizawa, Yoshimasa Kurumizaka, Hitoshi Laboratory of Chromatin Structure and Function Institute for Quantitative Biosciences The University of Tokyo Tokyo Japan Division of Molecular CytoMorphology Institute of Advanced Medical Sciences Tokushima University Tokushima Tokushima Japan Department of Cell Biology and Anatomy Graduate School of Medicine The University of Tokyo Tokyo Japan Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan Department of Biological Sciences Graduate School of Science The University of Tokyo Tokyo Japan RIKEN Center for Biosystems Dynamics Research Yokohama Japan

In eukaryotic cells, genomic DNA is compacted by nucleosomes, as basic repeating units, into chromatin. The nucleosome arrangement in chromatin fibers could be an important determinant for chromatin folding, by which genomic DNA is regulated in the nucleus. To study the structures of chromatin units in cells, we have established a method for the structural analysis of native mono- and poly-nucleosomes prepared from HeLa cells. In this method, the chromatin in isolated nuclei was crosslinked to preserve the proximity information between nucleosomes, followed by chromatin fragmentation by micrococcal nuclease treatment. The mono- and poly-nucleosomes were then fractionated by sucrose gradient ultracentrifugation, and their structures were analyzed by cryo-electron microscopy. Cryo-electron microscopy single particle analysis and cryo-electron tomography visualized a native nucleosome structure and secondary nucleosome arrangements in cellular chromatin. This method provides a complementary strategy to fill the gap between in vitro and in situ analyses of chromatin structure. © 2025 The Author(s). Genes to cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

关键词： chromatin cryo-electron tomography cryo-EM nucleosome single particle analysis

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Author Correction: PDCD6 regulates lactate metabolism to modulate LC3-associated phagocytosis and antibacterial defense

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Nature communications 2025年第1期16卷 1541页

作者： Lulu Sun Sijin Wu Hui Wang Tianyu Zhang Mengyu Zhang Xuepeng Bai Xiumei Zhang Bingqing Li Cai Zhang Yan Li Jun Zhou Tianliang Li Center for Cell Structure and Function Shandong Provincial Key Laboratory of Animal Resistance Biology Collaborative Innovation Center of Cell Biology in Universities of Shandong College of Life Sciences Shandong Normal University Jinan 250358 China. Academy of Pharmacy Xi'an Jiaotong-Liverpool University Suzhou 215123 China. Department of Cardiac Surgery Public Health Clinical Center Affiliated to Shandong University Jinan 250013 China. School of Health Care Security Shandong First Medical University & Shandong Academy of Medical Sciences Jinan 250117 China. Department of Pathogen Biology School of Clinical and Basic Medical Sciences Shandong First Medical University & Shandong Academy of Medical Sciences Jinan 250117 China. Institute of Immunopharmacology and Immunotherapy School of Pharmaceutical Sciences Shandong University Jinan 250012 China. Center for Cell Structure and Function Shandong Provincial Key Laboratory of Animal Resistance Biology Collaborative Innovation Center of Cell Biology in Universities of Shandong College of Life Sciences Shandong Normal University Jinan 250358 China. junzhou@***. State Key Laboratory of Medicinal Chemical Biology Haihe Laboratory of Cell Ecosystem College of Life Sciences Nankai University Tianjin 300071 China. junzhou@***. Center for Cell Structure and Function Shandong Provincial Key Laboratory of Animal Resistance Biology Collaborative Innovation Center of Cell Biology in Universities of Shandong College of Life Sciences Shandong Normal University Jinan 250358 China. li.tianliang@***.

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CCDC181 is required for proper spermiogenesis in mice

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Journal of Genetics and Genomics 2024年第11期51卷 1327-1330页

作者： Xirui Zi Qingchao Li Yue Lu Qian Lyu Heng Guo Xiaoqian Meng Jun Zhou Huijie Zhao Center for Cell Structure and Function Shandong Provincial Key Laboratory of Animal Resistance BiologyCollaborative Innovation Center of Cell Biology in Universities of ShandongCollege of Life SciencesShandong Normal UniversityJinanShandong 250014China State Key Laboratory of Medicinal Chemical Biology Haihe Laboratory of Cell EcosystemCollege of Life SciencesNankai UniversityTianjin 300071China

Cilia are hair-like cellular projections essential for development and homeostasis,which can be grouped into either immotile or motile cilia based on their *** vertebrates,motile cilia that line the brain ventricles,respiratory tracts,and reproductive tracts exist as multiple cilia and beat in a coordinated fashion to generate a directional fluid flow across the epithelial surfaces(Lyu et al.,2024).In contrast,sperm cells have a single flagellum that shares a similar axoneme arrangement but possesses unique accessory structures,including the mitochondrial sheath,the fibrous sheath,and the outer dense fibers(Linck et al.,2016).Some ciliary proteins display distinct cellular distributions in multiple motile cilia and sperm *** instance,outer dense fiber protein 2(ODF2)associates with basal bodies in tracheal motile cilia but is abundant in sperm flagella(Zhao et al.,2021;Zhu et al.,2022).These differences potentially grant sperm flagella distinctive properties.

关键词： outer arrangement fibers

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Lipid droplets in pathogen infection and host immunity

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中国药理学报（英文版） 2024年第3期45卷 449-464页

作者： Yan-jie Tan Yi Jin Jun Zhou Yun-fan Yang Center for Cell Structure and Function Shandong Provincial Key Laboratory of Animal Resistance BiologyCollaborative Innovation Center of Cell Biology in Universities of ShandongCollege of Life SciencesShandong Normal UniversityJinan 250014China Research Center of Translational Medicine Central Hospital Affiliated to Shandong First Medical UniversityJinan 250013China Center for Cell Structure and Function Shandong Provincial Key Laboratory of Animal Resistance BiologyCollaborative Innovation Center of Cell Biology in Universities of ShandongCollege of Life SciencesShandong Normal UniversityJinan 250014China State Key Laboratory of Medicinal Chemical Biology Haihe Laboratory of Cell EcosystemCollege of Life SciencesNankai UniversityTianjin 300071China Department of Cell Biology School of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

As the hub of cellular lipid metabolism,lipid droplets(LDs)have been linked to a variety of biological *** pathogen infection,the biogenesis,composition,and functions of LDs are tightly *** accumulation of LDs has been described as a hallmark of pathogen infection and is thought to be driven by pathogens for their own *** studies have revealed that LDs and their subsequent lipid mediators contribute to effective immunological responses to pathogen infection by promoting host stress tolerance and reducing *** this comprehensive review,we delve into the intricate roles of LDs in governing the replication and assembly of a wide spectrum of pathogens within host *** also discuss the regulatory function of LDs in host immunity and highlight the potential for targeting LDs for the diagnosis and treatment of infectious diseases.

关键词： lipid droplet lipid mediators pathogen host immunity

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Peripheral and central control of obesity by primary cilia

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Journal of Genetics and Genomics 2023年第5期50卷 295-304页

作者： Yue Wu Jun Zhou Yunfan Yang Center for Cell Structure and Function Shandong Provincial Key Laboratory of Animal Resistance BiologyCollaborative Innovation Center of Cell Biology in Universities of ShandongCollege of Life SciencesShandong Normal UniversityJinanShandong 250014China State Key Laboratory of Medicinal Chemical Biology Haihe Laboratory of Cell EcosystemCollege of Life SciencesNankai UniversityTianjin 300071China Department of Cell Biology School of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinanShandong 250012China

Primary cilia are hair-like structures that protrude from the cell *** are capable of sensing external cues and conveying a vast array of signals into cells to regulate a variety of physiological *** in cilium-associated genes are linked to a group of diseases with overlapping clinical manifestations,collectively known as ciliopathies.A significant proportion of human ciliopathy cases are accompanied by metabolic disorders such as obesity and type 2 ***,the mechanisms through which dysfunction of primary cilia contributes to obesity are *** this review,we present an overview of primary cilia and highlight obesity-related *** also discuss the potential role of primary cilia in peripheral organs,with a focus on adipose *** addition,we emphasize the significance of primary cilia in the central regulation of obesity,especially the involvement of ciliary signaling in the hypothalamic control of feeding *** review therefore proposes a framework of both peripheral and central regulation of obesity by primary cilia,which may benefit further exploration of the ciliary role in metabolic regulation.

关键词： Ciliopathy Metabolism Adipose tissue Adipogenesis Hypothalamus

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Pathologically relevant aldoses and environmental aldehydes cause cilium disassembly via formyl group-mediated mechanisms

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Journal of Molecular cell Biology 2024年第1期16卷 15-28页

作者： Te Li Min Liu Fan Yu Song Yang Weiwen Bu Kai Liu Jia Yang Hua Ni Mulin Yang Hanxiao Yin Renjie Hong Dengwen Li Huĳie Zhao Jun Zhou Haihe Laboratory of Cell Ecosystem State Key Laboratory of Medicinal Chemical BiologyTianjin Key Laboratory of Protein ScienceCollege of Life SciencesNankai UniversityTianjin 300071China Laboratory of Tissue Homeostasis Haihe Laboratory of Cell EcosystemTianjin 300462China Center for Cell Structure and Function Collaborative Innovation Center of Cell Biology in Universities of ShandongShandong Provincial Key Laboratory of Animal Resistance BiologyCollege of Life SciencesShandong Normal UniversityJinan 250014China

Carbohydrate metabolism disorders(CMDs),such as diabetes,galactosemia,and mannosidosis,cause ciliopathy-like multiorgan ***,the mechanistic link of cilia to CMD complications is still poorly ***,we describe significant cilium disassembly upon treatment of cells with pathologically relevant aldoses rather than the corresponding sugar ***,environmental aldehydes are able to trigger cilium disassembly by the steric hindrance effect of their formyl *** studies reveal that aldehydes stimulate extracellular calcium influx across the plasma membrane,which subsequently activates the calmodulin-Aurora A-histone deacetylase 6 pathway to deacetylate axonemal microtubules and triggers cilium *** vivo experiments further show that Hdac6 knockout mice are resistant to aldehyde-induced disassembly of tracheal cilia and sperm *** findings reveal a previously unrecognized role for formyl group-mediated cilium disassembly in the complications of CMDs.

关键词： carbohydrate metabolism disorder aldose aldehyde cilium disassembly formyl group calcium influx HDAC6

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Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation

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Nature Structural and Molecular Biology 2025年 1-13页

作者： Li, Yanran Bao, Kaiwen Sun, Jiyue Ge, Ruixin Zhang, Qiqing Zhang, Bing Yan, Xiaojie Li, Junlin Shi, Fengying Zhang, Meiling Zang, Jinzhi Liu, Min Zhou, Jun Mi, Wenyi Xie, Songbo Chen, Dongxing Shi, Lei Dong, Cheng Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education) Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics State Key Laboratory of Experimental Hematology Tianjin Medical University Cancer Institute and Hospital Tianjin Medical University Tianjin China Center for Cell Structure and Function Collaborative Innovation Center of Cell Biology in Universities of Shandong College of Life Sciences Shandong Normal University Jinan China Tianjin Institute of Immunology Department of Immunology School of Basic Medical Sciences Tianjin Medical University Tianjin China Department of Medicinal Chemistry Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics School of Pharmacy Tianjin Medical University Tianjin China Department of Ophthalmology Ministry of Education International Joint Laboratory of Ocular Diseases Tianjin Key Laboratory of Ocular Trauma Tianjin Institute of Eye Health and Eye Diseases China-UK ‘Belt and Road’ Ophthalmology Joint Laboratory Tianjin Medical University General Hospital Tianjin China

Proteolysis targeting chimeras (PROTACs) hijack E3 ligases and the ubiquitin–proteasome system to achieve selective degradation of neo-substrates. Their ability to target otherwise intractable substrates has rendered them a valuable modality in drug discovery. However, only a handful of over 600 human E3 ligases have been functionalized for PROTAC applications. Here we show that the E3 ligase GID4 (glucose-induced degradation deficient complex 4) can be leveraged for targeted protein degradation using a noncovalent small molecule. We design and synthesize GID4-based PROTACs, exemplified by NEP162, which can eliminate endogenous BRD4 in a GID4- and ubiquitin–proteasome system-dependent manner. NEP162 exhibits antiproliferative activity and inhibits tumor growth in a xenograft model, hinting toward potential anticancer applications. We further present the crystal structures of GID4–PROTAC–BRD4 ternary complexes in three distinct states, unveiling plastic interactions between GID4 and BRD4. These structural insights, combined with in vitro and in vivo data, decipher the molecular basis by which the hereby developed PROTACs recruit BRD4 to GID4 for targeted degradation and expand our arsenal of PROTAC-exploitable E3 ligases. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.

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High yield and efficient expression and purification of the human 5-HT3A receptor

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中国药理学报（英文版） 2015年第8期36卷 1024-1032页

作者： Zhong-shan WU Zhi-cheng CUI Hao CHENG Chen FAN Karsten MELCHER Yi JIANG Cheng-hai ZHANG Britton Chance Center for Biomedical Photonics Wuhan National Laboratory for Optoelectronics Huazhong University of Science and Technology Wuhan 430074 China VARI-SIMM Center Center for Structure and Function of Drug Targets CAS-Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China National Center for Protein Science Shanghai State Key Laboratory of Molecular Biology Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201210 China VARI-SIMM Center Center for Structure and Function of Drug Targets CAS-Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China Laboratory of Structural Sciences Van Andel Research Institute Grand Rapids MI 49503 USA

OBJECTIVE:To establish a method for efficient expression and purification of the human serotonin type 3A receptor (5-HT3A) that is suitable for structural studies.;METHODS:Codon-optimized cDNA of human 5-HT3A was inserted into a modified BacMam vector, which contained an IgG leader sequence, an 8×His tag linked with two-Maltose Binding Proteins (MBP), and a TEV protease cleavage site. The BacMam construct was used to generate baculoviruses for expression of 5-HT3A in HEK293F cells. The proteins were solubilized from the membrane with the detergent C12E 9, and purified using MBP affinity chromatography. The affinity tag was removed by TEV protease treatment and immobilized metal ion affinity chromatography. The receptors were further purified by size-exclusion chromatography (SEC). Western blot and SDS-PAGE were used to detect 5-HT3A during purification. The purified receptor was used in crystallization and analyzed with negative stain electron microscopy (EM).;RESULTS:The BacMam system yielded 0.5 milligram of the human 5-HT3A receptor per liter of cells. MBP affinity purification resulted in good yields with high purity and homogeneity. SEC profiles indicated that the purified receptors were pentameric. No protein crystals were obtained; however, a reconstructed 3D density map generated from the negative stain EM data fitted well with the mouse 5-HT3A structure.;CONCLUSIONS:With the BacMam system, robust expression of the human 5-HT3A receptor is obtained, which is monodisperse, therefore enabling 3D reconstruction of an EM map. This method is suitable for high-throughput screening of different constructs, thus facilitating structural and biochemical studies of the 5-HT3A receptor.

关键词： human 5-HT3A receptor BacMam expression and purification negative stain electron microscopy receptor structure

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