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CUL4B negatively regulates Toll-like receptor-triggered proinflammatory responses by repressing Pten transcription

Cellular & Molecular Immunology 2021年第2期18卷 339-349页

作者： Yu Song Peishan Li Liping Qin Zhiliang Xu baichun jiang Chunhong Ma Changshun Shao Yaoqin Gong Key Laboratory of Experimental Teratology Ministry of EducationInstitute of Molecular Medicine and GeneticsSchool of Basic Medical SciencesShandong UniversityJinanShandongChina Key Laboratory of Experimental Teratology Ministry of EducationDepartment of ImmunologySchool of Basic Medical ScienceShandong UniversityJinanShandongChina State Key Laboratory of Radiation Medicine and Protection Institutes for Translational MedicineSoochow UniversitySuzhouJiangsuChina

Toll-like receptors (TLRs) play critical roles in innate immunity and inflammation. The molecular mechanisms by which TLR signaling is fine-tuned remain to be completely elucidated. Cullin 4B (CUL4B), which assembles the CUL4B-RING E3 ligase complex (CRL4B), has been shown to regulate diverse developmental and physiological processes by catalyzing monoubiquitination for histone modification or polyubiquitination for proteasomal degradation. Here, we identified the role of CUL4B as an intrinsic negative regulator of the TLR-triggered inflammatory response. Deletion of CUL4B in macrophages increased the production of proinflammatory cytokines and decreased anti-inflammatory cytokine IL-10 production in response to pathogens that activate TLR3, TLR4, or TLR2. Myeloid cell-specific Cul4b knockout mice were more susceptible to septic shock when challenged with lipopolysaccharide, polyinosinic-polycytidylic acid or Salmonella typhimurium infection. We further demonstrated that enhanced TLR-induced inflammatory responses in the absence of CUL4B were mediated by increased GSK3β activity. Suppression of GSK3β activity efficiently blocked the TLR-triggered increase in proinflammatory cytokine production and attenuated TLR-triggered death in Cul4b mutant mice. Mechanistically, CUL4B was found to negatively regulate TLR-triggered signaling by epigenetically repressing the transcription of Pten, thus maintaining the anti-inflammatory PI3K-AKT-GSK3β pathway. The upregulation of PTEN caused by CUL4B deletion led to uncontrolled GSK3β activity and excessive inflammatory immune responses. Thus, our findings indicate that CUL4B functions to restrict TLR-triggered inflammatory responses through regulating the AKT-GSK3β pathway.

关键词： CUL4B TLR signaling Transcriptional repression

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CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPδ

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Bone Research 2023年第2期11卷 427-441页

作者： Ruiqi Yu Hong Han Shuxian Chu Yijun Ding Shiqi Jin Yufeng Wang Wei jiang Yuting Liu Yongxin Zou Molin Wang Qiao Liu Gongping Sun baichun jiang Yaoqin Gong The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics School of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China The Key Laboratory of Liquid-Solid Structural Evolution and Processing of Materials of Ministry of Education and Institute of Liquid Metal and Casting Technology School of Materials Science and EngineeringShandong UniversityJinan 250012China The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Histology and Embryology School of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Dysregulated lineage commitment of mesenchymal stem cells(MSCs)contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and *** intrinsic cellular mechanism that regulates MSC commitment remains ***,we identified Cullin 4B(CUL4B)as a critical regulator of MSC ***4B is expressed in bone marrow MSCs(BMSCs)and downregulated with aging in mice and *** knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone ***,depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after *** addition,CUL4B deficiency in MSCs reduced bone ***,CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδexpression,*** CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their ***,this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs,which has therapeutic implications in osteoporosis.

关键词： CUL4B impaired epigenetic

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CUL4B facilitates HBV replication by promoting HBx stabilization

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Cancer Biology & Medicine 2022年第1期19卷 120-131页

作者： Haixia Shan Bo Wang Xiaodong Zhang Hui Song Xi Li Yongxin Zou baichun jiang Huili Hu Hao Dou Changshun Shao Lifen Gao Chunhong Ma Xiaoyun Yang Xiaohong Liang Yaoqin Gong Key Laboratory for Experimental Teratology of the Ministry of Education Key Laboratory of Infection and Immunity of Shandong Province and Department of ImmunologySchool of Basic Medical SciencesShandong UniversityJinan 250012China Department of Laboratory Diagnosis Cangzhou Combination of Traditional Chinese and Western Medicine Hospital of Hebei ProvinceCangzhou 061000China Division of Gastroenterology and Hepatology Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Institute of Digestive DiseaseShanghai 200120China Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics School of Basic Medical SciencesShandong UniversityJinan 250012China Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong Jinan 250012China Department of Gastroenterology Qilu HospitalShandong UniversityJinan 250012China

Objective:Hepatitis B virus(HBV)infection is a major public health problem ***,the regulatory mechanisms underlying HBV replication remain *** 4 B-RING ubiquitin E3 ligase(CRL4 B)is involved in regulating diverse physiological and pathophysiological *** our study,we aimed to explain the role of CUL4 B in HBV ***:Cul4 b transgenic mice or conditional knockout mice,as well as liver cell lines with CUL4 B overexpression or knockdown,were used to assess the role of CUL4 B in HBV *** assays and immunofluorescence staining were performed to study the interaction between CUL4 B and *** chase assays and in vivo ubiquitination assays were performed to evaluate the half-life and the ubiquitination status of ***:The hydrodynamics-based hepatitis B model in Cul4 b transgenic or conditional knockout mice indicated that CUL4 B promoted HBV replication(P<0.05).Moreover,the overexpression or knockdown system in human liver cell lines validated that CUL4 B increased HBV replication in an HBx-dependent ***,immunoprecipitation assays and immunofluorescence staining showed an interaction between CUL4 B and ***,CUL4 B upregulated HBx protein levels by inhibiting HBx ubiquitination and proteasomal degradation(P<0.05).Finally,a positive correlation between CUL4 B expression and HBV pg RNA level was observed in liver tissues from HBV-positive patients and HBV transgenic ***:CUL4 B enhances HBV replication by interacting with HBx and disrupting its ubiquitin-dependent proteasomal ***4 B may therefore be a potential target for anti-HBV therapy.

关键词： CUL4B HBV ubiquitination HBx HCC

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Neuron-specific Cul4b knockout mice recapture the cognitive impairment phenotype in human X-linked mental retardation patients

Neuron-specific Cul4b knockout mice recapture the cognitive ...

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中华医学会第十五次全国医学遗传学学术会议暨中国医师协会医学遗传医师分会第一届全国学术会议暨2016年浙江省医学遗传学年会

作者： jiang baichun Zhao Wei Zhang Shuqian Hu Huili Shao Changshun Gong Yaoqin The Key Laboratory of Experimental Teratology Ministry of Education and Department of Medical GeneticsShandong University School of Medicine

Objective Mutations in CUL4 B gene are one of the most common causes of X-linked mental retardation. Although the E3 ubiquitin ligase complex formed by CUL4 B(CRL4 B) is known to target substrates for proteolysis or to coordinate with PRC2 complex in promoting H3 K27 trimethylation and transcriptional repression, how CUL4 B dysfunction causes mental retardation remains unclear. To gain insights into the mechanisms by which CUL4 B regulates neural development, we employed three lines of conditional knockout mice and observed the learning and memory abilities of these mice. Method We crossed Cul4 b floxed mice with Nestin-Cre transgenic mice to generate nervous system specific Cul4 b conditional knock-out mice(referred to as Cul4 bNestin-Cre hereinafter). We further crossed Cul4 b floxed mice to Nse-Cre or Gfap-Cre transgenic mice to generate neuronspecific Cul4 b knockout mice(Cul4 bNse-Cre) or astrocyte-specific Cul4 b knockout mice(Cul4 bGfapCre), respectively. Result Here we report that mice lacking expression of Cul4 b in nervous system(Cul4 bNestin-Cre) are impaired in spatial learning and memory. To further determine the cell type responsible for the impaired spatial learning and memory in Cul4 bNestin-Cre mice, we characterized two lines of mice that lack expression of Cul4 b in neurons(Cul4 bNse-Cre) and in astrocytes(Cul4 bGfap-Cre), respectively. We observed that learning and memory were impaired in Cul4 bNse-Cre mice, but not in the Cul4 bGfap-Cre line, suggesting that the impairment in spatial learning and memory in Cul4 bNestin-Cre mice was due to the lack of Cul4 b in neurons but not in astrocytes. Conclusion Together, our results demonstrate a critical role of CUL4 B in neuronal function and provide a potential model for human X-linked mental retardation.

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SLC33A1 ***113Arg(c.339T>G) mutation leads to neurod egeneration and accelerates injury-induced peripheral nerv e axonal regrowth in mice by modulating BMP signaling

SLC33A1 ***113Arg(c.339T>G) mutation leads to neurod egenera...

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中华医学会第十五次全国医学遗传学学术会议暨中国医师协会医学遗传医师分会第一届全国学术会议暨2016年浙江省医学遗传学年会

作者： Liu Pingting jiang baichun Ma Jian Lin Pengfei Shao Changshun Sun Wenjie Gong Yaoqin The Key Laboratory of Experimental Teratology Ministry of Education and Department of Genetics Shando ng University School of Medicine Laboratory of Neuromuscular Disorders and Department of Neurology Qilu Hospital Shandong University

Objective The mutation ***113 Arg(S113 R)(c.339 T>G)(MIM #603690.0001) in SLC33 A1(MI M #603690), an ER membrane acetyl-Co A transporter,has been previously identified in patients with hereditary spastic paraplegiatype 42(SPG42;MIM #612539). SLC33 A1 has also been recog nized as a novelinhibitory factor of bone morphogenetic protein(BMP) signaling pathway in zebra fish. Method To better understand the function of SLC33 A1, we generated and characterized Slc33 a1 S113 R knock-in mice. Next,we addressed whether modulation of BMP signaling by SLC33 A1 co uld influence peripheral nerve regeneration by using a mouse sciatic nerve crush injury model. Result Homozygous Slc33 a1 mutant mice were embryonic lethal, suggesting that SLC33 A1 is es sential for early embryonic development. While heterozygous Slc33 a1 mutant mice(Slc33 a1 wt/m ut) exhibited behavioral abnormalities and central neurodegeneration, no obvious abnormalities w ere found in the peripheral nerve. Results obtained with sciatic nerve crush injury model and dors al root ganglion(DRG) explants showed that Slc33 a1 wt/mut mice exhibited accelerated axonal re generation after sciatic nerve crush injury. Furthermore, we found an upregulation of BMP signali ng in the nervous system of Slc33 a1 wt/mut mice. Noggin, an endogenous BMP signaling antagon ist, could fully reverse the accelerated sciatic nerve regeneration after crush injury in Slc33 a1 wt/m ut mice. Conclusion These results indicated that SLC33 A1 can negatively regulate BMP signaling during axonal regeneration in mice, which may serve as a potential therapeutic agent for the treatment of SLC33 A1-related hereditary spastic paraplegia.

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泛素连接酶复合物骨架蛋白CUL4B功能研究进展

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中国科学：生命科学 2018年第11期48卷 1136-1151页

作者：蒋百春龚瑶琴山东大学基础医学院遗传学系实验畸形学教育部重点实验室济南250012

CUL4B属于Cullin家族,该家族成员作为骨架蛋白参与构成真核生物中最大的一类泛素连接酶复合物——Cullin-RING E3泛素连接酶复合物(Cullin-RING E3 ligases, CRLs).由CUL4B作为骨架蛋白构成的CRLs称为Cullin4B-RING泛素连接酶复合物,简... 详细信息

CUL4B属于Cullin家族,该家族成员作为骨架蛋白参与构成真核生物中最大的一类泛素连接酶复合物——Cullin-RING E3泛素连接酶复合物(Cullin-RING E3 ligases, CRLs).由CUL4B作为骨架蛋白构成的CRLs称为Cullin4B-RING泛素连接酶复合物,简称CRL4B复合物,通过催化底物蛋白多泛素化或单泛素化而在多种组织、病理生理过程中发挥重要作用.本实验室和英国研究组几乎同时发现CUL4B突变导致人类智力低下综合征,从此开启了研究CUL4B功能的新方向.利用细胞模型研究发现, CRL4B复合物在调控细胞增殖和DNA损伤修复等生物学过程中发挥重要作用.同时发现, CUL4B在多种实体瘤组织中高表达,通过表观转录调控多种抑癌基因表达来调控肿瘤进程.利用小鼠(Mus musculus)模型研究发现CUL4B在胚胎发育、神经系统发育、生殖细胞发育、髓系细胞分化、脂肪细胞分化、胰岛delta细胞发育等多种组织发育和细胞分化过程中发挥重要作用.本文主要介绍了以上CUL4B功能的研究进展.

关键词： CUL4B 智力低下肿瘤细胞增殖胚胎发育

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CPG Human Motion Phase Recognition Algorithm for a Hip Exoskeleton with VSA Actuator

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Journal of Signal and Information Processing 2024年第2期15卷 19-59页

作者： Jiaxuan Li Feng jiang Longhai Zhang Xun Wang Jinnan Duan baichun Wei Xiulai Wang Ningling Ma Yutao Zhang School of Mechatronics Engineering Harbin Institute of Technology Harbin China School of Future Technology Nanjing University of Information Science & Technology Nanjing China Nanjing Jinling Hospital Affiliated Hospital of Medical School Nanjing University Nanjing China

Due to the dynamic stiffness characteristics of human joints, it is easy to cause impact and disturbance on normal movements during exoskeleton assistance. This not only brings strict requirements for exoskeleton control design, but also makes it difficult to improve assistive level. The Variable Stiffness Actuator (VSA), as a physical variable stiffness mechanism, has the characteristics of dynamic stiffness adjustment and high stiffness control bandwidth, which is in line with the stiffness matching experiment. However, there are still few works exploring the assistive human stiffness matching experiment based on VSA. Therefore, this paper designs a hip exoskeleton based on VSA actuator and studies CPG human motion phase recognition algorithm. Firstly, this paper puts forward the requirements of variable stiffness experimental design and the output torque and variable stiffness dynamic response standards based on human lower limb motion parameters. Plate springs are used as elastic elements to establish the mechanical principle of variable stiffness, and a small variable stiffness actuator is designed based on the plate spring. Then the corresponding theoretical dynamic model is established and analyzed. Starting from the CPG phase recognition algorithm, this paper uses perturbation theory to expand the first-order CPG unit, obtains the phase convergence equation and verifies the phase convergence when using hip joint angle as the input signal with the same frequency, and then expands the second-order CPG unit under the premise of circular limit cycle and analyzes the frequency convergence criterion. Afterwards, this paper extracts the plate spring modal from Abaqus and generates the neutral file of the flexible body model to import into Adams, and conducts torque-stiffness one-way loading and reciprocating loading experiments on the variable stiffness mechanism. After that, Simulink is used to verify the validity of the criterion. Finally, based on the above crit

关键词： Variable Stiffness Actuator Plate Spring CPG Algorithm Convergence Criterion Human Motion Phase Recognition Simulink and Adams Co-Simulation

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CUL4B promote proliferation and migration of non-small-ce ll lung cells through epigenetically repression of miR-194

CUL4B promote proliferation and migration of non-small-ce ll...

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中华医学会第十五次全国医学遗传学学术会议暨中国医师协会医学遗传医师分会第一届全国学术会议暨2016年浙江省医学遗传学年会

作者： Mi Jun Zou Yongxin Lu Juanjuan Lin Xiaohua liu Xiaochen Zhao Hui Ye Xiang Hu Huili jiang baichun Han Bo Shao Changshun Gong Yaoqin The Key Laboratory of Experimental Teratology Ministry of Education and Department of Molecular Medicine and Genetics Shandong University School of Medicine Department of Pathology Shandong University School of Medicine

Objective CUL4 B, a scaffold protein that assembles CRL4 B ubiquitin ligase complexes, is overex pressed in many types of cancers and represses many tumor suppressors through epigenetic me chanisms. However, the roles of CUL4 B in lung cancer, particularly the non-small cell lung cancer s(NSCLC) are unknown. Method Cell proliferation was measured by MTT, Ed U incorporation and colony formation assa y. Wound-healing and transwell migration assays were employed to measure cell migration and i nvasion. Realtime PCR and western blot were used to detected m RNA and protein expression le vels. mi RNA pulldown and 3’ UTR luciferase assays were used to verify the effect of mi R-194 on CUL4 B expression. Result Here, we show that CUL4 B was upregulated in NSCLC tissues and was critically required for cell proliferation and migration. Furthermore, we found that CRL4 B represses mi R-194 by cata lyzing monoubiquitination at H2 AK119 and by coordinating with PRC2 to promote trimethylation a t H3 K27 at the clusters encoding mi R-194. Inhibition of mi R-194 was further shown to be able to r escue the defects in proliferation and migration of lung cancer cells resulted from CUL4 B knockdo wn. Moreover, knockdown of CUL4 B decreased the expression of the mi R-194 downstream targe ts RBX1, a subunit of CRL4 B and overexpressed in a number of human tumors. Conclusion Together with the previous results we obtained that CUL4 B is a target of mi R-194, th ese data thus establish a double negative feedback loop between mi R-194 and CRL4 B whose dy sregulation contributes to tumorigenesis. Given the important roles of mi R-194 cluster genes in tu mor progression, these results provided new evidence to support the oncogenic roles of CUL4 B, and trongly support further development of anti-CUL4 B inhibitor against NSCLC.

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CUL4B promotes replication licensing by upregulating the CDK2-CDC6 cascade

CUL4B promotes replication licensing by upregulating the CDK...

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第十二次全国医学遗传学学术会议

作者： Yongxin Zou Jun Mi Wenxing Wang Juanjuan Lu Wei Zhao Zhaojian Liu Huili Hu Yang Yang Xiaoxing Gao baichun jiang Changshun Shao Yaoqin Gong Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics Shandong University School of Medicine

Cullin-RING ubiquitin ligases(CRLs) participate in the regulation of diverse cellular processes including cell cycle *** in the X-linked CUL4B,a member of the cullin family,cause mental retardation and other developmental abnormalities in *** that are deficient in CUL4B are severely selected against in vivo in *** previously showed that CUL4B deficiency could lead to impairments in cell proliferation and S-phase progression in human ***:Here we investigated the role of CUL4B in DNA replication in mammalian ***:DNA fiber experiments Western blot Reverse-transcription PCR and real-time PCR ***:Here we report a role of CUL4B in the regulation of replication ***,CDC6,the licensing factor in replication,was positively regulated by CUL4B and contributed to the loading of MCM2 to *** positive regulation of CDC6 by CUL4B depends on CDK2,which phosphorylates CDC6,protecting it from APC-mediated ***,aside being required for cell cycle reentry from quiescence,CDK2 also contributes to pre-RC assembly in G1 phase of cycling ***,the upregulation of CDK2 by CUL4B is achieved via the repression of miR-372 and miR-373,which target CDK2. Conclusion:Our findings thus establish a CUL4B-CDK2-CDC6 cascade in the regulation of DNA replication licensing.

关键词： CUL4B CDC6 CDK2 miRNA

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电化学抛光在模具上的应用

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热处理 2000年第1期15卷 34-37页

作者：蒋霆峰蒋柏春上海德尔福派克电气有限公司 201805 东华大学 200051

本文测定了电化学抛光的各项技术参数 ,表明能明显减小金属制件的表面粗糙度 ,将Ra值减至 0 .16μm以下 ,达到镜面光洁度。将此工艺用于注塑模具 ,使难以用机械方法抛光的复杂表面明显光亮。从而 ,将使其制成的塑料产品增强销售竞争力。

关键词：电化学抛光注塑模表面抛光模具

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