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Cullin 4B-RING E3 ligase complex in immune cell differentiation and function

Cellular & Molecular Immunology 2023年第10期20卷 1254-1256页

作者： Yu Song Shiqi Jin gongping Sun yaoqin gong Key Laboratory of Experimental Teratology of the Ministry of Education Department of Molecular Medicine and GeneticsSchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinanShandong250012China Key Laboratory of Experimental Teratology of the Ministry of Education Department of Histology and EmbryologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinanShandong250012China

CUL4B,which encodes the scaffold protein in the CRL4B complex,is a commonly mutated gene in X-linked intellectual disability[10,11].In addition to intellectual disability,patients with CUL4B mutations present with an elevated number of monocytes in peripheral blood[10],implying a role for CUL4B in regulating monocytes/***/macrophages are critical players in innate *** et *** that depletion of CUL4B in myeloid cells aggravated lipopolysaccharide(LPS)-induced acute peritonitis[3].They further showed that after LPS stimulation,Cul4b-deficient macrophages secreted more chemokines than control macrophages,which might have accounted for the elevated infiltration of immune cells into the peritoneum[3].Our previous work demonstrated that myeloid-specific Cul4b-knockout mice exhibited reduced survival after LPS injection or Salmonella typhimurium infection compared to control mice[6].In contrast to work from Hung et al.,which showed that Cul4b-deficient macrophages secreted less TNFαand IL-6 after LPS stimulation[3],our works showed that deletion of CUL4B in macrophages increased the production of proinflammatory cytokines and decreased the expression of the anti-inflammatory cytokine IL-10 in response to the activation of Toll-like receptor(TLR).CUL4B regulation of macrophages relies on the ubiquitination activity of the CRL4B *** CRL4B complex catalyzes monoubiquitination of H2AK119 at the promoter of Pten,resulting in the repression of Pten transcription and subsequent activation of AKT and AKT-dependent inhibition of GSK3β,which suppresses TLR-triggered proinflammatory responses(Fig.1B)[6].

关键词： GSK3β elevated stimulation

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Mendelian randomization studies on atherosclerotic cardiovascular disease: evidence and limitations

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Science China(Life Sciences) 2019年第6期62卷 758-770页

作者： Qin Hu Panpan Hao Qiji Liu Mei Dong yaoqin gong Cheng Zhang Yun Zhang The Key Laboratory of Cardiovascular Remodeling and Function Research Ministry of Education of China Ministry of Health of China and Chinese Academy of Medical Sciences and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine Qilu Hospital of Shandong University Jinan 250012 China Department of Medical Genetics School of Medicine Key Laboratory of Experimental Teratology Ministry of Education Shandong University Jinan 250012 China

Epidemiological research has revealed a galaxy of biomarkers, such as genes, molecules or traits, which are associated with increased risk of atherosclerotic cardiovascular diseases(ASCVD). However, the etiological basis remains poorly *** randomization(MR) involves the use of observational genetic data to ascertain the roles of disease-associated risk factors and, in particular, differentiate those reflecting the presence or severity of a disease from those contributing causally to a disease. Over the past decade, MR has evolved into a fruitful approach to clarifying the causal relation of a biomarker with ASCVD and to verifying potential therapeutic targets for ASCVD. In this review, we selected high-quality MR studies on ASCVD, examined the causal relationship of a series of biomarkers with ASCVD, and elucidated the role of MR in validating biomarkers as a therapeutic target by comparing the results from MR studies and randomized clinical trials(RCTs) for the treatment of ASCVD. The good agreement between the results derived by MR and RCTs suggests that MR could be performed as a screening process before novel drug development. However, when designing and interpreting a MR study, the assumptions and limitations inherent in this approach should be taken into account. Novel methodological developments, such as sensitivity analysis, will help to strengthen the validity of MR studies.

关键词： Mendelian randomization atherosclerotic cardiovascular disease causality therapeutic target

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

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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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RECQL4 regulates DNA damage response and redox homeostasis in esophageal cancer

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Cancer Biology & Medicine 2021年第1期18卷 120-138页

作者： Guosheng Lyu Peng Su Xiaohe Hao Shiming Chen Shuai Ren Zixiao Zhao yaoqin gong Qiao Liu Changshun Shao Key Laboratory of Experimental Teratology Ministry of EducationDepartment of Molecular Medicine and GeneticsSchool of Basic Medical SciencesShandong UniversityJinan 250012China Department of Pathology Qilu Hospital of Shandong UniversityJinan 250012China State Key Laboratory of Radiation Medicine and Protection Institutes for Translational MedicineSoochow UniversitySuzhou 215123China

Objective:RECQL4(a member of the RECQ helicase family)upregulation has been reported to be associated with tumor progression in several ***,whether RECQL4 sustains esophageal squamous cell carcinoma(ESCC)has not been *** this study,we determined the functional role for RECQL4 in ESCC ***:RECQL4 expression in clinical samples of ESCC was examined by *** proliferation,cellular senescence,the epithelial-mesenchymal transition(EMT),DNA damage,and reactive oxygen species in ESCC cell lines with RECQL4 depletion or overexpression were *** levels of proteins involved in the DNA damage response(DDR),cell cycle progression,survival,and the EMT were determined by Western blot ***:RECQL4 was highly expressed in tumor tissues when compared to adjacent non-tumor tissues in ESCC(P<0.001)and positively correlated with poor differentiation(P=0.011),enhanced invasion(P=0.033),and metastasis(P=0.048).RECQL4 was positively associated with proliferation and migration in ESCC *** of RECQL4 also inhibited growth of tumor xenografts in ***4 depletion induced G0/G1 phase arrest and cellular ***,the levels of DNA damage and reactive oxygen species were increased when RECQL4 was ***,as measured by the activation of ATM,ATR,CHK1,and CHK2,was ***4 was also shown to promote the activation of AKT,ERK,and NF-k B in ESCC ***:The results indicated that RECQL4 was highly expressed in ESCC and played critical roles in the regulation of DDR,redox homeostasis,and cell survival.

关键词： ESCC RECQL4 senescence redox DNA damage response

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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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In-silico screening and molecular analysis of disease associated mutations on Cul4B

In-silico screening and molecular analysis of disease associ...

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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： Dou Hao Yu Qian Feng Yingjie gong yaoqin Institute of Genetics Shandong University

Objective Nowadays, the amounts of available gene sequencing data are growing rapidly. Comp utational methods were developed to interpret sequence variants and address their structural imp act on encoded proteins. CUL4 B gene located on X chromosome encodes Cul4 B protein. Cul4 B works as a scaffold to bind DDB1 and Rbx1, all of which form the CRL4 B E3 ligase and promote substrates ubiquitination in multiple signaling pathways. To date, the overexpression of CUL4 B g ene has been reported to be associated with many types of cancer. Variants in CUL4 B gene sequ ence were also found in numerous tumor tissues, including large intestine, stomach, breast, lung, liver and so on. Method Here, we used computational approaches to filter deleterious and pathogenic mutation in CUL4 B. Based on COSMIC and NCBI db SNP database, we analyzed hundreds of missense mut ations using Polyphen, SIFT, PANTHER and Mutation Taster server. 26% of variants are found to be damaging or deleterious. We mapped these mutations onto Cul4 B 3 D structural models includi ng native and neddylation states. Result We identified significant clustering of mutations in Cul4 B, which probably affects assembli ng CRL4 B E3 ligase complex. There are also some mutations, which might induce disruptions of proper protein folding. Interestingly, we found that C-terminus of Cul4 B(830-896 aa) is frequently mutated. This area is exposed in the native state but contacts E2 and co-E3 upon neddylation ac cording to 3 D models. For example, A835 E, R838 Q, I839 F, K841 N, and Y880 C might disrupt Cul4 B-E2 interaction. In addition, H848 Q, P862 T, D877 N might affect the neddylation of Cul4 B, thusgreatly reduce CRL4 B activity in facilitating substrate ubiquitination. Functional studies are requir ed to clarify whether these mutants have oncogenic characters. Conclusion Our study provided an efficient computational methodology to screen the cancer/dis ease associated mutations from large datasets and examine their m

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CRL4B/PRC2 complex epigenetically regulates pancreatic δ cell paracrine interaction

CRL4B/PRC2 complex epigenetically regulates pancreatic δ ce...

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中国生理学会内分泌代谢、比较生理与应激生理学术会议

作者： Qing Li Jin-Peng Sun yaoqin gong Xiao Yu Department of Physiology and Pathophysiology Shandong University School of Basic Medical Sciences Department of Biochemistry Shandong University School of Basic Medical Sciences Department of Genetics Shandong University School of Basic Medical Sciences

Somatostatin secreted by pancreatic δ cells mediates important paracrine interactions in Langerhans islets:the maintenance of glucose metabolism through the control of the reciprocal secretion of insulin and *** of this circuit contributes to the development of ***,we address two questions:(1) how paracrine interactions are precisely controlled in islets of Langerhans in response to physiological stimuli,such as glucose,to maintain normal glucose homeostasis and(2) whether key epigenetic regulators,such as cullin family members,play important roles in pancreatic islet *** found that the protein levels of CUL4B are tightly controlled under different physiological conditions,and they modulate pancreatic δ cell secretion in an epigenetic ***,mechanistic studies showed that the CRL4B/PRC2 complex,under the control of Hhex,determines the levels of intracellular calcium and cAMP through histone post-translational-modifications,thereby altering expression of the Cav1.2 channel(cacnalc) and adenylyl cyclase 6(adcy6) and modulating somatostatin secretion.

关键词： somatostatin paracrine epigenetics calcium channe adenylyl cyclase

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The function and mechanism of CUL4B in obesity and adipogenesis

The function and mechanism of CUL4B in obesity and adipogene...

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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： Li Peishan Song Yu Zan Wenying 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

Objective CULLIN-RING E3 ligases represent the largest mammalian E3 ligase family, in which each of Cullin family members including CUL4 B serves as a molecular scaffold. Mutations in hum an CUL4 B have been found to be a common cause of X-linked mental retardation. In addition to b eing mentally retarded, patients with CUL4 B mutations also manifest short stature, abnormal gait, absence of speech, central obesity, and other developmental defects. However, the role of CUL4 B in adipogenesis and obesity remains unknown. Method In this study, we investigate the role of CUL4 B in obesity and adipogenesis using adipoc yte-specific Cul4 b knockout mouse(referred to AKO). Result CUL4 B expression in adipose tissue was significantly down-regulated in obesity mice and during adipocyte differentiation, which indicating that the expression of CUL4 B appears to be neg atively correlated with obesity. Using 3 T3-L1 preadipocytes, we found CUL4 B functions as a nega tive regulator of adipogenesis. Next, we generated adipocyte-specific Cul4 b knockout mice. Whe n placed on a HFD, the weight gain and ing WAT mass in AKO mice was significantly accelerated compared to their WT littermates. Adipoctyes from AKO mice appeared to be smaller than WT adi pocytes, especially in ing WAT, indicating that hyperplasia may play a major role in adipose tissue expansion in AKO mice. This result was corrected with the data that knockdown Cul4 b in 3 T3-L1 cells increase adipogenesis. Both glucose intolerance and insulin resistance and adipose tissue i nflammation induced by HFD were significantly attenuated in AKO mice when compared to WT m ice, these results suggest that adipocyte-specific Cul4 b deficiency confers an overall improvemen t in the metabolic phenotypes associated with HFD-induced *** The results that CUL4 B negatively regulate obesity in animal model were consistentl y with the phenotype found in humans with CUL4 B mutations. As the AKO mice with smaller adip ocytes a

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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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