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Zhao X, Shan G, Xing D, Gao H, Xiong Z, Hui W, Gong M. Interfering with UBE2L3 expression targets regulation of MLKL to promote necroptosis inhibition of growth in osteosarcoma. World J Surg Oncol 2025; 23:63. [PMID: 39988669 PMCID: PMC11849225 DOI: 10.1186/s12957-025-03715-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 02/11/2025] [Indexed: 02/25/2025] Open
Abstract
BACKGROUND In previous studies, elevated expression of UBE2L3 has been observed in osteosarcoma cells, and silencing UBE2L3 has been shown to promote oxidative stress and induce necroptosis. However, the exact molecular mechanisms underlying these findings remain unclear. OBJECTIVE The purpose of this study is to investigate the molecular mechanisms by which interfering with UBE2L3 expression promotes necroptosis and impacts the progression of osteosarcoma, building upon previous in vitro cell experiments. METHODS Osteosarcoma cells were transfected with shNC and shUBE2L3 plasmids, and the cells were injected into the right tibia of nude mice to establish a tumor xenograft model. The growth rate, changes in body weight, and tumor volume of the mice in each group were observed. After 15 days, the mice were sacrificed, and the tumors were dissected and analyzed for tumor volume. Immunohistochemical staining was performed to detect changes in the expression of necroptosis-related proteins, such as PCNA, p-MLKL, and p-RIP1. Additionally, U2OS and HOS cells were transfected with UBE2L3-silencing plasmids, and immunoprecipitation was performed to investigate the interaction between UBE2L3 and the necroptosis protein MLKL. By combining these experiments, we aim to evaluate the impact of UBE2L3 on necroptosis both in vitro and in vivo and elucidate its specific role in targeting MLKL to regulate necroptosis as a therapeutic approach for osteosarcoma. RESULTS After interfering with UBE2L3, the growth rate of tumors in nude mice significantly slowed down, accompanied by a notable reduction in tumor volume and weight. These findings suggest that inhibiting the expression of UBE2L3 can suppress the growth of osteosarcoma. Furthermore, immunohistochemical analysis revealed that following UBE2L3 interference, the intensity of staining for the necrotic proteins p-MLKL and p-RIP1 was increased and PCNA staining was decreased, indicating that interfering with UBE2L3 expression can promote necroptosis. Moreover, through transfection of UBE2L3 silencing plasmids into osteosarcoma cells in vitro, immunoprecipitation and ubiquitination results demonstrated that UBE2L3 can specifically bind to MLKL. Overexpression of UBE2L3 promoted the ubiquitination of MLKL and reduced its expression. Thus, down-regulation of UBE2L3 could modulate downstream MLKL expression and promote necrosis of osteosarcoma cells. CONCLUSION UBE2L3 selectively binds to MLKL, exerting ubiquitination-mediated regulation on downstream MLKL. Decreased expression of UBE2L3 modulates MLKL expression and promotes necrosis, thereby inhibiting osteosarcoma growth.
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Affiliation(s)
- Xiwu Zhao
- Department of Traumatic Orthopedics, The Second Hospital of Shandong University, Jinan, 250033, China
- Department of Traumatic Orthopedics, Shandong Second Provincial General Hospital, Jinan, 250022, China
| | - Guoqiang Shan
- Department of Traumatic Orthopedics, Shandong Second Provincial General Hospital, Jinan, 250022, China
| | - Deguo Xing
- Department of Traumatic Orthopedics, The Second Hospital of Shandong University, Jinan, 250033, China
| | - Hongwei Gao
- Department of Traumatic Orthopedics, Shandong Public Health Clinical Center, Shandong University, Jinan, 250013, China
| | - Zhenggang Xiong
- Department of Traumatic Orthopedics, The Second Hospital of Shandong University, Jinan, 250033, China
| | - Wenpeng Hui
- Department of Spinal Surgery, Shandong Second Provincial General Hospital, Jinan, 250022, China
| | - Mingzhi Gong
- Department of Traumatic Orthopedics, The Second Hospital of Shandong University, Jinan, 250033, China.
- , No. 247, Beiyuan Street, Tianqiao District, Jinan City, Shandong Province, China.
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Wang H, Tan Y, Liu Q, Yang S, Cui L. Ubiquitin-proteasome system: a potential participant and therapeutic target in antiphospholipid syndrome. Front Immunol 2025; 16:1523799. [PMID: 40040717 PMCID: PMC11876059 DOI: 10.3389/fimmu.2025.1523799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 01/30/2025] [Indexed: 03/06/2025] Open
Abstract
APS (antiphospholipid syndrome) is an autoimmune disease characterized by thrombosis, pregnancy complications and persistent elevation of aPLs (antiphospholipid antibodies). Dysfunction of innate immune cells, ECs (endothelial cells), platelets and trophoblast cells are central to the development of APS. The UPS (ubiquitin-proteasome system) is a highly conserved post-translational modification in eukaryotes. Imbalance of the UPS potentially disrupts the protein homeostasis network and provokes prothrombotic and proinflammatory signaling during APS progression. In vivo, low-dose proteasome inhibitors are believed to effectively inhibit the production of proinflammatory factors and the clinical manifestations of APS. In this review, we would like to summarize the likely contribution of dysregulated UPS to the pathogenesis of APS. Given the significant progress made in understanding the molecular mechanisms of the UPS and how alterations in the UPS lead to the development of autoimmune diseases, targeting the UPS may represent a novel therapeutic strategy.
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Affiliation(s)
- He Wang
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Peking University Third Hospital, Beijing, China
| | - Yuan Tan
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Peking University Third Hospital, Beijing, China
- Institute of Medical Technology, Peking University Health Science Center, Beijing, China
| | - Qi Liu
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Peking University Third Hospital, Beijing, China
| | - Shuo Yang
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Peking University Third Hospital, Beijing, China
| | - Liyan Cui
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Peking University Third Hospital, Beijing, China
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Qin Q, Jiang Y, Fan H, Yuan R, Zhong B, Zhang Y, Zhang Z, Lei X, Cai J, Cheng S. Investigating the shared genetic structure between rheumatoid arthritis and stroke. Hereditas 2025; 162:23. [PMID: 39953635 PMCID: PMC11827134 DOI: 10.1186/s41065-025-00386-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 02/05/2025] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) increases the risk of stroke. However, the relationship between RA and stroke remains unclear. This study aimed to explore the shared genetics architecture (i.e., common genetic basis between different traits, diseases, or phenotypes) of RA and stroke, aiming to improve the intervention and management of patients with RA and stroke. METHODS Pooled statistics from publicly available genome-wide association studies for RA (8,255 cases and 409,001 controls) and stroke (43,132 cases and 43,132 controls) were used. A genome-wide positive association was conducted to (examine the comprehensive effects of genetic variants on a particular trait, disease, or phenotype at the genome-wide scale). Local genetic correlation studies used linkage disequilibrium score regression and super genetic covariance analyzer. Single nucleotide polymorphisms (SNPs) at risk were identified using genome-wide association study multiple trait analysis and PLINK software (Psnp <5e-08), followed by functional localization and annotation using Functional Mapping and Annotation of Genome-Wide Association Studies to identify specific genes and genetic variants that may contribute to the disease. Finally, a transcriptome-wide association study explored the relationship between genes and their association with RA risk. RESULTS A genome-wide significant positive correlation was evident between RA and stroke (genetic correlation = 0.3756). Among the localized genomic regions, the correlation between RA and stroke in the region of chr2:201572564-202,829,668 was the most significant (p = 0.0015). We identified 179 significant SNPs and five common risk genes for RA and stroke (IRF5, RNASET2, ZNF438, UBE2LS, and SYNGR1). These genes are involved in the immune-inflammatory pathway. CONCLUSIONS The findings suggest a shared genetic structure between RA and stroke. These findings may provide new insights into RA and stroke pathogenesis, and contribute to the development of new diagnostic markers and therapeutic targeted drugs to improve the clinical outcomes of patients with RA and stroke.
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Affiliation(s)
- Qian Qin
- Department of Neurosurgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
- Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
| | - Yong'An Jiang
- Department of Neurosurgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
- Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
| | - Hengyi Fan
- Department of Neurosurgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
| | - Raorao Yuan
- Department of Critical Care Medicine, Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Bo Zhong
- Department of Neurosurgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
- Department of Neurosurgery, Xinyu People's Hospital, Xinyu, 338000, Jiangxi, P. R. China
| | - Yichen Zhang
- Department of Neurosurgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
- Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
| | - Zile Zhang
- Department of Neurosurgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
- Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
| | - Xin Lei
- Department of Neurosurgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
- Nanchang University, Nanchang, 330006, Jiangxi, P. R. China
| | - Jianhui Cai
- Department of Neurosurgery, Nanchang County People's Hospital, Nanchang, 330200, Jiangxi, P. R. China.
- Nanchang Cranio-Cerebral Trauma Laboratory, Nanchang, 330200, Jiangxi, P. R. China.
| | - Shiqi Cheng
- Department of Neurosurgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P. R. China.
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Temple SD, Browning SR. Multiple-testing corrections in selection scans using identity-by-descent segments. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.29.635528. [PMID: 39975073 PMCID: PMC11838353 DOI: 10.1101/2025.01.29.635528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Failing to correct for multiple testing in selection scans can lead to false discoveries of recent genetic adaptations. The scanning statistics in selection studies are often too complicated to theoretically derive a genome-wide significance level or empirically validate control of the family-wise error rate (FWER). By modeling the autocorrelation of identity-by-descent (IBD) rates, we propose a computationally efficient method to determine genome-wide significance levels in an IBD-based scan for recent positive selection. In whole genome simulations, we show that our method has approximate control of the FWER and can adapt to the spacing of tests along the genome. We also show that these scans can have more than fifty percent power to reject the null model in hard sweeps with a selection coefficient s > = 0.01 and a sweeping allele frequency between twenty-five and seventy-five percent. A few human genes and gene complexes have statistically significant excesses of IBD segments in thousands of samples of African, European, and South Asian ancestry groups from the Trans-Omics for Precision Medicine project and the United Kingdom Biobank. Among the significant loci, many signals of recent selection are shared across ancestry groups. One shared selection signal at a skeletal cell development gene is extremely strong in African ancestry samples.
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Affiliation(s)
- Seth D. Temple
- Department of Statistics, University of Washington, Seattle, Washington, USA
- Department of Statistics, University of Michigan, Ann Arbor, Michigan, USA
- Michigan Institute for Data Science, University of Michigan, Ann Arbor, Michigan, USA
| | - Sharon R. Browning
- Department of Biostatistics, University of Washington, Seattle, Washington, USA
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Awan AB, Osman MJA, Khan OM. Ubiquitination Enzymes in Cancer, Cancer Immune Evasion, and Potential Therapeutic Opportunities. Cells 2025; 14:69. [PMID: 39851497 PMCID: PMC11763706 DOI: 10.3390/cells14020069] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/16/2024] [Accepted: 12/24/2024] [Indexed: 01/26/2025] Open
Abstract
Ubiquitination is cells' second most abundant posttranslational protein modification after phosphorylation. The ubiquitin-proteasome system (UPS) is critical in maintaining essential life processes such as cell cycle control, DNA damage repair, and apoptosis. Mutations in ubiquitination pathway genes are strongly linked to the development and spread of multiple cancers since several of the UPS family members possess oncogenic or tumor suppressor activities. This comprehensive review delves into understanding the ubiquitin code, shedding light on its role in cancer cell biology and immune evasion. Furthermore, we highlighted recent advances in the field for targeting the UPS pathway members for effective therapeutic intervention against human cancers. We also discussed the recent update on small-molecule inhibitors and PROTACs and their progress in preclinical and clinical trials.
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Affiliation(s)
- Aiman B. Awan
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar; (A.B.A.); (M.J.A.O.)
| | - Maryiam Jama Ali Osman
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar; (A.B.A.); (M.J.A.O.)
- Research Branch, Sidra Medicine, Doha P.O. Box 34110, Qatar
| | - Omar M. Khan
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar; (A.B.A.); (M.J.A.O.)
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Xu LL, Gan T, Li Y, Chen P, Shi SF, Liu LJ, Lv JC, Zhang H, Zhou XJ. Combined Genetic Association and Differed Expression Analysis of UBE2L3 Uncovers a Genetic Regulatory Role of (Immuno)proteasome in IgA Nephropathy. KIDNEY DISEASES (BASEL, SWITZERLAND) 2024; 10:167-180. [PMID: 38835407 PMCID: PMC11149991 DOI: 10.1159/000537987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 02/20/2024] [Indexed: 06/06/2024]
Abstract
Introduction IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the (immuno)proteasome probably plays an important role in IgAN. Methods We firstly analyzed the association of variants in the UBE2L3 region with susceptibility to IgAN in 3,495 patients and 9,101 controls, and then analyzed the association between lead variant and clinical phenotypes in 1,803 patients with regular follow-up data. The blood mRNA levels of members of the ubiquitin-proteasome system including UBE2L3 were analyzed in peripheral blood mononuclear cells from 53 patients and 28 healthy controls. The associations between UBE2L3 and the expression levels of genes involved in Gd-IgA1 production were also explored. Results The rs131654 showed the most significant association signal in UBE2L3 region (OR: 1.10, 95% CI: 1.04-1.16, p = 2.29 × 10-3), whose genotypes were also associated with the levels of Gd-IgA1 (p = 0.04). The rs131654 was observed to exert cis-eQTL effects on UBE2L3 in various tissues and cell types, particularly in immune cell types in multiple databases. The UBE2L3, LUBAC, and proteasome subunits were highly expressed in patients compared with healthy controls. High expression levels of UBE2L3 were not only associated with higher proteinuria (r = 0.34, p = 0.01) and lower eGFR (r = -0.28, p = 0.04), but also positively correlated with the gene expression of LUBAC and other proteasome subunits. Additionally, mRNA expression levels of UBE2L3 were also positively correlated with IL-6 and RELA, but negatively correlated with the expression levels of the key enzyme in the process of glycosylation including C1GALT1 and C1GALT1C1. Conclusion In conclusion, by combined genetic association and differed expression analysis of UBE2L3, our data support a role of genetically conferred dysregulation of the (immuno)proteasome in regulating galactose-deficient IgA1 in the development of IgAN.
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Affiliation(s)
- Lin-Lin Xu
- Renal Division, Peking University First Hospital, Beijing, China
- Kidney Genetics Center, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Ting Gan
- Renal Division, Peking University First Hospital, Beijing, China
- Kidney Genetics Center, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Yang Li
- Renal Division, Peking University First Hospital, Beijing, China
- Kidney Genetics Center, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Pei Chen
- Renal Division, Peking University First Hospital, Beijing, China
- Kidney Genetics Center, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Su-Fang Shi
- Renal Division, Peking University First Hospital, Beijing, China
- Kidney Genetics Center, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Li-Jun Liu
- Renal Division, Peking University First Hospital, Beijing, China
- Kidney Genetics Center, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Ji-Cheng Lv
- Renal Division, Peking University First Hospital, Beijing, China
- Kidney Genetics Center, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Beijing, China
- Kidney Genetics Center, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Xu-Jie Zhou
- Renal Division, Peking University First Hospital, Beijing, China
- Kidney Genetics Center, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Peking University, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
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Sun W, Zhu C, Li Y, Wu X, Shi X, Liu W. B cell activation and autoantibody production in autoimmune diseases. Best Pract Res Clin Rheumatol 2024; 38:101936. [PMID: 38326197 DOI: 10.1016/j.berh.2024.101936] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 01/23/2024] [Accepted: 01/25/2024] [Indexed: 02/09/2024]
Abstract
B cells are central players in the immune system, responsible for producing antibodies and modulating immune responses. This review explores the intricate relationship between aberrant B cell activation and the development of autoimmune diseases, emphasizing the essential role of B cells in these conditions. We also summarize B cell receptor signaling and Toll-like receptor signaling in B cell activation, as well as their association with autoimmune diseases, shedding light on the molecular mechanisms behind these associations. Additionally, we explore the clinical observations involving B cell activation and their significance in autoimmune disease management. Various clinical studies related to B cell-targeted therapies are also discussed, offering insights into potential avenues for improving treatment strategies. Overall, this review serves as a resource for researchers and clinicians in the field of immunology and autoimmune diseases, providing a general view of B cell signaling and its role in autoimmunity.
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Affiliation(s)
- Wenbo Sun
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, No. 1, Qinghua Yuan, New Biology Bldg, Haidian District, Beijing, 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China; The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University, Hefei, 230032, China.
| | - Can Zhu
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, No. 1, Qinghua Yuan, New Biology Bldg, Haidian District, Beijing, 100084, China.
| | - Yuxin Li
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, No. 1, Qinghua Yuan, New Biology Bldg, Haidian District, Beijing, 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China.
| | - Xinfeng Wu
- Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, No. 636, Guanlin Road, 471000, Luoyang, China.
| | - Xiaofei Shi
- Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, No. 636, Guanlin Road, 471000, Luoyang, China.
| | - Wanli Liu
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, No. 1, Qinghua Yuan, New Biology Bldg, Haidian District, Beijing, 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China; The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University, Hefei, 230032, China.
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Marrugal Á, Ferrer I, Quintanal-Villalonga Á, Ojeda L, Pastor MD, García-Luján R, Carnero A, Paz-Ares L, Molina-Pinelo S. Inhibition of HSP90 in Driver Oncogene-Defined Lung Adenocarcinoma Cell Lines: Key Proteins Underpinning Therapeutic Efficacy. Int J Mol Sci 2023; 24:13830. [PMID: 37762133 PMCID: PMC10530904 DOI: 10.3390/ijms241813830] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/04/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
The use of 90 kDa heat shock protein (HSP90) inhibition as a therapy in lung adenocarcinoma remains limited due to moderate drug efficacy, the emergence of drug resistance, and early tumor recurrence. The main objective of this research is to maximize treatment efficacy in lung adenocarcinoma by identifying key proteins underlying HSP90 inhibition according to molecular background, and to search for potential biomarkers of response to this therapeutic strategy. Inhibition of the HSP90 chaperone was evaluated in different lung adenocarcinoma cell lines representing the most relevant molecular alterations (EGFR mutations, KRAS mutations, or EML4-ALK translocation) and wild-type genes found in each tumor subtype. The proteomic technique iTRAQ was used to identify proteomic profiles and determine which biological pathways are involved in the response to HSP90 inhibition in lung adenocarcinoma. We corroborated the greater efficacy of HSP90 inhibition in EGFR mutated or EML4-ALK translocated cell lines. We identified proteins specifically and significantly deregulated after HSP90 inhibition for each molecular alteration. Two proteins, ADI1 and RRP1, showed independently deregulated molecular patterns. Functional annotation of the altered proteins suggested that apoptosis was the only pathway affected by HSP90 inhibition across all molecular subgroups. The expression of ADI1 and RRP1 could be used to monitor the correct inhibition of HSP90 in lung adenocarcinoma. In addition, proteins such as ASS1, ITCH, or UBE2L3 involved in pathways related to the inhibition of a particular molecular background could be used as potential response biomarkers, thereby improving the efficacy of this therapeutic approach to combat lung adenocarcinoma.
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Affiliation(s)
- Ángela Marrugal
- H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain (L.P.-A.)
| | - Irene Ferrer
- H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain (L.P.-A.)
- CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain;
| | | | - Laura Ojeda
- H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain (L.P.-A.)
| | - María Dolores Pastor
- Instituto de Biomedicina de Sevilla (IBiS) (HUVR, CSIC, Universidad de Sevilla), 41013 Sevilla, Spain
| | - Ricardo García-Luján
- Respiratory Department, Hospital Universitario Doce de Octubre, 28041 Madrid, Spain
| | - Amancio Carnero
- CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain;
- Instituto de Biomedicina de Sevilla (IBiS) (HUVR, CSIC, Universidad de Sevilla), 41013 Sevilla, Spain
| | - Luis Paz-Ares
- H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain (L.P.-A.)
- CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain;
- Medical Oncology Department, Hospital Universitario Doce de Octubre, 28041 Madrid, Spain
- Medical School, Universidad Complutense, 28040 Madrid, Spain
| | - Sonia Molina-Pinelo
- CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain;
- Instituto de Biomedicina de Sevilla (IBiS) (HUVR, CSIC, Universidad de Sevilla), 41013 Sevilla, Spain
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9
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Sestan M, Kifer N, Arsov T, Cook M, Ellyard J, Vinuesa CG, Jelusic M. The Role of Genetic Risk Factors in Pathogenesis of Childhood-Onset Systemic Lupus Erythematosus. Curr Issues Mol Biol 2023; 45:5981-6002. [PMID: 37504294 PMCID: PMC10378459 DOI: 10.3390/cimb45070378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/09/2023] [Accepted: 07/12/2023] [Indexed: 07/29/2023] Open
Abstract
The pathogenesis of childhood-onset systemic lupus erythematosus (cSLE) is complex and not fully understood. It involves three key factors: genetic risk factors, epigenetic mechanisms, and environmental triggers. Genetic factors play a significant role in the development of the disease, particularly in younger individuals. While cSLE has traditionally been considered a polygenic disease, it is now recognized that in rare cases, a single gene mutation can lead to the disease. Although these cases are uncommon, they provide valuable insights into the disease mechanism, enhance our understanding of pathogenesis and immune tolerance, and facilitate the development of targeted treatment strategies. This review aims to provide a comprehensive overview of both monogenic and polygenic SLE, emphasizing the implications of specific genes in disease pathogenesis. By conducting a thorough analysis of the genetic factors involved in SLE, we can improve our understanding of the underlying mechanisms of the disease. Furthermore, this knowledge may contribute to the identification of effective biomarkers and the selection of appropriate therapies for individuals with SLE.
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Affiliation(s)
- Mario Sestan
- Department of Paediatrics, University of Zagreb School of Medicine, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
| | - Nastasia Kifer
- Department of Paediatrics, University of Zagreb School of Medicine, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
| | - Todor Arsov
- Faculty of Medical Sciences, University Goce Delchev, 2000 Shtip, North Macedonia
- The Francis Crick Institute, London NW1 1AT, UK
| | - Matthew Cook
- Department of Immunology and Infectious Diseases, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
- Department of Medicine, University of Cambridge, Cambridge CB2 1TN, UK
| | - Julia Ellyard
- Department of Immunology and Infectious Diseases, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
| | | | - Marija Jelusic
- Department of Paediatrics, University of Zagreb School of Medicine, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
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10
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Wu L, Zhou L, An J, Shao X, Zhang H, Wang C, Zhao G, Chen S, Cui X, Zhang X, Yang F, Li X, Zhang X. Comprehensive profiling of extracellular vesicles in uveitis and scleritis enables biomarker discovery and mechanism exploration. J Transl Med 2023; 21:388. [PMID: 37322475 PMCID: PMC10273650 DOI: 10.1186/s12967-023-04228-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 05/25/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND Uveitis and posterior scleritis are sight-threatening diseases with undefined pathogenesis and accurate diagnosis remains challenging. METHODS Two plasma-derived extracellular vesicle (EV) subpopulations, small and large EVs, obtained from patients with ankylosing spondylitis-related uveitis, Behcet's disease uveitis, Vogt-Koyanagi-Harada syndrome, and posterior scleritis were subjected to proteomics analysis alongside plasma using SWATH-MS. A comprehensive bioinformatics analysis was performed on the proteomic profiles of sEVs, lEVs, and plasma. Candidate biomarkers were validated in a new cohort using ELISA. Pearson correlation analysis was performed to analyze the relationship between clinical parameters and proteomic data. Connectivity map database was used to predict therapeutic agents. RESULTS In total, 3,668 proteins were identified and over 3000 proteins were quantified from 278 samples. When comparing diseased group to healthy control, the proteomic profiles of the two EV subgroups were more correlated with disease than plasma. Comprehensive bioinformatics analysis highlighted potential pathogenic mechanisms for these diseases. Potential biomarker panels for four diseases were identified and validated. We found a negative correlation between plasma endothelin-converting enzyme 1 level and mean retinal thickness. Potential therapeutic drugs were proposed, and their targets were identified. CONCLUSIONS This study provides a proteomic landscape of plasma and EVs involved in ankylosing spondylitis-related uveitis, Behcet's disease uveitis, Vogt-Koyanagi-Harada syndrome, and posterior scleritis, offers insights into disease pathogenesis, identifies valuable biomarker candidates, and proposes promising therapeutic agents.
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Affiliation(s)
- Lingzi Wu
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Lei Zhou
- Department of Applied Biology and Chemical Technology, School of Optometry, Research Centre for SHARP Vision (RCSV), The Hong Kong Polytechnic University, Hong Kong, China
- Centre for Eye and Vision Research (CEVR), 17W Hong Kong Science Park, Hong Kong, China
| | - Jinying An
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Xianfeng Shao
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Hui Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Chunxi Wang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | | | - Shuang Chen
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Xuexue Cui
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Xinyi Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Fuhua Yang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Xiaorong Li
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Xiaomin Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China.
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11
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Mauro D, Manou-Stathopoulou S, Rivellese F, Sciacca E, Goldmann K, Tsang V, Lucey-Clayton I, Pagani S, Alam F, Pyne D, Rajakariar R, Gordon PA, Whiteford J, Bombardieri M, Pitzalis C, Lewis MJ. UBE2L3 regulates TLR7-induced B cell autoreactivity in Systemic Lupus Erythematosus. J Autoimmun 2023; 136:103023. [PMID: 37001433 DOI: 10.1016/j.jaut.2023.103023] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 02/28/2023] [Indexed: 03/31/2023]
Abstract
Both TLR7 and NF-κB hyperactivity are known to contribute to pathogenesis in Systemic Lupus Erythematosus (SLE), driving a pro-interferon response, autoreactive B cell expansion and autoantibody production. UBE2L3 is an SLE susceptibility gene which drives plasmablast/plasma cell expansion in SLE, but its role in TLR7 signalling has not been elucidated. We aimed to investigate the role of UBE2L3 in TLR7-mediated NF-κB activation, and the effect of UBE2L3 inhibition by Dimethyl Fumarate (DMF) on SLE B cell differentiation in vitro. Our data demonstrate that UBE2L3 is critical for activation of NF-κB downstream of TLR7 stimulation, via interaction with LUBAC. DMF, which directly inhibits UBE2L3, significantly inhibited TLR7-induced NF-κB activation, differentiation of memory B cells and plasmablasts, and autoantibody secretion in SLE. DMF also downregulated interferon signature genes and plasma cell transcriptional programmes. These results demonstrate that UBE2L3 inhibition could potentially be used as a therapy in SLE through repurposing of DMF, thus preventing TLR7-driven autoreactive B cell maturation.
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12
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Kelsall IR. Non-lysine ubiquitylation: Doing things differently. Front Mol Biosci 2022; 9:1008175. [PMID: 36200073 PMCID: PMC9527308 DOI: 10.3389/fmolb.2022.1008175] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/01/2022] [Indexed: 11/23/2022] Open
Abstract
The post-translational modification of proteins with ubiquitin plays a central role in nearly all aspects of eukaryotic biology. Historically, studies have focused on the conjugation of ubiquitin to lysine residues in substrates, but it is now clear that ubiquitylation can also occur on cysteine, serine, and threonine residues, as well as on the N-terminal amino group of proteins. Paradigm-shifting reports of non-proteinaceous substrates have further extended the reach of ubiquitylation beyond the proteome to include intracellular lipids and sugars. Additionally, results from bacteria have revealed novel ways to ubiquitylate (and deubiquitylate) substrates without the need for any of the enzymatic components of the canonical ubiquitylation cascade. Focusing mainly upon recent findings, this review aims to outline the current understanding of non-lysine ubiquitylation and speculate upon the molecular mechanisms and physiological importance of this non-canonical modification.
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13
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Yin X, Liu Q, Liu F, Tian X, Yan T, Han J, Jiang S. Emerging Roles of Non-proteolytic Ubiquitination in Tumorigenesis. Front Cell Dev Biol 2022; 10:944460. [PMID: 35874839 PMCID: PMC9298949 DOI: 10.3389/fcell.2022.944460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 06/15/2022] [Indexed: 12/13/2022] Open
Abstract
Ubiquitination is a critical type of protein post-translational modification playing an essential role in many cellular processes. To date, more than eight types of ubiquitination exist, all of which are involved in distinct cellular processes based on their structural differences. Studies have indicated that activation of the ubiquitination pathway is tightly connected with inflammation-related diseases as well as cancer, especially in the non-proteolytic canonical pathway, highlighting the vital roles of ubiquitination in metabolic programming. Studies relating degradable ubiquitination through lys48 or lys11-linked pathways to cellular signaling have been well-characterized. However, emerging evidence shows that non-degradable ubiquitination (linked to lys6, lys27, lys29, lys33, lys63, and Met1) remains to be defined. In this review, we summarize the non-proteolytic ubiquitination involved in tumorigenesis and related signaling pathways, with the aim of providing a reference for future exploration of ubiquitination and the potential targets for cancer therapies.
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Affiliation(s)
- Xiu Yin
- Clinical Medical Laboratory Center, Jining First People's Hospital, Jining Medical University, Jining, China
| | - Qingbin Liu
- Clinical Medical Laboratory Center, Jining First People's Hospital, Jining Medical University, Jining, China
| | - Fen Liu
- Clinical Medical Laboratory Center, Jining First People's Hospital, Jining Medical University, Jining, China
| | - Xinchen Tian
- Clinical Medical Laboratory Center, Jining First People's Hospital, Jining Medical University, Jining, China.,Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tinghao Yan
- Clinical Medical Laboratory Center, Jining First People's Hospital, Jining Medical University, Jining, China.,Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jie Han
- Department of Thyroid and Breast Surgery, Jining First People's Hospital, Jining Medical University, Jining, China
| | - Shulong Jiang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Jining Medical University, Jining, China
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14
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Kelsall IR, McCrory EH, Xu Y, Scudamore CL, Nanda SK, Mancebo-Gamella P, Wood NT, Knebel A, Matthews SJ, Cohen P. HOIL-1 ubiquitin ligase activity targets unbranched glucosaccharides and is required to prevent polyglucosan accumulation. EMBO J 2022; 41:e109700. [PMID: 35274759 PMCID: PMC9016349 DOI: 10.15252/embj.2021109700] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/05/2022] [Accepted: 02/16/2022] [Indexed: 01/12/2023] Open
Abstract
HOIL-1, a component of the linear ubiquitin chain assembly complex (LUBAC), ubiquitylates serine and threonine residues in proteins by esterification. Here, we report that mice expressing an E3 ligase-inactive HOIL-1[C458S] mutant accumulate polyglucosan in brain, heart and other organs, indicating that HOIL-1's E3 ligase activity is essential to prevent these toxic polysaccharide deposits from accumulating. We found that HOIL-1 monoubiquitylates glycogen and α1:4-linked maltoheptaose in vitro and identify the C6 hydroxyl moiety of glucose as the site of ester-linked ubiquitylation. The monoubiquitylation of maltoheptaose was accelerated > 100-fold by the interaction of Met1-linked or Lys63-linked ubiquitin oligomers with the RBR domain of HOIL-1. HOIL-1 also transferred pre-formed ubiquitin oligomers to maltoheptaose en bloc, producing polyubiquitylated maltoheptaose in one catalytic step. The Sharpin and HOIP components of LUBAC, but not HOIL-1, bound to unbranched and infrequently branched glucose polymers in vitro, but not to highly branched mammalian glycogen, suggesting a potential function in targeting HOIL-1 to unbranched glucosaccharides in cells. We suggest that monoubiquitylation of unbranched glucosaccharides may initiate their removal from cells, preventing precipitation as polyglucosan.
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Affiliation(s)
- Ian R Kelsall
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
| | - Elisha H McCrory
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
| | - Yingqi Xu
- Cross-Faculty NMR Centre, Department of Life Sciences, Imperial College London, London, UK
| | | | - Sambit K Nanda
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
| | - Paula Mancebo-Gamella
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
| | - Nicola T Wood
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
| | - Axel Knebel
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
| | - Stephen J Matthews
- Cross-Faculty NMR Centre, Department of Life Sciences, Imperial College London, London, UK
| | - Philip Cohen
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
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15
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Alsheikh AJ, Wollenhaupt S, King EA, Reeb J, Ghosh S, Stolzenburg LR, Tamim S, Lazar J, Davis JW, Jacob HJ. The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases. BMC Med Genomics 2022; 15:74. [PMID: 35365203 PMCID: PMC8973751 DOI: 10.1186/s12920-022-01216-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 03/17/2022] [Indexed: 02/08/2023] Open
Abstract
Background The remarkable growth of genome-wide association studies (GWAS) has created a critical need to experimentally validate the disease-associated variants, 90% of which involve non-coding variants. Methods To determine how the field is addressing this urgent need, we performed a comprehensive literature review identifying 36,676 articles. These were reduced to 1454 articles through a set of filters using natural language processing and ontology-based text-mining. This was followed by manual curation and cross-referencing against the GWAS catalog, yielding a final set of 286 articles. Results We identified 309 experimentally validated non-coding GWAS variants, regulating 252 genes across 130 human disease traits. These variants covered a variety of regulatory mechanisms. Interestingly, 70% (215/309) acted through cis-regulatory elements, with the remaining through promoters (22%, 70/309) or non-coding RNAs (8%, 24/309). Several validation approaches were utilized in these studies, including gene expression (n = 272), transcription factor binding (n = 175), reporter assays (n = 171), in vivo models (n = 104), genome editing (n = 96) and chromatin interaction (n = 33). Conclusions This review of the literature is the first to systematically evaluate the status and the landscape of experimentation being used to validate non-coding GWAS-identified variants. Our results clearly underscore the multifaceted approach needed for experimental validation, have practical implications on variant prioritization and considerations of target gene nomination. While the field has a long way to go to validate the thousands of GWAS associations, we show that progress is being made and provide exemplars of validation studies covering a wide variety of mechanisms, target genes, and disease areas. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-022-01216-w.
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Affiliation(s)
- Ammar J Alsheikh
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA.
| | - Sabrina Wollenhaupt
- Information Research, AbbVie Deutschland GmbH & Co. KG, 67061, Knollstrasse, Ludwigshafen, Germany
| | - Emily A King
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
| | - Jonas Reeb
- Information Research, AbbVie Deutschland GmbH & Co. KG, 67061, Knollstrasse, Ludwigshafen, Germany
| | - Sujana Ghosh
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
| | | | - Saleh Tamim
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
| | - Jozef Lazar
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
| | - J Wade Davis
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
| | - Howard J Jacob
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
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16
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Modulating the Ubiquitin–Proteasome System: A Therapeutic Strategy for Autoimmune Diseases. Cells 2022; 11:cells11071093. [PMID: 35406655 PMCID: PMC8997991 DOI: 10.3390/cells11071093] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/20/2022] [Accepted: 03/22/2022] [Indexed: 12/12/2022] Open
Abstract
Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease associated with the central nervous system (CNS). Autoimmunity is caused by an abnormal immune response to self-antigens, which results in chronic inflammation and tissue death. Ubiquitination is a post-translational modification in which ubiquitin molecules are attached to proteins by ubiquitinating enzymes, and then the modified proteins are degraded by the proteasome system. In addition to regulating proteasomal degradation of proteins, ubiquitination also regulates other cellular functions that are independent of proteasomal degradation. It plays a vital role in intracellular protein turnover and immune signaling and responses. The ubiquitin–proteasome system (UPS) is primarily responsible for the nonlysosomal proteolysis of intracellular proteins. The 26S proteasome is a multicatalytic adenosine-triphosphate-dependent protease that recognizes ubiquitin covalently attached to particular proteins and targets them for degradation. Damaged, oxidized, or misfolded proteins, as well as regulatory proteins that govern many essential cellular functions, are removed by this degradation pathway. When this system is affected, cellular homeostasis is altered, resulting in the induction of a range of diseases. This review discusses the biochemistry and molecular biology of the UPS, including its role in the development of MS and proteinopathies. Potential therapies and targets involving the UPS are also addressed.
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17
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Mechanistic insights into the subversion of the linear ubiquitin chain assembly complex by the E3 ligase IpaH1.4 of Shigella flexneri. Proc Natl Acad Sci U S A 2022; 119:e2116776119. [PMID: 35294289 PMCID: PMC8944867 DOI: 10.1073/pnas.2116776119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
SignificanceShigella flexneri, a deleterious bacterium, causes massive human infection cases and deaths worldwide. To facilitate survival and replication in infected host cells, S. flexneri can secrete two highly similar E3 ligase effectors, IpaH1.4 and IpaH2.5, to subvert the linear ubiquitin chain assembly complex (LUBAC), a key player involved in numerous antibacterial signaling pathways of host cells but with poorly understood mechanisms. In this study, through systematic biochemical and structural characterization, we elucidate the multiple tactics adopted by IpaH1.4/2.5 to disarm the human LUBAC and provide mechanistic insights into the subversion of host LUBAC by IpaH1.4/2.5 of S. flexneri.
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18
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Zhang X, Huo C, Liu Y, Su R, Zhao Y, Li Y. Mechanism and Disease Association With a Ubiquitin Conjugating E2 Enzyme: UBE2L3. Front Immunol 2022; 13:793610. [PMID: 35265070 PMCID: PMC8899012 DOI: 10.3389/fimmu.2022.793610] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Ubiquitin conjugating enzyme E2 is an important component of the post-translational protein ubiquitination pathway, which mediates the transfer of activated ubiquitin to substrate proteins. UBE2L3, also called UBcH7, is one of many E2 ubiquitin conjugating enzymes that participate in the ubiquitination of many substrate proteins and regulate many signaling pathways, such as the NF-κB, GSK3β/p65, and DSB repair pathways. Studies on UBE2L3 have found that it has an abnormal expression in many diseases, mainly immune diseases, tumors and Parkinson's disease. It can also promote the occurrence and development of these diseases. Resultantly, UBE2L3 may become an important target for some diseases. Herein, we review the structure of UBE2L3, and its mechanism in diseases, as well as diseases related to UBE2L3 and discuss the related challenges.
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Affiliation(s)
- Xiaoxia Zhang
- Department of Ophthalmology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Chengdong Huo
- Department of Ophthalmology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Yating Liu
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Ruiliang Su
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Yang Zhao
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Yumin Li
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
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Gopalakrishnan J, Tessneer KL, Fu Y, Pasula S, Pelikan RC, Kelly JA, Wiley GB, Gaffney PM. Variants on the UBE2L3/YDJC Autoimmune Disease Risk Haplotype Increase UBE2L3 Expression by Modulating CCCTC-Binding Factor and YY1 Binding. Arthritis Rheumatol 2022; 74:163-173. [PMID: 34279042 PMCID: PMC8712360 DOI: 10.1002/art.41925] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 06/10/2021] [Accepted: 07/08/2021] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Genetic variants spanning UBE2L3 are associated with increased expression of the UBE2L3-encoded E2 ubiquitin-conjugating enzyme H7 (UbcH7), which facilitates activation of proinflammatory NF-κB signaling and susceptibility to autoimmune diseases. We undertook this study to delineate how genetic variants carried on the UBE2L3/YDJC autoimmune risk haplotype function to drive hypermorphic UBE2L3 expression. METHODS We used bioinformatic analyses, electrophoretic mobility shift assays, and luciferase reporter assays to identify and functionally characterize allele-specific effects of risk variants positioned in chromatin accessible regions of immune cells. Chromatin conformation capture with quantitative polymerase chain reaction (3C-qPCR), chromatin immunoprecipitation (ChIP)-qPCR, and small interfering RNA (siRNA) knockdown assays were performed on patient-derived Epstein-Barr virus-transformed B cells homozygous for the UBE2L3/YDJC nonrisk or risk haplotype to determine if the risk haplotype increases UBE2L3 expression by altering the regulatory chromatin architecture in the region. RESULTS Of the 7 prioritized variants, 5 demonstrated allele-specific increases in nuclear protein binding affinity and regulatory activity. High-throughput sequencing of chromosome conformation capture coupled with ChIP (HiChIP) and 3C-qPCR uncovered a long-range interaction between the UBE2L3 promoter (rs140490, rs140491, rs11089620) and the downstream YDJC promoter (rs3747093) that was strengthened in the presence of the UBE2L3/YDJC risk haplotype, and correlated with the loss of CCCTC-binding factor (CTCF) and gain of YY1 binding at the risk alleles. Depleting YY1 by siRNA disrupted the long-range interaction between the 2 promoters and reduced UBE2L3 expression. CONCLUSION The UBE2L3/YDJC autoimmune risk haplotype increases UBE2L3 expression through strengthening a YY1-mediated interaction between the UBE2L3 and YDJC promoters.
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Affiliation(s)
- Jaanam Gopalakrishnan
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Kandice L. Tessneer
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Yao Fu
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Satish Pasula
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Richard C. Pelikan
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Jennifer A. Kelly
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Graham B. Wiley
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Patrick M. Gaffney
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
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Manou-Stathopoulou S, Lewis MJ. Diversity of NF-κB signalling and inflammatory heterogeneity in Rheumatic Autoimmune Disease. Semin Immunol 2021; 58:101649. [PMID: 36064646 DOI: 10.1016/j.smim.2022.101649] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Systemic Autoimmune Rheumatic Diseases, including Rheumatoid Arthritis, Systemic Lupus Erythematosus and Sjogren's syndrome, are characterised by a loss of immune tolerance and chronic inflammation. There is marked heterogeneity in clinical and molecular phenotypes in each condition, and the aetiology of these is unclear. NF-κB is an inducible transcription factor that is critical in the physiological inflammatory response, and which has been implicated in chronic inflammation. Genome-wide association studies have linked risk alleles related to the NF-κB pathway to the pathogenesis of multiple Systemic Autoimmune Rheumatic Diseases. This review describes how cell- and pathway-specific NF-κB activation contribute to the spectrum of clinical phenotypes and molecular pathotypes in rheumatic disease. Potential clinical applications are explored, including therapeutic interventions and utilisation of NF-κB as a biomarker of disease subtypes and treatment response.
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Affiliation(s)
- Sotiria Manou-Stathopoulou
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London, School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Myles J Lewis
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London, School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
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21
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Yang M, Chen Q, Mei L, Wen G, An W, Zhou X, Niu K, Liu C, Ren M, Sun K, Xiao Q, Zhang L. Neutrophil elastase promotes neointimal hyperplasia by targeting toll-like receptor 4 (TLR4)-NF-κB signalling. Br J Pharmacol 2021; 178:4048-4068. [PMID: 34076894 DOI: 10.1111/bph.15583] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 05/18/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE Neointimal hyperplasia (NIH) is the fundamental cause for vascular diseases and vascular smooth muscle cell (VSMC) dysregulation has been widely implicated in NIH. Neutrophil elastase is a potential therapeutic target for multiple diseases. We investigated the role of neutrophil elastase in VSMC functions and injury-induced NIH and explored the therapeutic potential of targeting neutrophil elastase in NIH. EXPERIMENTAL APPROACH VSMCs were used to analyse the effects of neutrophil elastase. Proteomic analysis was used to identify potential neutrophil elastase targets. Artery injury model and neutrophil elastase inhibitor GW311616A were used to investigate the role of neutrophil elastase in NIH. KEY RESULTS TNF-α up-regulated neutrophil elastase in VSMCs through modulating GAPBα/Runx1/CEBPα/c-Myb signalling. Up-regulated neutrophil elastase promoted VSMC migration, proliferation and inflammation. Toll-like receptor 4 (TLR4) was identified as a target protein for neutrophil elastase in VSMCs and the TLR4/MyD88/IRAK1/TRAF6/NF-κB regulatory axis was shown to be the signalling pathway for neutrophil elastase in VSMC pathology. Importantly, TLR4 inhibition abolished neutrophil elastase-mediated VSMC dysregulation. Injury-induced NIH was significantly reduced in both neutrophil elastase-deficient mice and mice treated with GW311616A. The formation of neutrophil extracellular traps was impaired in injured arteries from neutrophil elastase-deficient mice. Finally, a similar role for neutrophil elastase in human VSMC pathology was confirmed and we observed higher expression levels of neutrophil elastase but lower expression levels of TLR4 in human atherosclerotic lesions. CONCLUSION AND IMPLICATIONS We provide new insight into the molecular mechanisms underlying NIH and identify neutrophil elastase as a potential therapeutic target for vascular disease.
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Affiliation(s)
- Mei Yang
- Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Qishan Chen
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Li Mei
- Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Guanmei Wen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Weiwei An
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Xinmiao Zhou
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kaiyuan Niu
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Chenxin Liu
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Meixia Ren
- Fujian Key Laboratory of Geriatrics, Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China
| | - Kun Sun
- Department of Pediatric Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qingzhong Xiao
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Li Zhang
- Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
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22
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Li L, Huang KL, Gao Y, Cui Y, Wang G, Elrod ND, Li Y, Chen YE, Ji P, Peng F, Russell WK, Wagner EJ, Li W. An atlas of alternative polyadenylation quantitative trait loci contributing to complex trait and disease heritability. Nat Genet 2021; 53:994-1005. [PMID: 33986536 DOI: 10.1038/s41588-021-00864-5] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/05/2021] [Indexed: 12/14/2022]
Abstract
Genome-wide association studies have identified thousands of noncoding variants associated with human traits and diseases. However, the functional interpretation of these variants is a major challenge. Here, we constructed a multi-tissue atlas of human 3'UTR alternative polyadenylation (APA) quantitative trait loci (3'aQTLs), containing approximately 0.4 million common genetic variants associated with the APA of target genes, identified in 46 tissues isolated from 467 individuals (Genotype-Tissue Expression Project). Mechanistically, 3'aQTLs can alter poly(A) motifs, RNA secondary structure and RNA-binding protein-binding sites, leading to thousands of APA changes. Our CRISPR-based experiments indicate that such 3'aQTLs can alter APA regulation. Furthermore, we demonstrate that mapping 3'aQTLs can identify APA regulators, such as La-related protein 4. Finally, 3'aQTLs are colocalized with approximately 16.1% of trait-associated variants and are largely distinct from other QTLs, such as expression QTLs. Together, our findings show that 3'aQTLs contribute substantially to the molecular mechanisms underlying human complex traits and diseases.
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Affiliation(s)
- Lei Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Kai-Lieh Huang
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
| | - Yipeng Gao
- Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, USA
| | - Ya Cui
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Gao Wang
- The Gertrude H. Sergievsky Center and Department of Neurology, Columbia University, New York, NY, USA
| | - Nathan D Elrod
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
| | - Yumei Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Yiling Elaine Chen
- Department of Statistics, University of California, Los Angeles, CA, USA
| | - Ping Ji
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
| | - Fanglue Peng
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - William K Russell
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
| | - Eric J Wagner
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
| | - Wei Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA.
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Ding X, Cai M, Wang S, Yang Q, Zheng X, Zuo X, Liu S. Gene-based association analysis identified a novel gene associated with systemic lupus erythematosus. Ann Hum Genet 2021; 85:213-220. [PMID: 34145571 DOI: 10.1111/ahg.12439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 05/26/2021] [Accepted: 06/01/2021] [Indexed: 11/24/2022]
Abstract
OBJECTIVE Systemic lupus erythematosus (SLE) is a complex autoimmune disease with strong genetic predisposition. Genome-wide association studies (GWAS) of SLE have identified more than 50 robust susceptibility loci. However, traditional individual SNP-based GWAS have made it difficult to identify variants with small effects. Moreover, variants revealed by GWAS only explain a limited disease heritability, suggesting that many susceptibility genes remain uncovered. METHODS We first curated the published SLE GWAS data from 1047 SLE patients and 1205 healthy controls of Chinese ancestry and performed a gene-based association study. Then quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was conducted to verify novel genes identified above. RESULTS Gene-based association study identified 10 SLE-associated genes, nine of which were reported by previous GWAS, the other one, ILRUN, is a newly identified gene and was further validated by qRT-PCR. Gene expression analysis of Gene Expression Omnibus (GEO) datasets also showed that the expression of ILRUN in patients with SLE was lower than that in normal subjects. CONCLUSION In this study, gene-based association study and qRT-PCR identified that ILRUN is a novel susceptibility gene of SLE. ILRUN may regulate inflammation and antiviral response through its effect on the transcription of type I interferons )I-IFN, and participate in the pathogenesis of SLE.
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Affiliation(s)
- Xian Ding
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
| | - Minglong Cai
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
| | - Sun Wang
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
| | - Qingqing Yang
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
| | - Xiaodong Zheng
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
| | - Xianbo Zuo
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
| | - Shengxiu Liu
- Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
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24
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Ankylosing spondylitis: an autoimmune or autoinflammatory disease? Nat Rev Rheumatol 2021; 17:387-404. [PMID: 34113018 DOI: 10.1038/s41584-021-00625-y] [Citation(s) in RCA: 183] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2021] [Indexed: 12/20/2022]
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown aetiology. Unlike other systemic autoimmune diseases, in AS, the innate immune system has a dominant role characterized by aberrant activity of innate and innate-like immune cells, including γδ T cells, group 3 innate lymphoid cells, neutrophils, mucosal-associated invariant T cells and mast cells, at sites predisposed to the disease. The intestine is involved in disease manifestations, as it is at the forefront of the interaction between the mucosal-associated immune cells and the intestinal microbiota. Similarly, biomechanical factors, such as entheseal micro-trauma, might also be involved in the pathogenesis of the articular manifestation of AS, and sentinel immune cells located in the entheses could provide links between local damage, genetic predisposition and the development of chronic inflammation. Although these elements might support the autoinflammatory nature of AS, studies demonstrating the presence of autoantibodies (such as anti-CD74, anti-sclerostin and anti-noggin antibodies) and evidence of activation and clonal expansion of T cell populations support an autoimmune component to the disease. This Review presents the evidence for autoinflammation and the evidence for autoimmunity in AS and, by discussing the pathophysiological factors associated with each, aims to reconcile the two hypotheses.
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25
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Shared genetic study gives insights into the shared and distinct pathogenic immunity components of IgA nephropathy and SLE. Mol Genet Genomics 2021; 296:1017-1026. [PMID: 34076728 DOI: 10.1007/s00438-021-01798-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 05/24/2021] [Indexed: 10/21/2022]
Abstract
An autoimmune component has been suggested to play a role in pathogenesis of IgA nephropathy (IgAN). And genetic studies have reported the shared susceptibility loci between IgAN and the prototype autoimmune disease systemic lupus erythematosus (SLE). This study was designed to systemically identify and annotate the shared susceptibility genes between IgAN and SLE. We first conducted an imputation-based genome-wide association analysis in 1180 IgAN cases and 899 controls, 1639 SLE cases and 2410 controls. Then we integrated blood expression quantitative trait loci (eQTL) databases and gene expression data to prioritize the potentially functional genes. The results showed that a total of 1928 SNPs mapping to 14 loci were identified to be shared genes between IgAN and SLE. Conditional analysis prioritized 18 independent SNPs, among which alleles of 4 SNPs in HLA and 7 SNPs in non-HLA loci were risk for SLE were protective alleles for IgAN. Most of the shared SNPs and their proxies (r2 ≥ 0.8 in Asians) (181/184, 98.37%) in non-HLA loci were located in non-coding regions. By analyzing two publicly independent blood-eQTL databases, four genes UBE2L3, FCGR2B, ANXA6, and BLK, which seemed to be restricted to PBMC or its subsets were prioritized. Among them only UBE2L3 showed consistent direction between SLE and IgAN, while the others showed opposite directions. Differential gene analysis showed that UBE2L3 was highly expressed in both SLE and IgAN, while FCGR2B and BLK showed marginal significance in SLE and IgAN, respectively. By exploring the pleiotropy of shared genes between IgAN and SLE, our results provide important clues for understanding the shared role of plasmablasts but the distinct role of B cells in pathogenesis of these two diseases.
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Browning SR, Browning BL. Probabilistic Estimation of Identity by Descent Segment Endpoints and Detection of Recent Selection. Am J Hum Genet 2020; 107:895-910. [PMID: 33053335 PMCID: PMC7553009 DOI: 10.1016/j.ajhg.2020.09.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/25/2020] [Indexed: 12/18/2022] Open
Abstract
Most methods for fast detection of identity by descent (IBD) segments report identity by state segments without any quantification of the uncertainty in the endpoints and lengths of the IBD segments. We present a method for determining the posterior probability distribution of IBD segment endpoints. Our approach accounts for genotype errors, recent mutations, and gene conversions which disrupt DNA sequence identity within IBD segments, and it can be applied to large cohorts with whole-genome sequence or SNP array data. We find that our method's estimates of uncertainty are well calibrated for homogeneous samples. We quantify endpoint uncertainty for 77.7 billion IBD segments from 408,883 individuals of white British ancestry in the UK Biobank, and we use these IBD segments to find regions showing evidence of recent natural selection. We show that many spurious selection signals are eliminated by the use of unbiased estimates of IBD segment endpoints and a pedigree-based genetic map. Eleven of the twelve regions with the greatest evidence for recent selection in our scan have been identified as selected in previous analyses using different approaches. Our computationally efficient method for quantifying IBD segment endpoint uncertainty is implemented in the open source ibd-ends software package.
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Affiliation(s)
- Sharon R Browning
- Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
| | - Brian L Browning
- Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA
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27
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Cutolo M, Straub RH. Sex steroids and autoimmune rheumatic diseases: state of the art. Nat Rev Rheumatol 2020; 16:628-644. [PMID: 33009519 DOI: 10.1038/s41584-020-0503-4] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/01/2020] [Indexed: 12/16/2022]
Abstract
In autoimmune rheumatic diseases, oestrogens can stimulate certain immune responses (including effects on B cells and innate immunity), but can also have dose-related anti-inflammatory effects on T cells, macrophages and other immune cells. By contrast, androgens and progesterone have predominantly immunosuppressive and anti-inflammatory effects. Hormone replacement therapies and oral contraception (and also pregnancy) enhance or decrease the severity of autoimmune rheumatic diseases at a genetic or epigenetic level. Serum androgen concentrations are often low in men and in women with autoimmune rheumatic diseases, suggesting that androgen-like compounds might be a promising therapeutic approach. However, androgen-to-oestrogen conversion (known as intracrinology) is enhanced in inflamed tissues, such as those present in patients with autoimmune rheumatic diseases. In addition, it is becoming evident that the gut microbiota differs between the sexes (known as the microgenderome) and leads to sex-dependent genetic and epigenetic changes in gastrointestinal inflammation, systemic immunity and, potentially, susceptibility to autoimmune or inflammatory rheumatic diseases. Future clinical research needs to focus on the therapeutic use of androgens and progestins or their downstream signalling cascades and on new oestrogenic compounds such as tissue-selective oestrogen complex to modulate altered immune responses.
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Affiliation(s)
- Maurizio Cutolo
- Research Laboratories and Academic Division of Clinical Rheumatology, Postgraduate School of Rheumatology, Department of Internal Medicine DIMI, University of Genova, IRCCS San Martino Polyclinic, Genoa, Italy.
| | - Rainer H Straub
- Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Division of Rheumatology, Department of Internal Medicine, University Hospital of Regensburg, Regensburg, Germany
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28
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Zhang T, Sun J, Cheng J, Yin W, Li J, Miller H, Herrada AA, Gu H, Song H, Chen Y, Gong Q, Liu C. The role of ubiquitinase in B cell development and function. J Leukoc Biol 2020; 109:395-405. [PMID: 32816356 DOI: 10.1002/jlb.1mr0720-185rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 07/16/2020] [Accepted: 07/18/2020] [Indexed: 11/10/2022] Open
Abstract
Ubiquitinases are a select group of enzymes that modify target proteins through ubiquitination, which plays a crucial role in the regulation of protein degradation, location, and function. B lymphocytes that originated from bone marrow hematopoietic stem cells (HSC), exert humoral immune functions by differentiating into plasma cells and producing antibodies. Previous studies have shown that ubiquitination is involved in the regulation of the cell cycle and signal transduction important for B lymphocyte development and function. In this review, how ubiquitinases regulate B cell development, activation, apoptosis, and proliferation is discussed, which could help in understanding the physiological processes and diseases related to B cells and also provides potential new targets for further studies.
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Affiliation(s)
- Tong Zhang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianxuan Sun
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiali Cheng
- Department of hematology, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Yin
- Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingwen Li
- Department of hematology, Wuhan Union Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan, China
| | - Heather Miller
- Department of Intracellular Pathogens, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
| | - Andrés A Herrada
- Lymphatic and Inflammation Research Laboratory, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Heng Gu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongmei Song
- Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No 1, Shuaifuyuan, Dongcheng District, Beijing, China
| | - Yan Chen
- The Second Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China.,Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, China
| | - Chaohong Liu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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29
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Liu H, Yan P, Ren J, Wu C, Yuan W, Rao M, Zhang Z, Kong E. Identifying the Potential Substrates of the Depalmitoylation Enzyme Acyl-protein Thioesterase 1. Curr Mol Med 2020; 19:364-375. [PMID: 30914023 DOI: 10.2174/1566524019666190325143412] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 03/15/2019] [Accepted: 03/19/2019] [Indexed: 01/03/2023]
Abstract
BACKGROUND The homeostasis of palmitoylation and depalmitoylation is involved in various cellular processes, the disruption of which induces severe physiological consequences. Acyl-protein thioesterase (APT) and palmitoyl-protein thioesterases (PPT) catalyze the depalmitoylation process. The natural mutation in human PPT1 caused neurodegenerative disease, yet the understanding of APT1 remains to be elucidated. While the deletion of APT1 in mice turned out to be potentially embryonically lethal, the decoding of its function strictly relied on the identification of its substrates. OBJECTIVE To determine the potential substrates of APT1 by using the generated human APT1 knockout cell line. METHODS The combined techniques of palmitoyl-protein enrichment and massspectrometry were used to analyze the different proteins. Palmitoyl-proteins both in HEK293T and APT1-KO cells were extracted by resin-assisted capture (RAC) and data independent acquisition (DIA) quantitative method of proteomics for data collection. RESULTS In total, 382 proteins were identified. The gene ontology classification segregated these proteins into diverse biological pathways e.g. endoplasmic reticulum process and ubiquitin-mediated proteolysis. A few potential substrates were selected for verification; indeed, major proteins were palmitoylated. Importantly, their levels of palmitoylation were clearly changed in APT1-KO cells. Interestingly, the proliferation of APT1-KO cells escalated dramatically as compared to that of the WT cells, which could be rescued by APT1 overexpression. CONCLUSION Our study provides a large scale of potential substrates of APT1, thus facilitating the understanding of its intervened molecular functions.
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Affiliation(s)
- Huicong Liu
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
| | - Peipei Yan
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
| | - Junyan Ren
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
| | - Can Wu
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
| | - Wei Yuan
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
| | - Muding Rao
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
| | - Zhongjian Zhang
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
| | - Eryan Kong
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, China
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30
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Gan T, Li Y, Zhou XJ, Zhang H. Immunoproteasome in IgA Nephropathy: State-of-Art and Future Perspectives. Int J Biol Sci 2020; 16:2518-2526. [PMID: 32792854 PMCID: PMC7415421 DOI: 10.7150/ijbs.48330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 07/10/2020] [Indexed: 12/14/2022] Open
Abstract
IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and renal failure. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the immunoproteasome probably plays an important role in IgAN. The immunoproteasome is a proteasome variant that is expressed when cells are stressed or receive inflammatory signals. While immunoproteasome is suggested to be mainly involved in major histocompatibility complex-I (MHC-I) antigen presentation, recent studies indicate that it may assert broad functions in trafficking events that activate both innate and adaptive immunity. In this review, we first summarize new insights into its functions in immunity, and discuss how it underlies its associations with IgAN. We also highlight its potential as a therapeutic target for the future.
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Affiliation(s)
- Ting Gan
- Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, 100034, People's Republic of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences
| | - Yang Li
- Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, 100034, People's Republic of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences
| | - Xu-Jie Zhou
- Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, 100034, People's Republic of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences
| | - Hong Zhang
- Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, 100034, People's Republic of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences
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Yvan-Charvet L, Bonacina F, Guinamard RR, Norata GD. Immunometabolic function of cholesterol in cardiovascular disease and beyond. Cardiovasc Res 2020; 115:1393-1407. [PMID: 31095280 DOI: 10.1093/cvr/cvz127] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 03/20/2019] [Accepted: 05/07/2019] [Indexed: 12/16/2022] Open
Abstract
Inflammation represents the driving feature of many diseases, including atherosclerosis, cancer, autoimmunity and infections. It is now established that metabolic processes shape a proper immune response and within this context the alteration in cellular cholesterol homeostasis has emerged as a culprit of many metabolic abnormalities observed in chronic inflammatory diseases. Cholesterol accumulation supports the inflammatory response of myeloid cells (i.e. augmentation of toll-like receptor signalling, inflammasome activation, and production of monocytes and neutrophils) which is beneficial in the response to infections, but worsens diseases associated with chronic metabolic inflammation including atherosclerosis. In addition to the innate immune system, cells of adaptive immunity, upon activation, have also been shown to undergo a reprogramming of cellular cholesterol metabolism, which results in the amplification of inflammatory responses. Aim of this review is to discuss (i) the molecular mechanisms linking cellular cholesterol metabolism to specific immune functions; (ii) how cellular cholesterol accumulation sustains chronic inflammatory diseases such as atherosclerosis; (iii) the immunometabolic profile of patients with defects of genes affecting cholesterol metabolism including familial hypercholesterolaemia, cholesteryl ester storage disease, Niemann-Pick type C, and immunoglobulin D syndrome/mevalonate kinase deficiency. Available data indicate that cholesterol immunometabolism plays a key role in directing immune cells function and set the stage for investigating the repurposing of existing 'metabolic' drugs to modulate the immune response.
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Affiliation(s)
- Laurent Yvan-Charvet
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Fédération Hospitalo-Universitaire (FHU) Oncoage, Nice, France
| | - Fabrizia Bonacina
- Department of Excellence of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Rodolphe Renè Guinamard
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Fédération Hospitalo-Universitaire (FHU) Oncoage, Nice, France
| | - Giuseppe Danilo Norata
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Fédération Hospitalo-Universitaire (FHU) Oncoage, Nice, France.,Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy
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32
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Kim T, Bae SC, Kang C. Synergistic activation of NF-κB by TNFAIP3 (A20) reduction and UBE2L3 (UBCH7) augment that synergistically elevate lupus risk. Arthritis Res Ther 2020; 22:93. [PMID: 32334614 PMCID: PMC7183688 DOI: 10.1186/s13075-020-02181-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 04/02/2020] [Indexed: 02/03/2023] Open
Abstract
Background Systemic lupus erythematosus (SLE) is an autoimmune inflammatory rheumatic disease. SLE susceptibility is affected by multiple genetic elements, environmental factors, and their interactions. We aimed in this study to statistically and functionally characterize a gene-gene interaction (epistasis) recently documented to affect SLE risk. Methods Two single-nucleotide polymorphisms, rs2230926 in TNFAIP3 (A20) gene and rs131654 in UBE2L3 (UBCH7) gene, were genotyped in all 3525 Korean participants, and their SLE risk association and epistasis were statistically analyzed by calculating odds ratio (OR), 95% confidence interval (CI), and P values in genotype comparisons between 1318 SLE patients and 2207 healthy controls. Furthermore, their effects on gene functions were assessed by comparatively examining separate and combined effects of TNFAIP3 and UBE2L3 knockdowns on NF-κB transcription factor activity in human cells. Results SLE susceptibility is associated with TNFAIP3 rs2230926 (OR = 1.9, 95% CI 1.6–2.4, P = 8.6 × 10−11) and UBE2L3 rs131654 (OR = 1.2, 95% CI 1.1–1.4, P = 1.1 × 10−4) in a Korean population of this study. Their risk-associated alleles synergistically elevate SLE susceptibility in both multivariate logistic regression analysis (ORinteraction = 1.6, P = 0.0028) and genotype-stratified analysis (ORinteraction = 2.4), confirming the synergistic TNFAIP3-UBE2L3 interaction in SLE risk. Additionally, the SLE-susceptible alleles confer decreased TNFAIP3 expression (P = 1.1 × 10−6, n = 610) and increased UBE2L3 expression (P = 9.5 × 10−11, n = 475), respectively, in B cell analysis of the International HapMap Project individuals with adjustment for ethnicity. Furthermore, when compared with TNFAIP3 non-knockdown and UBE2L3 knockdown in human HeLa cells, TNFAIP3 knockdown and UBE2L3 non-knockdown synergistically increase three cytokines, CCL2, CXCL8 (IL8), and IL6, all regulated by NF-κB in the human TNFR signaling pathway. Conclusions A synergistic interaction between TNFAIP3 and UBE2L3 genes is observed in SLE risk, as being evident in comparison of genotype distributions between SLE patients and controls. Additionally, the synergistic gene-gene interaction is functionally validated, as TNFAIP3 reduction and UBE2L3 augment exert synergism in activation of NF-κB and subsequent induction of inflammatory cytokines. Accordingly, SLE inflammation and risk could be synergistically alleviated by TNFAIP3 upregulation and UBE2L3 downregulation.
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Affiliation(s)
- Taehyeung Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Sang-Cheol Bae
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.
| | - Changwon Kang
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
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Webber D, Cao J, Dominguez D, Gladman DD, Levy DM, Ng L, Paterson AD, Touma Z, Urowitz MB, Wither JE, Silverman ED, Hiraki LT. Association of systemic lupus erythematosus (SLE) genetic susceptibility loci with lupus nephritis in childhood-onset and adult-onset SLE. Rheumatology (Oxford) 2020; 59:90-98. [PMID: 31236574 DOI: 10.1093/rheumatology/kez220] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 05/08/2019] [Indexed: 01/19/2023] Open
Abstract
OBJECTIVE LN is one of the most common and severe manifestations of SLE. Our aim was to test the association of SLE risk loci with LN risk in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE). METHODS Two Toronto-based tertiary care SLE cohorts included cSLE (diagnosed <18 years) and aSLE patients (diagnosed ⩾18 years). Patients met ACR and/or SLICC SLE criteria and were genotyped on the Illumina Multi-Ethnic Global Array or Omni1-Quad arrays. We identified those with and without biopsy-confirmed LN. HLA and non-HLA additive SLE risk-weighted genetic risk scores (GRSs) were tested for association with LN risk in logistic models, stratified by cSLE/aSLE and ancestry. Stratified effect estimates were meta-analysed. RESULTS Of 1237 participants, 572 had cSLE (41% with LN) and 665 had aSLE (30% with LN). Increasing non-HLA GRS was significantly associated with increased LN risk [odds ratio (OR) = 1.26; 95% CI 1.09, 1.46; P = 0.0006], as was increasing HLA GRS in Europeans (OR = 1.55; 95% CI 1.07, 2.25; P = 0.03). There was a trend for stronger associations between both GRSs and LN risk in Europeans with cSLE compared with aSLE. When restricting cases to proliferative LN, the magnitude of these associations increased for both the non-HLA (OR = 1.30; 95% CI 1.10, 1.52; P = 0.002) and HLA GRS (OR = 1.99; 95% CI 1.29, 3.08; P = 0.002). CONCLUSION We observed an association between known SLE risk loci and LN risk in children and adults with SLE, with the strongest effect observed among Europeans with cSLE. Future studies will include SLE-risk single nucleotide polymorphisms specific to non-European ancestral groups and validate findings in an independent cohort.
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Affiliation(s)
- Declan Webber
- Division of Rheumatology, Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Jingjing Cao
- Genetics & Genome Biology, Research Institute, SickKids Hospital, Toronto, Canada
| | - Daniela Dominguez
- Division of Rheumatology, Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Dafna D Gladman
- Krembil Research Institute, Toronto Western Hospital, Toronto, Canada
| | - Deborah M Levy
- Division of Rheumatology, Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Lawrence Ng
- Division of Rheumatology, Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Andrew D Paterson
- Genetics & Genome Biology, Research Institute, SickKids Hospital, Toronto, Canada
| | - Zahi Touma
- Krembil Research Institute, Toronto Western Hospital, Toronto, Canada
| | - Murray B Urowitz
- Krembil Research Institute, Toronto Western Hospital, Toronto, Canada
| | - Joan E Wither
- Krembil Research Institute, Toronto Western Hospital, Toronto, Canada
| | - Earl D Silverman
- Division of Rheumatology, Department of Pediatrics, University of Toronto, Toronto, Canada.,Division of Translational Medicine Research Institute, Toronto, Canada
| | - Linda T Hiraki
- Division of Rheumatology, Department of Pediatrics, University of Toronto, Toronto, Canada.,Child Health Evaluative Sciences, Research Institute, SickKids Hospital, Toronto, Canada
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Tao NN, Zhang ZZ, Ren JH, Zhang J, Zhou YJ, Wai Wong VK, Kwan Law BY, Cheng ST, Zhou HZ, Chen WX, Xu HM, Chen J. Overexpression of ubiquitin-conjugating enzyme E2 L3 in hepatocellular carcinoma potentiates apoptosis evasion by inhibiting the GSK3β/p65 pathway. Cancer Lett 2020; 481:1-14. [PMID: 32268166 DOI: 10.1016/j.canlet.2020.03.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 03/19/2020] [Accepted: 03/26/2020] [Indexed: 01/07/2023]
Abstract
UBE2L3 is a ubiquitin-conjugating protein belonging to the E2 family that consists of 153 amino acid residues. In this study, we found that UBE2L3 was generally upregulated in clinical HCC samples compared to non-tumour samples and that there was a strong association between high UBE2L3 expression and tumour size, clinical grade and prognosis in HCC patients. UBE2L3 depletion inhibited the proliferation and induced the apoptosis of HCC cells. At the molecular level, we observed that UBE2L3 depletion enhanced the protein stability of GSK3β, thus promoting the expression and activation of GSK3β. Subsequently, activated GSK3β phosphorylated p65 and promoted its nuclear translocation to increase the expression of target genes, including PUMA, Bax, Bim, Bad, and Bid. In vivo, knockout of UBE2L3 in HCC cells inhibited tumour growth in orthotopic liver injection nude mouse models. Moreover, inhibition of p65 or GSK3β significantly restored the effects induced by UBE2L3 knockout in HCC. Together, this study reveals the stimulatory effect of UBE2L3 on HCC cell proliferation, suggesting that UBE2L3 may be an important pro-tumorigenic factor in liver carcinogenesis and a potential therapeutic target of HCC.
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Affiliation(s)
- Na-Na Tao
- Department of Infectious Disease, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Clinical Laboratory, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Zhen-Zhen Zhang
- Department of Infectious Disease, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ji-Hua Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Juan Zhang
- Department of Clinical Laboratory, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Yu-Jiao Zhou
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Vincent Kam Wai Wong
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Betty Yuen Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Sheng-Tao Cheng
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hong-Zhong Zhou
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Wei-Xian Chen
- Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong-Mei Xu
- Department of Infectious Disease, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
| | - Juan Chen
- Department of Infectious Disease, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
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Fernandez-Jimenez N, Bilbao JR. Mendelian randomization analysis of celiac GWAS reveals a blood expression signature with diagnostic potential in absence of gluten consumption. Hum Mol Genet 2020; 28:3037-3042. [PMID: 31127932 PMCID: PMC6737291 DOI: 10.1093/hmg/ddz113] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 05/10/2019] [Accepted: 05/20/2019] [Indexed: 12/26/2022] Open
Abstract
Celiac disease (CeD) is an immune-mediated enteropathy with a strong genetic component where the main environmental trigger is dietary gluten, and currently a correct diagnosis of the disease is impossible if gluten-free diet (GFD) has already been started. We hypothesized that merging different levels of genomic information through Mendelian randomization (MR) could help discover genetic biomarkers useful for CeD diagnosis. MR was performed using public databases of expression quantitative trait loci (QTL) and methylation QTL as exposures and the largest CeD genome-wide association study conducted to date as the outcome, in order to identify potential causal genes. As a result, we identified UBE2L3, an ubiquitin ligase located in a CeD-associated region. We interrogated the expression of UBE2L3 in an independent data set of peripheral blood mononuclear cells (PBMCs) and found that its expression is altered in CeD patients on GFD when compared to non-celiac controls. The relative expression of UBE2L3 isoforms predicts CeD with 100% specificity and sensitivity and could be used as a diagnostic marker, especially in the absence of gluten consumption. This approach could be applicable to other diseases where diagnosis of asymptomatic patients can be complicated.
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Affiliation(s)
- Nora Fernandez-Jimenez
- University of the Basque Country (UPV/EHU), BioCruces-Bizkaia Health Research Institute, Leioa, Basque Country, Spain
| | - Jose Ramon Bilbao
- University of the Basque Country (UPV/EHU), BioCruces-Bizkaia Health Research Institute, Leioa, Basque Country, Spain.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM) Madrid, Spain
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36
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Immunopathogenesis of HBV Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1179:71-107. [DOI: 10.1007/978-981-13-9151-4_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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37
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Luo H, Wang L, Bao D, Wang L, Zhao H, Lian Y, Yan M, Mohan C, Li QZ. Novel Autoantibodies Related to Cell Death and DNA Repair Pathways in Systemic Lupus Erythematosus. GENOMICS PROTEOMICS & BIOINFORMATICS 2019; 17:248-259. [PMID: 31494269 PMCID: PMC6818352 DOI: 10.1016/j.gpb.2018.11.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 10/16/2018] [Accepted: 12/25/2018] [Indexed: 12/12/2022]
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune syndrome characterized by various co-existing autoantibodies (autoAbs) in patients’ blood. However, the full spectrum of autoAbs in SLE has not been comprehensively elucidated. In this study, a commercial platform bearing 9400 antigens (ProtoArray) was used to identify autoAbs that were significantly elevated in the sera of SLE patients. By comparing the autoAb profiles of SLE patients with those of healthy controls, we identified 437 IgG and 1213 IgM autoAbs that the expression levels were significantly increased in SLE (P < 0.05). Use of the ProtoArray platform uncovered over 300 novel autoAbs targeting a broad range of nuclear, cytoplasmic, and membrane antigens. Molecular interaction network analysis revealed that the antigens targeted by the autoAbs were most significantly enriched in cell death, cell cycle, and DNA repair pathways. A group of autoAbs associated with cell apoptosis and DNA repair function, including those targeting APEX1, AURKA, POLB, AGO1, HMGB1, IFIT5, MAPKAPK3, PADI4, RGS3, SRP19, UBE2S, and VRK1, were further validated by ELISA and Western blot in a larger cohort. In addition, the levels of autoAbs against APEX1, HMGB1, VRK1, AURKA, PADI4, and SRP19 were positively correlated with the level of anti-dsDNA in SLE patients. Comprehensive autoAb screening has identified novel autoAbs, which may shed light on potential pathogenic pathways leading to lupus.
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Affiliation(s)
- Hui Luo
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ling Wang
- Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Nephrology, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China
| | - Ding Bao
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325035, China
| | - Li Wang
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Hongjun Zhao
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yun Lian
- Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Mei Yan
- Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Chandra Mohan
- Department of Biomedical Engineering, University of Houston, Houston, TX 77004, USA
| | - Quan-Zhen Li
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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Zhou L, Ren JH, Cheng ST, Xu HM, Chen WX, Chen DP, Wong VKW, Law BYK, Liu Y, Cai XF, Tang H, Yu HB, Hu JL, Hu Y, Zhou HZ, Ren F, He L, Hu ZW, Jiang H, Xu HY, Huang AL, Chen J. A Functional Variant in Ubiquitin Conjugating Enzyme E2 L3 Contributes to Hepatitis B Virus Infection and Maintains Covalently Closed Circular DNA Stability by Inducing Degradation of Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3A. Hepatology 2019; 69:1885-1902. [PMID: 30614547 DOI: 10.1002/hep.30497] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 12/20/2018] [Indexed: 12/11/2022]
Abstract
Hepatitis B virus (HBV) infection is a common infectious disease, in which nuclear covalently closed circular DNA (cccDNA) plays a key role in viral persistence, viral reactivation after treatment withdrawal, and drug resistance. A recent genome-wide association study has identified that the ubiquitin conjugating enzyme E2 L3 (UBE2L3) gene is associated with increased susceptibility to chronic HBV (CHB) infection in adults. However, the association between UBE2L3 and children with CHB and the underlying mechanism remain unclear. In this study, we performed two-stage case-control studies including adults and independent children in the Chinese Han population. The rs59391722 allele in the promoter of the UBE2L3 gene was significantly associated with HBV infection in both adults and children, and it increased the promoter activity of UBE2L3. Serum UBE2L3 protein levels were positively correlated with HBV viral load and hepatitis B e antigen (HBeAg) levels in children with CHB. In an HBV infection cell model, UBE2L3 knockdown significantly reduced total HBV RNAs, 3.5-kb RNA, as well as cccDNA in HBV-infected HepG2-Na+ /taurocholate cotransporting polypeptide cells and human primary hepatocytes. A mechanistic study found that UBE2L3 maintained cccDNA stability by inducing proteasome-dependent degradation of apolipoprotein B mRNA editing enzyme catalytic subunit 3A, which is responsible for the degradation of HBV cccDNA. Moreover, interferon-α (IFN-α) treatment markedly decreased UBE2L3 expression, while UBE2L3 silencing reinforced the antiviral activity of IFN-α on HBV RNAs, cccDNA, and DNA. rs59391722 in UBE2L3 was correlated with HBV DNA suppression and HBeAg loss in response to IFN-α treatment of children with CHB. Conclusion: These findings highlight a host gene, UBE2L3, contributing to the susceptibility to persistent HBV infection; UBE2L3 may be involved in IFN-mediated viral suppression and serve as a potential target in the prevention and treatment of HBV infection.
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Affiliation(s)
- Li Zhou
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
- Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Ji-Hua Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Sheng-Tao Cheng
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hong-Mei Xu
- Department of Infectious Diseases, The Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Wei-Xian Chen
- Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Da-Peng Chen
- Department of Clinical Laboratory, The Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Vincent Kam Wai Wong
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Betty Yuen Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Yi Liu
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Xue-Fei Cai
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hua Tang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hai-Bo Yu
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Jie-Li Hu
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Yuan Hu
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hong-Zhong Zhou
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Fang Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Lin He
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Zhong-Wen Hu
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hui Jiang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hong-Yan Xu
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Ai-Long Huang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Juan Chen
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
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Wei CJ, Cui P, Li H, Lang WJ, Liu GY, Ma XF. Shared genes between Alzheimer's disease and ischemic stroke. CNS Neurosci Ther 2019; 25:855-864. [PMID: 30859738 PMCID: PMC6630005 DOI: 10.1111/cns.13117] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 02/12/2019] [Accepted: 02/13/2019] [Indexed: 02/06/2023] Open
Abstract
Aims Although converging evidence from experimental and epidemiological studies indicates Alzheimer's disease (AD) and ischemic stroke (IS) are related, the genetic basis underlying their links is less well characterized. Traditional SNP‐based genome‐wide association studies (GWAS) have failed to uncover shared susceptibility variants of AD and IS. Therefore, this study was designed to investigate whether pleiotropic genes existed between AD and IS to account for their phenotypic association, although this was not reported in previous studies. Methods Taking advantage of large‐scale GWAS summary statistics of AD (17,008 AD cases and 37,154 controls) and IS (10,307 IS cases and 19,326 controls), we performed gene‐based analysis implemented in VEGAS2 and Fisher's meta‐analysis of the set of overlapped genes of nominal significance in both diseases. Subsequently, gene expression analysis in AD‐ or IS‐associated expression datasets was conducted to explore the transcriptional alterations of pleiotropic genes identified. Results 16 AD‐IS pleiotropic genes surpassed the cutoff for Bonferroni‐corrected significance. Notably, MS4A4A and TREM2, two established AD‐susceptibility genes showed remarkable alterations in the spleens and brains afflicted by IS, respectively. Among the prioritized genes identified by virtue of literature‐based knowledge, most are immune‐relevant genes (EPHA1, MS4A4A, UBE2L3 and TREM2), implicating crucial roles of the immune system in the pathogenesis of AD and IS. Conclusions The observation that AD and IS had shared disease‐associated genes offered mechanistic insights into their common pathogenesis, predominantly involving the immune system. More importantly, our findings have important implications for future research directions, which are encouraged to verify the involvement of these candidates in AD and IS and interpret the exact molecular mechanisms of action.
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Affiliation(s)
- Chang-Juan Wei
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Neurological Institute, Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China
| | - Pan Cui
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Neurological Institute, Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China
| | - He Li
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Neurological Institute, Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China
| | - Wen-Jing Lang
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Neurological Institute, Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China
| | - Gui-You Liu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Xiao-Feng Ma
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Neurological Institute, Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China
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40
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Zhang Z, Liu D, Zhang X, Wang X. Erythropoietin Treatment Ameliorates Lupus Nephritis of MRL/lpr Mice. Inflammation 2019; 41:1888-1899. [PMID: 29951872 DOI: 10.1007/s10753-018-0832-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
An increasing body of data has shown that erythropoietin (EPO) plays multiple roles in inflammation control and immunoregulation. However, less attention has been given to its effects on lupus nephritis (LN). In this study, we investigated the therapeutic effects of EPO on LN in MRL/lpr mice, a well-studied animal model for lupus. MRL/lpr mice were randomly divided into an EPO and control group. Mice in the EPO group were treated with EPO; saline was given to the control group. Both groups were treated for 10 weeks. We analyzed the differences of general disease condition, histopathologic changes, Th lymphocytes subsets, and the expression of inflammatory factors of mice between the groups. Compared to the control group, mice in the EPO group showed less spleen hyperplasia, less urinary protein, and lower serum anti-dsDNA antibody; they also had lower renal histopathologic scores and less deposition of IgG/C3 within glomeruli. Moreover, Th1 and Th17 levels were decreased, while Th2 and Treg levels were increased in the spleen, and the expression of inflammatory cytokines decreased in both the spleen and kidneys. EPO increased Th2 and Treg lymphocytes, decreased Th1, Th17 lymphocytes in the spleen, and inhibited the inflammatory reactions in both the spleen and kidneys, thus ameliorating LN of MRL/lpr mice.
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Affiliation(s)
- Zeming Zhang
- Department of Rheumatology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning Province, China
| | - Dongmei Liu
- Department of Rheumatology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning Province, China
| | - Xiaoli Zhang
- Department of Rheumatology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning Province, China
| | - Xiaofei Wang
- Department of Rheumatology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning Province, China.
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Abstract
Systemic lupus erythematosus (SLE) is characterized by aberrant production of
auto-antibodies and a sexual dimorphism both in the phenotypic expression and
frequency of the disease between males and females. The striking female
predominance was initially attributed primarily to sex hormones. However, recent
data challenge this simplistic view and point more towards genetic and
epigenetic factors accounting for this difference. More specifically, several
SLE-associated single-nucleotide polymorphisms (SNPs) have been found to play an
important role in the gender predilection in SLE. Their effect is mediated
through their involvement in sex-hormone and immune system signalling and
dysregulation of the expression of genes and miRNAs pertinent to the immune
system. Additionally, the genetic factors are interchangeably associated with
epigenetic modifications such as DNA methylation and histone modification, thus
revealing a highly complex network of responsible mechanisms. Of importance,
disturbance in the epigenetic process of X chromosome inactivation in females as
well as in rare X chromosome abnormalities leads to increased expression of
X-linked immune-related genes and miRNAs, which might predispose females to SLE.
Microbiota dysbiosis has also been implicated in the sexual dimorphism by the
production of oestrogens within the gut and the regulation of
oestrogen-responsive immune-related genes. Sexual dimorphism in SLE is an area
of active research, and elucidation of its molecular basis may facilitate
ongoing efforts towards personalized care.
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Affiliation(s)
- E A A Christou
- 1 Laboratory of Inflammation and Autoimmunity, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - A Banos
- 1 Laboratory of Inflammation and Autoimmunity, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - D Kosmara
- 2 Department of Rheumatology, Clinical Immunology and Allergy, University of Crete School of Medicine, Heraklion, Greece.,3 Laboratory of Autoimmunity and Inflammation, Institute of Molecular Biology and Biotechnology, Foundation for Research & Technology - Hellas (FORTH), Heraklion, Greece
| | - G K Bertsias
- 2 Department of Rheumatology, Clinical Immunology and Allergy, University of Crete School of Medicine, Heraklion, Greece.,3 Laboratory of Autoimmunity and Inflammation, Institute of Molecular Biology and Biotechnology, Foundation for Research & Technology - Hellas (FORTH), Heraklion, Greece
| | - D T Boumpas
- 1 Laboratory of Inflammation and Autoimmunity, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,4 Joint Rheumatology Program, 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.,5 Rheumatology-Clinical immunology Unit, Medical School, University of Cyprus, Nicosia, Cyprus
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42
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Liu Y, Song C, Ni H, Jiao W, Gan W, Dong X, Liu J, Zhu L, Zhai X, Hu Z, Li J. UBE2L3, a susceptibility gene that plays oncogenic role in hepatitis B-related hepatocellular carcinoma. J Viral Hepat 2018; 25:1363-1371. [PMID: 29969176 DOI: 10.1111/jvh.12963] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 06/11/2018] [Indexed: 12/22/2022]
Abstract
Previously, we identified UBE2L3 as a susceptibility gene for chronic hepatitis B virus (HBV) infection through genome-wide association study. Here, we analysed the association between genetic variants of UBE2L3 and the susceptibility to HBV-related hepatocellular carcinoma (HCC) and further explored its role in HCC. This case-control study included 1344 subjects who cleared HBV, 1560 HBV carriers and 1057 HBV-related HCC patients. Two single nucleotide polymorphisms (SNPs) were genotyped, including rs2266959 and rs4821116. Logistic regression analysis was performed to compute the odds ratio (OR) and 95% confidence interval (CI). We further analysed the expression of UBE2L3 and its association with pathological features based on The Cancer Genome Atlas (TCGA) data and our tissue microarray. Proliferation and migration assays were performed in hepatoma cell lines with or without UBE2L3 knockdown. Further RNA-seq analysis was performed to explore the underlying oncogenic mechanism. The variant genotypes of rs4821116 in UBE2L3 were associated with decreased risk for HCC and chronic HBV infection. Moreover, based on both TCGA and our tissue microarray data, higher levels of UBE2L3 expression were correlated with higher tumour grade, advanced tumour stage and poor survival. In vitro analysis revealed that UBE2L3 may promote hepatocyte proliferation and migration. RNA-seq analysis showed that UBE2L3 was inversely correlated with CDKN2B, a negative regulator of cell cycle, and CLDN1, loss of which may promote cancer metastasis. In conclusion, UBE2L3 may also be a susceptibility gene in HBV-related HCC, and it may promote HCC proliferation and migration by negatively regulating CDKN2B and CLDN1.
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Affiliation(s)
- Yao Liu
- Department of Pathology, Medical College of Soochow University, Suzhou, China
| | - Ci Song
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hengli Ni
- Department of Pathology, Medical College of Soochow University, Suzhou, China
| | - Weijuan Jiao
- Department of Pathology, Medical College of Soochow University, Suzhou, China
| | - Wenjuan Gan
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaoqiang Dong
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jibin Liu
- Department of Hepatobiliary Surgery, Nantong Tumor Hospital, Nantong, China
| | - Liguo Zhu
- Department of Infection Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China
| | - Xiangjun Zhai
- Department of Infection Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jianming Li
- Department of Pathology, Medical College of Soochow University, Suzhou, China
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43
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Akcay IM, Katrinli S, Ozdil K, Doganay GD, Doganay L. Host genetic factors affecting hepatitis B infection outcomes: Insights from genome-wide association studies. World J Gastroenterol 2018; 24:3347-3360. [PMID: 30122875 PMCID: PMC6092584 DOI: 10.3748/wjg.v24.i30.3347] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 05/29/2018] [Accepted: 06/25/2018] [Indexed: 02/06/2023] Open
Abstract
The clinical outcome of hepatitis B virus (HBV) infection depends on the success or failure of the immune responses to HBV, and varies widely among individuals, ranging from asymptomatic self-limited infection, inactive carrier state, chronic hepatitis, cirrhosis, hepatocellular carcinoma, to liver failure, depending on the success or failure of immune response to HBV. Genome-wide association studies (GWAS) identified key genetic factors influencing the pathogenesis of HBV-related traits. In this review, we discuss GWAS for persistence of HBV infection, antibody response to hepatitis B vaccine, and HBV-related advanced liver diseases. HBV persistence is associated with multiple genes with diverse roles in immune mechanisms. The strongest associations are found within the classical human leukocyte antigen (HLA) genes, highlighting the central role of antigen presentation in the immune response to HBV. Associated variants affect both epitope binding specificities and expression levels of HLA molecules. Several other susceptibility genes regulate the magnitude of adaptive immune responses, determining immunity vs tolerance. HBV persistence and nonresponse to vaccine share the same risk variants, implying overlapping genetic bases. On the other hand, the risk variants for HBV-related advanced liver diseases are largely different, suggesting different host-virus dynamics in acute vs chronic HBV infections. The findings of these GWAS are likely to pave the way for developing more effective preventive and therapeutic interventions by personalizing the management of HBV infection.
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Affiliation(s)
- Izzet Mehmet Akcay
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Seyma Katrinli
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Kamil Ozdil
- Department of Gastroenterology and Hepatology, Umraniye Teaching and Research Hospital, Istanbul 34764, Turkey
| | - Gizem Dinler Doganay
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Levent Doganay
- Department of Gastroenterology and Hepatology, Umraniye Teaching and Research Hospital, Istanbul 34764, Turkey
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44
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Liefferinckx C, Franchimont D. Viewpoint: Toward the Genetic Architecture of Disease Severity in Inflammatory Bowel Diseases. Inflamm Bowel Dis 2018; 24:1428-1439. [PMID: 29788122 DOI: 10.1093/ibd/izy109] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is characterized by uneven disease courses with various clinical outcomes. A few prognostic markers of disease severity may help stratify patients and identify those who will benefit the most from early aggressive treatment. The concept of disease severity remains too broad and vague, mainly because the definition must embrace several disease mechanisms, mainly inflammation and fibrosis, with various rates of disease progression. The magnitude of inflammation is an obvious key driver of disease severity in IBD that ultimately influence disease behavior. Advances in the genetics underlying disease severity are currently emerging, but attempts to overlap the genetics of disease susceptibility and severity have until now been unsatisfactory, suggesting that the genetic architecture of disease severity may be distinct from the genetics of disease susceptibility. In this review, we report on the current knowledge on disease severity and on the main research venues to decipher the genetic architecture of disease severity.
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Affiliation(s)
| | - Denis Franchimont
- Department of Gastroenterology, Erasme Hospital, ULB, Brussels, Belgium
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45
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Walden H, Rittinger K. RBR ligase-mediated ubiquitin transfer: a tale with many twists and turns. Nat Struct Mol Biol 2018; 25:440-445. [PMID: 29735995 DOI: 10.1038/s41594-018-0063-3] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 03/29/2018] [Indexed: 12/28/2022]
Abstract
RBR ligases are an enigmatic class of E3 ubiquitin ligases that combine properties of RING and HECT-type E3s and undergo multilevel regulation through autoinhibition, post-translational modifications, multimerization and interaction with binding partners. Here, we summarize recent progress in RBR structures and function, which has uncovered commonalities in the mechanisms by which different family members transfer ubiquitin through a multistep process. However, these studies have also highlighted clear differences in the activity of different family members, suggesting that each RBR ligase has evolved specific properties to fit the biological process it regulates.
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Affiliation(s)
- Helen Walden
- Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow, Scotland, UK.
| | - Katrin Rittinger
- Molecular Structure of Cell Signalling Laboratory, The Francis Crick Institute, London, UK.
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46
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Mishra R, Upadhyay A, Prajapati VK, Mishra A. Proteasome-mediated proteostasis: Novel medicinal and pharmacological strategies for diseases. Med Res Rev 2018; 38:1916-1973. [DOI: 10.1002/med.21502] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 03/13/2018] [Accepted: 04/04/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Ribhav Mishra
- Cellular and Molecular Neurobiology Unit; Indian Institute of Technology Jodhpur; Rajasthan India
| | - Arun Upadhyay
- Cellular and Molecular Neurobiology Unit; Indian Institute of Technology Jodhpur; Rajasthan India
| | - Vijay Kumar Prajapati
- Department of Biochemistry; School of Life Sciences; Central University of Rajasthan; Rajasthan India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit; Indian Institute of Technology Jodhpur; Rajasthan India
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47
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Sharma A, Liu X, Hadley D, Hagopian W, Chen WM, Onengut-Gumuscu S, Törn C, Steck AK, Frohnert BI, Rewers M, Ziegler AG, Lernmark Å, Toppari J, Krischer JP, Akolkar B, Rich SS, She JX. Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort. J Autoimmun 2018; 89:90-100. [PMID: 29310926 PMCID: PMC5902429 DOI: 10.1016/j.jaut.2017.12.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 12/05/2017] [Accepted: 12/06/2017] [Indexed: 12/28/2022]
Abstract
Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip. Cox proportional hazards analyses were performed to discover the SNPs associated with the risk for IA, T1D, or both. Three regions were associated with the risk of developing any persistent confirmed islet autoantibody: one known region near SH2B3 (HR = 1.35, p = 3.58 × 10-7) with Bonferroni-corrected significance and another known region near PTPN22 (HR = 1.46, p = 2.17 × 10-6) and one novel region near PPIL2 (HR = 2.47, p = 9.64 × 10-7) with suggestive evidence (p < 10-5). Two known regions (PTPN22: p = 2.25 × 10-6, INS; p = 1.32 × 10-7) and one novel region (PXK/PDHB: p = 8.99 × 10-6) were associated with the risk for multiple islet autoantibodies. First appearing islet autoantibodies differ with respect to association. Two regions (INS: p = 5.67 × 10-6 and TTC34/PRDM16: 6.45 × 10-6) were associated if the fist appearing autoantibody was IAA and one region (RBFOX1: p = 8.02 × 10-6) was associated if the first appearing autoantibody was GADA. The analysis of T1D identified one region already known to be associated with T1D (INS: p = 3.13 × 10-7) and three novel regions (RNASET2, PLEKHA1, and PPIL2; 5.42 × 10-6 > p > 2.31 × 10-6). These results suggest that a number of low frequency variants influence the risk of developing IA and/or T1D and these variants can be identified by large prospective cohort studies using a survival analysis approach.
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Affiliation(s)
- Ashok Sharma
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA; Division of Biostatistics and Data Science, Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Xiang Liu
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - David Hadley
- Division of Population Health Sciences and Education, St George's University of London, London, United Kingdom
| | | | - Wei-Min Chen
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Suna Onengut-Gumuscu
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Carina Törn
- Department of Clinical Sciences, Lund University/CRC, Malmö, Sweden
| | - Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, Aurora, CO, USA
| | - Brigitte I Frohnert
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, Aurora, CO, USA
| | - Marian Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, Aurora, CO, USA
| | - Anette-G Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, Munich-Neuherberg, Germany; Klinikum rechts der Isar, Technische Universität München, Munich-Neuherberg, Germany; Forschergruppe Diabetes e.V., Munich-Neuherberg, Germany
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University/CRC, Malmö, Sweden
| | - Jorma Toppari
- Department of Pediatrics, Turku University Hospital, Turku, Finland
| | - Jeffrey P Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Beena Akolkar
- National Institutes of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, MD, USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Jin-Xiong She
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.
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48
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de Almeida RC, Chagas VS, Castro MAA, Petzl-Erler ML. Integrative Analysis Identifies Genetic Variants Associated With Autoimmune Diseases Affecting Putative MicroRNA Binding Sites. Front Genet 2018; 9:139. [PMID: 29755505 PMCID: PMC5932181 DOI: 10.3389/fgene.2018.00139] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 04/04/2018] [Indexed: 12/20/2022] Open
Abstract
Genome-wide and fine mapping studies have shown that more than 90% of genetic variants associated with autoimmune diseases (AID) are located in non-coding regions of the human genome and especially in regulatory sequences, including microRNAs (miRNA) target sites. MiRNAs are small endogenous noncoding RNAs that modulate gene expression at the post-transcriptional level. Single nucleotide polymorphisms (SNPs) located within the 3' untranslated region of their target mRNAs (miRSNP) can alter miRNA binding sites. Yet, little is known about their effect on regulation by miRNA and the consequences for AID. Conversely, it is well known that two or more AID may share part of their genetic background. Here, we hypothesized that miRSNPs could be associated with more than one AID. To identify miRSNPs associated with AID, we integrated results from three different prediction tools (Polymirts, miRSNP, and miRSNPscore) using a naïve Bayes classifier approach to identify miRSNPs predicted to affect binding sites of miRNAs. Further, to detect miRSNPs associated with two or more AID, we integrated predictions with summary statistics from 12 AID studies. In addition, to prioritize miRSNPs, miRNAs and AID-associated target genes, we used public expression quantitative trait locus (eQTL) data and mRNA-seq and small RNA-seq data. We identified 34 miRNSPs associated with at least two AID. Furthermore, we found 86 miRNAs predicted to target 18 of the associated gene's mRNAs. Our integrative approach revealed new insights into miRNAs and AID associated target genes. Thus, it helped to prioritize AID noncoding risk SNPs that might be involved in the causal mechanisms, providing valuable information for further functional studies.
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Affiliation(s)
- Rodrigo C. de Almeida
- Human Molecular Genetics Laboratory, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands
| | - Vinícius S. Chagas
- Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, Curitiba, Brazil
| | - Mauro A. A. Castro
- Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, Curitiba, Brazil
| | - Maria L. Petzl-Erler
- Human Molecular Genetics Laboratory, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
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49
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Laufer VA, Chen JY, Langefeld CD, Bridges SL. Integrative Approaches to Understanding the Pathogenic Role of Genetic Variation in Rheumatic Diseases. Rheum Dis Clin North Am 2018; 43:449-466. [PMID: 28711145 DOI: 10.1016/j.rdc.2017.04.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The use of high-throughput omics may help to understand the contribution of genetic variants to the pathogenesis of rheumatic diseases. We discuss the concept of missing heritability: that genetic variants do not explain the heritability of rheumatoid arthritis and related rheumatologic conditions. In addition to an overview of how integrative data analysis can lead to novel insights into mechanisms of rheumatic diseases, we describe statistical approaches to prioritizing genetic variants for future functional analyses. We illustrate how analyses of large datasets provide hope for improved approaches to the diagnosis, treatment, and prevention of rheumatic diseases.
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Affiliation(s)
- Vincent A Laufer
- Division of Clinical Immunology and Rheumatology, School of Medicine, University of Alabama at Birmingham, 1720 2nd Avenue South, SHEL 236, Birmingham, AL 35294-2182, USA
| | - Jake Y Chen
- The Informatics Institute, School of Medicine, University of Alabama at Birmingham, 1720 2nd Avenue South, THT 137, Birmingham, AL 35294-0006, USA
| | - Carl D Langefeld
- Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; Public Health Genomics, Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA
| | - S Louis Bridges
- Division of Clinical Immunology and Rheumatology, School of Medicine, University of Alabama at Birmingham, 1720 2nd Avenue South, SHEL 178, Birmingham, AL 35294-2182, USA.
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50
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Courtois G, Fauvarque MO. The Many Roles of Ubiquitin in NF-κB Signaling. Biomedicines 2018; 6:E43. [PMID: 29642643 PMCID: PMC6027159 DOI: 10.3390/biomedicines6020043] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 03/31/2018] [Accepted: 04/02/2018] [Indexed: 12/24/2022] Open
Abstract
The nuclear factor κB (NF-κB) signaling pathway ubiquitously controls cell growth and survival in basic conditions as well as rapid resetting of cellular functions following environment changes or pathogenic insults. Moreover, its deregulation is frequently observed during cell transformation, chronic inflammation or autoimmunity. Understanding how it is properly regulated therefore is a prerequisite to managing these adverse situations. Over the last years evidence has accumulated showing that ubiquitination is a key process in NF-κB activation and its resolution. Here, we examine the various functions of ubiquitin in NF-κB signaling and more specifically, how it controls signal transduction at the molecular level and impacts in vivo on NF-κB regulated cellular processes.
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