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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2020

01-12-2020 | Systemic Lupus Erythematosus | Research article

Synergistic activation of NF-κB by TNFAIP3 (A20) reduction and UBE2L3 (UBCH7) augment that synergistically elevate lupus risk

Authors: Taehyeung Kim, Sang-Cheol Bae, Changwon Kang

Published in: Arthritis Research & Therapy | Issue 1/2020

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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.
Literature
1.
Lawrence JS, Martins CL, Drake GL. A family survey of lupus erythematosus. 1. Heritability. J Rheumatol. 1987;14:913–21.PubMed
2.
Wang J, Yang S, Chen JJ, Zhou SM, He SM, Liang YH, et al. Systemic lupus erythematosus: a genetic epidemiology study of 695 patients from China. Arch Dermatol Res. 2007;298:485–91.PubMedCrossRef
3.
Sun C, Molineros JE, Looger LL, Zhou XJ, Kim K, Okada Y, et al. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat Genet. 2016;48:323–30.PubMedPubMedCentralCrossRef
4.
5.
6.
Zuo XB, Sheng YJ, Hu SJ, Gao JP, Li Y, Tang HY, et al. Variants in TNFSF4, TNFAIP3, TNIP1, BLK, SLC15A4 and UBE2L3 interact to confer risk of systemic lupus erythematosus in Chinese population. Rheumatol Int. 2014;34:459–64.PubMedCrossRef
7.
Lewis MJ, Vyse S, Shields AM, Boeltz S, Gordon PA, Spector TD, et al. UBE2L3 polymorphism amplifies NF-kappaB activation and promotes plasma cell development, linking linear ubiquitination to multiple autoimmune diseases. Am J Hum Genet. 2015;96:221–34.PubMedPubMedCentralCrossRef
8.
Parkes M, Cortes A, van Heel DA, Brown MA. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet. 2013;14:661–73.PubMedCrossRef
9.
Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature. 2004;430:694–9.PubMedCrossRef
10.
Bosanac I, Wertz IE, Pan B, Yu C, Kusam S, Lam C, et al. Ubiquitin binding to A20 ZnF4 is required for modulation of NF-kappaB signaling. Mol Cell. 2010;40:548–57.PubMedCrossRef
11.
12.
Tokunaga F, Nishimasu H, Ishitani R, Goto E, Noguchi T, Mio K, et al. Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-kappaB regulation. EMBO J. 2012;31:3856–70.PubMedPubMedCentralCrossRef
13.
Verhelst K, Carpentier I, Kreike M, Meloni L, Verstrepen L, Kensche T, et al. A20 inhibits LUBAC-mediated NF-kappaB activation by binding linear polyubiquitin chains via its zinc finger 7. EMBO J. 2012;31:3845–55.PubMedPubMedCentralCrossRef
14.
15.
16.
Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011;471:591–6.PubMedCrossRef
17.
Fu B, Li S, Wang L, Berman MA, Dorf ME. The ubiquitin conjugating enzyme UBE2L3 regulates TNFalpha-induced linear ubiquitination. Cell Res. 2014;24:376–9.PubMedCrossRef
18.
Kim J, Yum S, Kang C, Kang SJ. Gene-gene interactions in gastrointestinal cancer susceptibility. Oncotarget. 2016;7:67612–25.PubMedPubMedCentral
19.
Lee HS, Kim T, Bang SY, Na YJ, Kim I, Kim K, et al. Ethnic specificity of lupus-associated loci identified in a genome-wide association study in Korean women. Ann Rheum Dis. 2014;73:1240–5.PubMedCrossRef
20.
Kim K, Cho SK, Han TU, Kim JH, Kang SJ, Kang C, et al. A redundant epistatic interaction between IRF5 and STAT4 of the type I interferon pathway in susceptibility to lupus and rheumatoid arthritis. Lupus. 2013;22:1336–40.PubMedCrossRef
21.
Han TU, Lee HS, Kang C, Bae SC. Association of joint erosion with SLC22A4 gene polymorphisms inconsistently associated with rheumatoid arthritis susceptibility. Autoimmunity. 2015;48:313–7.PubMedCrossRef
22.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.PubMedPubMedCentralCrossRef
23.
Kim K, Brown EE, Choi CB, Alarcon-Riquelme ME, Biolupus, Kelly JA, et al. Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries. Ann Rheum Dis. 2012;71:1809–14.PubMedCrossRef
24.
Kim K, Bang SY, Joo YB, Kim T, Lee HS, Kang C, et al. Response to intravenous cyclophosphamide treatment for lupus nephritis associated with polymorphisms in the FCGR2B-FCRLA locus. J Rheumatol. 2016;43:1045–9.PubMedCrossRef
25.
Han TU, Cho SK, Kim T, Joo YB, Bae SC, Kang C. Association of an activity-enhancing variant of IRAK1 and an MECP2-IRAK1 haplotype with increased susceptibility to rheumatoid arthritis. Arthritis Rheum. 2013;65:590–8.PubMedCrossRef
26.
VanderWeele TJ, Knol MJ. A tutorial on interaction. Epidemiol Methods. 2014;3:33–72.
27.
Rothman KJ. Epidemiology: an introduction. 2nd ed. New York: Oxford University Press; 2012.
28.
Kim K. Massive false-positive gene-gene interactions by Rothman’s additive model. Ann Rheum Dis. 2019;78:437–9.PubMedCrossRef
29.
Nabokina SM, Inoue K, Subramanian VS, Valle JE, Yuasa H, Said HM. Molecular identification and functional characterization of the human colonic thiamine pyrophosphate transporter. J Biol Chem. 2014;289:4405–16.PubMedCrossRef
30.
31.
Choi KC, Lee YH, Jung MG, Kwon SH, Kim MJ, Jun WJ, et al. Gallic acid suppresses lipopolysaccharide-induced nuclear factor-kappaB signaling by preventing RelA acetylation in A549 lung cancer cells. Mol Cancer Res. 2009;7:2011–21.PubMedCrossRef
32.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−delta delta C(T)) method. Methods. 2001;25:402–8.PubMedCrossRef
33.
Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009;41:1234–7.PubMedCrossRef
34.
Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX, et al. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 2010;6:e1000841.PubMedPubMedCentralCrossRef
35.
Freudenberg J, Lee HS, Han BG, Shin HD, Kang YM, Sung YK, et al. Genome-wide association study of rheumatoid arthritis in Koreans: population-specific loci as well as overlap with European susceptibility loci. Arthritis Rheum. 2011;63:884–93.PubMedCrossRef
36.
Stranger BE, Montgomery SB, Dimas AS, Parts L, Stegle O, Ingle CE, et al. Patterns of cis regulatory variation in diverse human populations. PLoS Genet. 2012;8:e1002639.PubMedPubMedCentralCrossRef
37.
38.
Fagny M, Paulson JN, Kuijjer ML, Sonawane AR, Chen CY, Lopes-Ramos CM, et al. Exploring regulation in tissues with eQTL networks. Proc Natl Acad Sci U S A. 2017;114:E7841–E50.PubMedPubMedCentralCrossRef
39.
Consortium GT. The genotype-tissue expression (GTEx) project. Nat Genet. 2013;45:580–5.CrossRef
40.
Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell. 2009;36:831–44.PubMedCrossRef
41.
Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S, et al. SHARPIN is a component of the NF-kappaB-activating linear ubiquitin chain assembly complex. Nature. 2011;471:633–6.PubMedCrossRef
42.
43.
Hitotsumatsu O, Ahmad RC, Tavares R, Wang M, Philpott D, Turer EE, et al. The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity. 2008;28:381–90.PubMedPubMedCentralCrossRef
44.
Damgaard RB, Nachbur U, Yabal M, Wong WW, Fiil BK, Kastirr M, et al. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol Cell. 2012;46:746–58.PubMedCrossRef
45.
46.
Inn KS, Gack MU, Tokunaga F, Shi M, Wong LY, Iwai K, et al. Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type I interferon induction. Mol Cell. 2011;41:354–65.PubMedPubMedCentralCrossRef
47.
48.
49.
50.
51.
52.
Sasaki Y, Derudder E, Hobeika E, Pelanda R, Reth M, Rajewsky K, et al. Canonical NF-kappaB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation. Immunity. 2006;24:729–39.PubMedCrossRef
53.
54.
Chuang HC, Lan JL, Chen DY, Yang CY, Chen YM, Li JP, et al. The kinase GLK controls autoimmunity and NF-kappaB signaling by activating the kinase PKC-theta in T cells. Nat Immunol. 2011;12:1113–8.PubMedCrossRef
55.
Kalergis AM, Iruretagoyena MI, Barrientos MJ, Gonzalez PA, Herrada AA, Leiva ED, et al. Modulation of nuclear factor-kappaB activity can influence the susceptibility to systemic lupus erythematosus. Immunology. 2009;128:e306–14.PubMedPubMedCentralCrossRef
56.
Chu Y, Vahl JC, Kumar D, Heger K, Bertossi A, Wojtowicz E, et al. B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood. 2011;117:2227–36.PubMedCrossRef
57.
Hovelmeyer N, Reissig S, Xuan NT, Adams-Quack P, Lukas D, Nikolaev A, et al. A20 deficiency in B cells enhances B-cell proliferation and results in the development of autoantibodies. Eur J Immunol. 2011;41:595–601.PubMedCrossRef
58.
Tavares RM, Turer EE, Liu CL, Advincula R, Scapini P, Rhee L, et al. The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity. 2010;33:181–91.56.PubMedPubMedCentralCrossRef
59.
Adrianto I, Wen F, Templeton A, Wiley G, King JB, Lessard CJ, et al. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nat Genet. 2011;43:253–8.PubMedPubMedCentralCrossRef
60.
Wang S, Wen F, Wiley GB, Kinter MT, Gaffney PM. An enhancer element harboring variants associated with systemic lupus erythematosus engages the TNFAIP3 promoter to influence A20 expression. PLoS Genet. 2013;9:e1003750.PubMedPubMedCentralCrossRef
61.
Wang S, Wen F, Tessneer KL, Gaffney PM. TALEN-mediated enhancer knockout influences TNFAIP3 gene expression and mimics a molecular phenotype associated with systemic lupus erythematosus. Genes Immun. 2016;17(3):165–70.PubMedPubMedCentralCrossRef
62.
Wang S, Adrianto I, Wiley GB, Lessard CJ, Kelly JA, Adler AJ, et al. A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. Genes Immun. 2012;13:380–7.PubMedPubMedCentralCrossRef
Metadata
Title
Synergistic activation of NF-κB by TNFAIP3 (A20) reduction and UBE2L3 (UBCH7) augment that synergistically elevate lupus risk
Authors
Taehyeung Kim
Sang-Cheol Bae
Changwon Kang
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2020
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-020-02181-4

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