title: UBE2L3 polymorphism amplifies NF-κB activation and promotes plasma cell development, linking linear ubiquitination to multiple autoimmune diseases.
abstract: UBE2L3 is associated with increased susceptibility to numerous autoimmune diseases, but the underlying mechanism is unexplained. By using data from a genome-wide association study of systemic lupus erythematosus (SLE), we observed a single risk haplotype spanning UBE2L3, consistently aligned across multiple autoimmune diseases, associated with increased UBE2L3 expression in B cells and monocytes. rs140490 in the UBE2L3 promoter region showed the strongest association. UBE2L3 is an E2 ubiquitin-conjugating enzyme, specially adapted to function with HECT and RING-in-between-RING (RBR) E3 ligases, including HOIL-1 and HOIP, components of the linear ubiquitin chain assembly complex (LUBAC). Our data demonstrate that UBE2L3 is the preferred E2 conjugating enzyme for LUBAC in vivo, and UBE2L3 is essential for LUBAC-mediated activation of NF-κB. By accurately quantifying NF-κB translocation in primary human cells from healthy individuals stratified by rs140490 genotype, we observed that the autoimmune disease risk UBE2L3 genotype was correlated with basal NF-κB activation in unstimulated B cells and monocytes and regulated the sensitivity of NF-κB to CD40 stimulation in B cells and TNF stimulation in monocytes. The UBE2L3 risk allele correlated with increased circulating plasmablast and plasma cell numbers in SLE individuals, consistent with substantially elevated UBE2L3 protein levels in plasmablasts and plasma cells. These results identify key immunological consequences of the UBE2L3 autoimmune risk haplotype and highlight an important role for UBE2L3 in plasmablast and plasma cell development.
authors: Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK. Electronic address: myles.lewis@qmul.ac.uk.
authors: Myles J
authors: MJ
authors: Lewis
authors: Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK.
authors: Simon
authors: S
authors: Vyse
authors: Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK.
authors: Adrian M
authors: AM
authors: Shields
authors: Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK.
authors: Sebastian
authors: S
authors: Boeltz
authors: Rheumatology Department, King's College Hospital, London SE5 9RS, UK.
authors: Patrick A
authors: PA
authors: Gordon
authors: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 9RT, UK.
authors: Timothy D
authors: TD
authors: Spector
authors: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors: Paul J
authors: PJ
authors: Lehner
authors: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors: Henning
authors: H
authors: Walczak
authors: Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK. Electronic address: tim.vyse@kcl.ac.uk.
authors: Timothy J
authors: TJ
authors: Vyse
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008156:Luciferases; D046228:Microarray Analysis; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D017931:DNA Primers; D016328:NF-kappa B; D034741:RNA, Small Interfering; D008156:Luciferases; C079437:UBE2L3 protein, human; D044763:Ubiquitin-Conjugating Enzymes
references: Nature. 2014 Feb 20;506(7488):376-81
references: 24390342
references: Nat Genet. 2013 Dec;45(12):1499-503
references: 24162738
references: Genes Cells. 2014 Mar;19(3):254-72
references: 24461064
references: Science. 2014 May 2;344(6183):519-23
references: 24786080
references: Cell. 1995 Jan 27;80(2):321-30
references: 7834752
references: J Exp Med. 1997 Mar 3;185(5):953-61
references: 9120401
references: EMBO J. 2006 Oct 18;25(20):4877-87
references: 17006537
references: Cancer Cell. 2007 Aug;12(2):115-30
references: 17692804
references: Nat Genet. 2007 Oct;39(10):1217-24
references: 17873874
references: Nat Genet. 2008 Feb;40(2):204-10
references: 18204446
references: Nat Cell Biol. 2009 Feb;11(2):123-32
references: 19136968
references: Trends Biochem Sci. 2009 Mar;34(3):128-35
references: 19233657
references: Trends Immunol. 2009 Aug;30(8):383-91
references: 19643665
references: Nat Rev Mol Cell Biol. 2009 Nov;10(11):755-64
references: 19851334
references: Nat Genet. 2009 Nov;41(11):1234-7
references: 19838193
references: Nat Genet. 2009 Nov;41(11):1228-33
references: 19838195
references: Mol Cell. 2009 Dec 11;36(5):831-44
references: 20005846
references: Nat Genet. 2010 Apr;42(4):295-302
references: 20190752
references: Nat Genet. 2010 Jun;42(6):508-14
references: 20453842
references: Nature. 2010 Aug 19;466(7309):941-6
references: 20725033
references: Nat Genet. 2010 Dec;42(12):1118-25
references: 21102463
references: Nat Genet. 2011 Mar;43(3):253-8
references: 21336280
references: Nature. 2011 Mar 31;471(7340):591-6
references: 21455173
references: Nature. 2011 Mar 31;471(7340):633-6
references: 21455180
references: Nature. 2011 Mar 31;471(7340):637-41
references: 21455181
references: Nature. 2011 Jun 2;474(7349):105-8
references: 21532592
references: PLoS One. 2011;6(8):e23061
references: 21829693
references: Nat Genet. 2012 May;44(5):502-10
references: 22446964
references: Cell. 2000 Aug 18;102(4):533-9
references: 10966114
references: J Exp Med. 2000 Oct 16;192(8):1175-82
references: 11034607
references: J Immunol. 2000 Nov 15;165(10):5970-9
references: 11067960
references: Genes Immun. 2012 Jul;13(5):380-7
references: 22476155
references: Mol Cell Proteomics. 2012 Aug;11(8):329-41
references: 22496338
references: EMBO Rep. 2012 Sep;13(9):840-6
references: 22791023
references: EMBO J. 2012 Oct 3;31(19):3845-55
references: 23032186
references: EMBO J. 2012 Oct 3;31(19):3856-70
references: 23032187
references: EMBO J. 2012 Oct 3;31(19):3833-44
references: 22863777
references: Nature. 2012 Nov 1;491(7422):119-24
references: 23128233
references: Nat Immunol. 2012 Dec;13(12):1178-86
references: 23104095
references: Nat Genet. 2012 Dec;44(12):1341-8
references: 23143594
references: Nat Genet. 2013 Jun;45(6):664-9
references: 23603761
references: Cell. 2013 Jun 6;153(6):1312-26
references: 23746843
references: EMBO J. 2013 Sep 11;32(18):2463-76
references: 23942237
references: Cell Res. 2014 Mar;24(3):376-9
references: 24060851