UBE2L3 Polymorphism Amplifies NF-κB Activation and Promotes Plasma Cell Development, Linking Linear Ubiquitination to Multiple Autoimmune Diseases

Myles J Lewis,Simon Vyse,Adrian M Shields,Sebastian Boeltz,Patrick A Gordon,Timothy D Spector,Paul J Lehner,Henning Walczak,Timothy J Vyse

doi:10.1016/j.ajhg.2014.12.024

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.

Highlights

UBE2L3 is strongly associated with systemic lupus erythematosus (SLE) in genome-wide association studies and other genetic studies,[1,2,3,4] as well as multiple autoimmune diseases (Table S1).[5,6,7,8,9,10,11] UBE2L3 is an E2 ubiquitin-conjugating enzyme, known as UbcH7
Haplotype analysis shows that the UBE2L3 locus has an unusually simple structure, with two haplotypes covering the majority of genetic variation and extending across the full length of the gene
A single haplotype block is associated with SLE in our own data and the same risk haplotype is associated with multiple other autoimmune diseases (Figure S1)

Summary

Introduction

UBE2L3 is strongly associated with systemic lupus erythematosus (SLE) in genome-wide association studies and other genetic studies,[1,2,3,4] as well as multiple autoimmune diseases (Table S1).[5,6,7,8,9,10,11] UBE2L3 is an E2 ubiquitin-conjugating enzyme, known as UbcH7. Presence of HOIP in B cells was necessary for CD40 signaling,[23] and reduced immunoglobulin levels and impaired peritoneal B-1 cell development were observed in mice with conditional HOIP deficiency in B cells.[24] HOIL-1 and HOIP are both RBR E3 ligases, so we hypothesized that UBE2L3 would. In this study we set out to investigate the relative importance of UBE2L3 to LUBAC function in vivo

Subjects and Methods

Results

Findings

Discussion