UBE2L3 regulates TLR7-induced B cell autoreactivity in Systemic Lupus Erythematosus

J Autoimmun. 2023 Apr:136:103023. doi: 10.1016/j.jaut.2023.103023. Epub 2023 Mar 29.

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.

Keywords: Autoimmunity; B-cells; Systemic lupus erythematosus; TLR7; UBE2L3; Ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies
  • Humans
  • Interferons
  • Lupus Erythematosus, Systemic*
  • NF-kappa B
  • Toll-Like Receptor 7* / genetics
  • Ubiquitin-Conjugating Enzymes

Substances

  • Toll-Like Receptor 7
  • NF-kappa B
  • Autoantibodies
  • Interferons
  • UBE2L3 protein, human
  • Ubiquitin-Conjugating Enzymes
  • TLR7 protein, human