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

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, b...

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Published in:Journal of autoimmunity 2023-04, Vol.136, p.103023-103023, Article 103023
Main Authors: Mauro, Daniele, Manou-Stathopoulou, Sotiria, Rivellese, Felice, Sciacca, Elisabetta, Goldmann, Katriona, Tsang, Victoria, Lucey-Clayton, Isabelle, Pagani, Sara, Alam, Farah, Pyne, Debasish, Rajakariar, Ravindra, Gordon, Patrick A., Whiteford, James, Bombardieri, Michele, Pitzalis, Costantino, Lewis, Myles J.
Format: Article
Language:English
Subjects:
Autoantibodies
Autoimmunity
B-cells
Humans
Interferons
Lupus Erythematosus, Systemic
NF-kappa B
Systemic lupus erythematosus
TLR7
Toll-Like Receptor 7 - genetics
UBE2L3
Ubiquitin-Conjugating Enzymes
Ubiquitination
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Summary: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. [Display omitted] •Linear Ubiquitination is activated following TLR7.•UBE2L3 mediates NF-κB activation following TLR7 stimulation.•UBE2L3 is necessary for NF-κB activation and autoreactive plasmablast development.•UBE2L3 is inhibited by dimethyl fumarate (DMF).•DMF suppresses plasma cell differentiation and alters the transcriptional programmes.
ISSN:0896-8411
1095-9157
DOI:10.1016/j.jaut.2023.103023