Loss of function of XBP1 splicing activity of IRE1α favors B cell tolerance breakdown

J Autoimmun. 2024 Jan:142:103152. doi: 10.1016/j.jaut.2023.103152. Epub 2023 Dec 9.

Abstract

Anti-nuclear antibodies are the hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and scleroderma. However, the molecular mechanisms of B cell tolerance breakdown in these pathological contexts are poorly known. The study of rare familial forms of autoimmune diseases could therefore help to better describe common biological mechanisms leading to B cell tolerance breakdown. By Whole-Exome Sequencing, we identified a new heterozygous mutation (p.R594C) in ERN1 gene, encoding IRE1α (Inositol-Requiring Enzyme 1α), in a multiplex family with several members presenting autoantibody-mediated autoimmunity. Using human cell lines and a knock-in (KI) transgenic mouse model, we showed that this mutation led to a profound defect of IRE1α ribonuclease activity on X-Box Binding Protein 1 (XBP1) splicing. The KI mice developed a broad panel of autoantibodies, however in a subclinical manner. These results suggest that a decrease of spliced form of XBP1 (XBP1s) production could contribute to B cell tolerance breakdown and give new insights into the function of IRE1α which are important to consider for the development of IRE1α targeting strategies.

Keywords: Autoimmunity; Breakdown of tolerance; IRE1α; Unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / metabolism

Substances

  • Protein Serine-Threonine Kinases
  • Endoribonucleases
  • X-Box Binding Protein 1
  • XBP1 protein, human