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

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. Copyright © 2023 Elsevier Ltd. All rights reserved.

Citation

Quentin Reuschlé, Laurien Van Heddegem, Victor Bosteels, Matthieu Moncan, Sabine Depauw, Nadège Wadier, Sandra Maréchal, Clint De Nolf, Virginia Delgado, Yosra Messai, Marie-Claude Stolzenberg, Aude Magérus, Angélique Werck, Jérôme Olagne, Quan Li, Guillaume Lefevre, Anne-Sophie Korganow, Frédéric Rieux-Laucat, Sophie Janssens, Pauline Soulas-Sprauel. Loss of function of XBP1 splicing activity of IRE1α favors B cell tolerance breakdown. Journal of autoimmunity. 2024 Jan;142:103152

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PMID: 38071801

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