2025
Sci Adv. 2025 Oct 17;11(42):eadz1726. doi: 10.1126/sciadv.adz1726. Epub 2025 Oct 17.
Lyn restrains lupus via kinase-independent mechanisms that limit Toll-like receptor activation and type I interferon responsiveness
Department of Immunology, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
Service type: Knock-in mice
Abstract
Lyn phosphorylates inhibitory immunoreceptors to terminate signaling; consequently, Lyn deficiency in mice causes hyperactive immune cells and lupus-like autoimmune disease. Lyn may also suppress autoimmunity independent of its kinase activity through inhibitory protein-protein binding interactions, although the importance of this mechanism is unclear. To analyze the kinase-independent functions of Lyn, mice expressing a catalytically inactive mutant of Lyn were generated and their phenotype compared to Lyn-deficient mice. Disease progression was blunted in Lyn kinase-dead mice indicating a contribution for kinase-independent Lyn functions in restraining autoantibody production, glomerulonephritis, Toll-like receptor signaling, and splenomegaly. Further comparative analyses identified an exclusive role for the kinase-dependent functions of Lyn in regulating B cell receptor signaling, dendritic cell phenotype, and type I interferon production. By contrast, interferon-stimulated gene expression and the regulation of thymic epithelial cell development and T cell selection are previously unidentified, exclusively kinase-independent functions for Lyn. Collectively, these findings further our understanding of the nuanced roles of Lyn in health and disease.
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