Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice
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Rietdijk, S.; Keszei, M.; Castro,W.; Terhorst, C.; Abadía-Molina, A.C. Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice. Int. J. Mol. Sci. 2023, 24, 5024. [https://doi.org/10.3390/ijms24055024]
SponsorshipPlan Estatal de Investigación Científica y Técnica y de Innovación, ISCIII. Subdirección, General de Evaluación y Fomento de la Investigación, Ministerio de Economía y Competitividad, Spain. (Grants PI16/01642); Grupo de Investigación de Biología e Inmunología Celular, BIO-225, Consejería de Universidad Investigación e Innovación, Junta de Andalucía, Spain. This work was supported by the following grants to C. Terhorst from the National Institutes of Health (DK073339 and AI-065687)
Ly108 (SLAMF6) is a homophilic cell surface molecule that binds SLAM-associated protein (SAP), an intracellular adapter protein that modulates humoral immune responses. Furthermore, Ly108 is crucial for the development of natural killer T (NKT) cells and CTL cytotoxicity. Significant attention has been paid towards expression and function of Ly108 since multiple isoforms were identified, i.e., Ly108-1, Ly108-2, Ly108-3, and Ly108-H1, some of which are differentially expressed in several mouse strains. Surprisingly, Ly108-H1 appeared to protect against disease in a congenic mouse model of Lupus. Here, we use cell lines to further define Ly108-H1 function in comparison with other isoforms. We show that Ly108-H1 inhibits IL-2 production while having little effect upon cell death. With a refined method, we could detect phosphorylation of Ly108-H1 and show that SAP binding is retained. We propose that Ly108-H1 may regulate signaling at two levels by retaining the capability to bind its extracellular as well as intracellular ligands, possibly inhibiting downstream pathways. In addition, we detected Ly108-3 in primary cells and show that this isoform is also differentially expressed between mouse strains. The presence of additional binding motifs and a non-synonymous SNP in Ly108-3 further extends the diversity between murine strains. This work highlights the importance of isoform awareness, as inherent homology can present a challenge when interpreting mRNA and protein expression data, especially as alternatively splicing potentially affects function.