Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice Rietdijk, Svend Keszei, Marton Castro, Wilson Terhorst, Cox Abadía Molina, Ana Clara Ly108 NTB-A SLAMF6 Isoforms SAP SLAM Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/ijms24055024/s1. References [58,59] are cited in the Supplementary Materials. 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. 2023-04-14T08:55:10Z 2023-04-14T08:55:10Z 2023-03-06 info:eu-repo/semantics/article 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] https://hdl.handle.net/10481/81045 10.3390/ijms24055024 eng http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Atribución 4.0 Internacional MDPI