Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice
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 b...
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| Format: | Article |
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/5/5024 |
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| author | Svend Rietdijk Marton Keszei Wilson Castro Cox Terhorst Ana C. Abadía-Molina |
| author_facet | Svend Rietdijk Marton Keszei Wilson Castro Cox Terhorst Ana C. Abadía-Molina |
| author_sort | Svend Rietdijk |
| collection | DOAJ |
| description | 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 <i>Ly108-3</i> 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. |
| first_indexed | 2024-03-11T07:21:13Z |
| format | Article |
| id | doaj.art-0a5295ec9b3a4bd3bdc7e94b2a054f9b |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T07:21:13Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0a5295ec9b3a4bd3bdc7e94b2a054f9b2023-11-17T07:56:41ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01245502410.3390/ijms24055024Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone MiceSvend Rietdijk0Marton Keszei1Wilson Castro2Cox Terhorst3Ana C. Abadía-Molina4Unidad de Inmunología, IBIMER, CIBM, Universidad de Granada, 18016 Granada, SpainDivision of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADivision of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADivision of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USAUnidad de Inmunología, IBIMER, CIBM, Universidad de Granada, 18016 Granada, SpainLy108 (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 <i>Ly108-3</i> 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.https://www.mdpi.com/1422-0067/24/5/5024Ly108NTB-ASLAMF6isoformsSAPSLAM |
| spellingShingle | Svend Rietdijk Marton Keszei Wilson Castro Cox Terhorst Ana C. Abadía-Molina Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice International Journal of Molecular Sciences Ly108 NTB-A SLAMF6 isoforms SAP SLAM |
| title | Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice |
| title_full | Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice |
| title_fullStr | Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice |
| title_full_unstemmed | Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice |
| title_short | Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice |
| title_sort | characterization of ly108 h1 signaling reveals ly108 3 expression and additional strain specific differences in lupus prone mice |
| topic | Ly108 NTB-A SLAMF6 isoforms SAP SLAM |
| url | https://www.mdpi.com/1422-0067/24/5/5024 |
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