Siglec-15 serves as a paradigm for several siglecs, including Siglec-14, Siglec-16 and Siglec-H, that contain a basic amino acid within the transmembrane domain. This leads to association of these siglecs with a transmembrane adaptor protein containing an immunoreceptor tyrosine based activation motif (ITAM). Siglec-15 is unusual compared to other siglecs that share this paradigm in two respects. For one, it can associate with two ITAM containing adaptors, DAP12 and DAP10, whereas Siglec-14, Siglec-16, and Siglec-H show a restricted association with DAP12. In addition, Siglec-15 is unusual in having four cysteine residues in the V-set domain predicted to result in an inter-sheet disulfide that is absent from all other known siglecs. These potentially ‘activating’ siglecs are expressed on myeloid cells and dendritic cells and may be involved in innate responses to pathogen challenge.
CFG Participating Investigators contributing to the understanding of this paradigm
As yet, no CFG Participating Investigators (PIs) have contributed to Siglec-15, but contributors to the related Siglec-H include Marco Colonna and Paul Crocker.
Progress toward understanding this GBP paradigm
This section documents what is currently known about Siglec-15, its carbohydrate ligand(s), and how they interact to mediate cell communication.
Human Siglec-15 has been shown to prefer the sialyl Tn (Neu5Acα2-6GalNAcα1-) structure, while mouse Siglec-15 recognizes both sialyl Tn and 3'-sialyl Lac[NAc] (Neu5Acα2-3Galβ1-4Glc[NAc]) structures.
Cellular expression of GBP and ligands
Human Siglec-15 is expressed on DC-SIGN positive cells in lymph nodes. Exact identity of these cells (i.e., whether these cells are dendritic cells or macrophages) is not yet conclusively determined.
Biosynthesis of ligands
Siglec-15 has two Ig-like domains, followed by a single-pass transmembrane domain and a short cytoplasmic tail. Siglec-15 is unusual compared to other siglecs in that it has four cysteine residues in the V-set domain predicted to result in an inter-sheet disulfide that is absent from all other known siglecs. The transmembrane domain of Siglec-15 contains a basic amino acid. This leads to association with a transmembrane adaptor protein containing an immunoreceptor tyrosine based activation motif (ITAM), DAP12 and DAP10. A stretch of conserved amino acids (containing a tyrosine residue) is found in the cytoplasmic tail of human and mouse Siglec-15, although its functional importance is not yet known.
Biological roles of GBP-ligand interaction
As yet, no clear biological roles for the GBP-ligand interaction have been shown for Siglec-15. Considering the absence of reported cases of Siaα2-6GalNAcα1- structure in pathogens, the ligand for Siglec-15 may be of endogenous origin.
CFG resources used in investigations
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for Siglec-15.
No data available.
No data available. Probes for human Siglec-15 were included on version 4 of the CFG glycogene microarray.
Knockout mouse lines
The CFG has generated Siglec-15-deficient ES cells that will permit generation of a Siglec-15-deficient mouse in the future. Two Siglec-H-deficient mouse lines (Siglec-H-conditional knockout and Siglec-H-total knockout) were also generated and are currently under investigation.
No data available.
Siglec-14, Siglec-16, Siglec-H (CFG data).
- ↑ 1.0 1.1 1.2 Angata, T., Tabuchi, Y., Nakamura, K. & Nakamura, M. Siglec-15: an immune system Siglec conserved throughout vertebrate evolution. Glycobiology 17, 838-846 (2007).
- ↑ Angata, T., Hayakawa, T., Yamanaka, M., Varki, A. & Nakamura, M. Discovery of Siglec-14, a novel sialic acid receptor undergoing concerted evolution with Siglec-5 in primates. FASEB J 20, 1964-1973 (2006).
- ↑ Yamanaka, M., Kato, Y., Angata, T. & Narimatsu, H. Deletion polymorphism of SIGLEC14 and its functional implications. Glycobiology 19, 841-846 (2009)
- ↑ Cao, H. et al. SIGLEC16 encodes a DAP12-associated receptor expressed in macrophages that evolved from its inhibitory counterpart SIGLEC11 and has functional and non-functional alleles in humans. Eur J Immunol 38, 2303-2315 (2008).
- ↑ Zhang, J. et al. Characterization of Siglec-H as a novel endocytic receptor expressed on murine plasmacytoid dendritic cell precursors. Blood 107, 3600-3608 (2006).
- ↑ Blasius, A. L., Cella, M., Maldonado, J., Takai, T. & Colonna, M. Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12. Blood 107, 2474-2476 (2006).
- ↑ Angata, T. & Varki, A. Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective. Chem Rev 102, 439-469 (2002)
The CFG is grateful to the following PIs for their contributions to this wiki page: Takashi Angata, Paul Crocker, James Paulson