Siglec-15
Siglec-15[1] serves as a paradigm for several siglecs, including Siglec-14[2][3], Siglec-16[4] and Siglec-H[5][6], 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. Firstly 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. Siglec-15 is also 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
Carbohydrate ligands
Human Siglec-15 has been shown to prefer sialyl Tn (Neu5Acα2-6GalNAcα1-) structure, while mouse Siglec-15 recognize both sialyl Tn and 3'-sialyl Lac[NAc] (Neu5Acα2-3Galβ1-4Glc[NAc]) structures[1].
Cellular expression
Human Siglec-15 is expressed on DC-SIGN positive cells in lymph nodes[1]. Exact identity of these cells (i.e., whether these cells are dendritic cells or macrophages) is not yet conclusively determined.
Structure
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 he cytoplasmic tail of mammalian Siglec-15, while its functional importance is not yet known.
Biological roles of GBP-ligand interaction
As yet, no clear biological roles for GBP-ligand interaction is shown for Siglec-15. Given the near-absence of Siaα2-6Gal[NAc] structure in pathogens, **to be edited further**
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.
Glycan profiling
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.
Glycan array
Related GBPs
Siglec-14, Siglec-16, Siglec-H
References
- ↑ 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).
Acknowledgements
The CFG is grateful to the following PIs for their contributions to this wiki page: Takashi Angata, Paul Crocker, James Paulson
