High impact information on SIGLEC8

• Here we define a novel function of Siglec-8 on eosinophils [1].
• The pancaspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp-(Ome)-fluoromethyl ketone (zVAD-FMK) completely blocked this response, implicating caspases in Siglec-8 cross-linking-induced apoptosis [1].
• Sialic acid binding immunoglobulin-like lectin 8 (Siglec-8), which exists in 2 isoforms including one possessing cytoplasmic tyrosine motifs, is expressed only on human eosinophils, basophils, and mast cells [1].
• Siglec-8 activation may provide a useful therapeutic approach to reduce numbers of eosinophils (and perhaps basophils and mast cells) in disease states where these cells are important [1].
• Glycan array screening reveals a candidate ligand for Siglec-8 [2].

Biological context of SIGLEC8

• A full-length cDNA encoding siglec-8 was isolated from a human eosinophil cDNA library [3].
• RESULTS: With the use of expressed sequence tag sequencing, we have identified a novel siglec molecule, SAF-2 [4].
• Antibodies to SAF-2 do not modulate Ca(++) mobilization or chemotaxis of human eosinophils induced by eotaxin [4].
• Both Siglec8 and Siglec8-L are comprised of seven exons, of which the first five are identical, followed by marked differences in exon usage and mRNA splicing [5].
• Through efforts to investigate the CD33-like subgroup of sialic acid binding immunoglobulin-like lectins (Siglecs), which are believed to be located on chromosome 19q13.4, we have identified the precise genomic region containing the Siglec8 gene [5].

Anatomical context of SIGLEC8

• When siglec-8 was expressed on COS cells or as a recombinant protein fused to the Fc region of human IgG(1), it was able to mediate sialic acid-dependent binding to human erythrocytes and to soluble sialoglycoconjugates [3].
• Identification of SAF-2, a novel siglec expressed on eosinophils, mast cells, and basophils [4].
• Siglec-8 crosslinking on eosinophils increased dissipation of mitochondrial membrane potential upstream of caspase activation [6].

Associations of SIGLEC8 with chemical compounds

• Previous studies demonstrated sialic acid-dependent binding of Siglec-8 but failed to reveal significant substructure specificity or high affinity of that binding [2].
• We conclude that Siglec-8 binds preferentially to the sLex structure bearing an additional sulfate ester on the galactose 6-hydroxyl [2].
• Like the other members of the CD33-like subgroup of Siglecs, except for the previously published Siglec8, Siglec8-L also contains the two tyrosine-based motifs that have been found to recruit both SH2 domain-containing tyrosine and inositol phosphatases [5].
• It was shown that siglecs-1, -4, -5, -6, -7, -9, and -10 did not interact with these compounds; binding of 6-O-Su-3'SiaLacNAc and 6-O-Su-3'SiaTF to siglec-8 was weaker than that of the corresponding sulfate-free sialoside probes [7].

Other interactions of SIGLEC8

• The SLG gene is localized 32.9 kb downstream of Siglec-8 on chromosome 19q13 [8].
• The glycan pools from siglec-5 and siglec-7 contained a larger proportion of sialylated and core-fucosylated biantennary, triantennary and tetra-antennary oligosaccharides, whereas the carbohydrate mixture released from siglec-8 is noticeably less sialylated and is more abundant in 'high-mannose'-type glycans [9].

Analytical, diagnostic and therapeutic context of SIGLEC8

• Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis [1].

References