Siglec-11 Expression in the Brain

Session Date: 
Oct 16, 2021

Sialic acid-recognizing immunoglobulin-type lectins (Siglecs) are a family of cell surface proteins prominently expressed on immune cells in mammals. The extracellular N-terminus of Siglecs has an Ig-like V-set domain involved in sialic acid recognition, followed by a variable number of C2-set domains; and intracellular domains with inhibitory or activating signaling that regulate intracellular responses. Sialic acids are nine-carbon backbone acidic monosaccharides found primarily in animals of the “Deuterosome” lineage (vertebrates and higher invertebrates) but are sometimes found on specific bacterial pathogens that invade the Deuterosomes. One of the major roles of the inhibitory Siglecs is to recognize endogenous sialic acids as “Self-Associated Molecular Patterns” (SAMPs) and dampen innate immune responses. Siglec-11 is an example of an inhibitory Siglec. It was the first protein in the brain found to be “human-specific”: non-human primates express Siglec-11 in other tissues but not in the central nervous system. Siglec-11 exists as a paired-receptor with Siglec-16, which shares a very high sequence identity in the extracellular N-terminus. Genome evolution and chromosomal analyses suggest that gene conversion events over the last 1-1.2 million years gave rise to the present pair of receptors. Despite their high sequence homology in the sialic acid-binding domain, when activated, Siglec-11 and Siglec-16 lead to opposing inflammatory responses: Siglec-11 dampens inflammation, and Siglec-16 heightens it. When immune cells are exposed to E. coli K1, one of the human-specific pathogens coated in polysialic acids, Siglec-11 leads to decreased bacteria-killing while Siglec-16 expression leads to increased killing. Like Siglec-11, Siglec-16 also has several uniquely human features, including its expression in the central nervous system, but an additional feature is that most of the human population have the SIGLEC16P Pseudogene genotype which does not allow protein expression of the full receptor. In summary, Siglec-11 and Siglec-16 are paired receptors with homologous ligand-binding domains but opposing intracellular signaling when activated by polysialic acid. These paired receptors do not have orthologs in all mammals, play significant roles in regulating inflammation, and have several uniquely human features including expression in brain, endogenous ligands in the developing human brain, a unique form in microglia with one less C2-set domain, that can be secreted as exosomes (therefore potentially influencing functions at a distance); interactions with the human-specific pathogen E. coli K1, loss of Siglec-16 in many humans, and is also expressed in other unusual sites in human-specific manner e.g., the columnar epithelium of the uterine cervix. Further studies are needed to understand the significance of the “human-specific” features of these molecules.

File 2021_10_16_05_Varki.mp4464.35 MB