Glycome Atlas
protein
Also known as sialic acid-binding immunoglobulin-type lectins, I-type lectins
Gal (β1-4) → GlcNAc; Neu5Ac (α2-6) → Gal
How to read these diagrams (SNFG)
Each shape is a class of sugar and each colour a specific one. Structures read right to left, with the reducing end (the point of attachment) on the right.
Plain-language answer
Siglecs are immune-cell receptors that recognize sialic acid, a sugar that caps the ends of glycan chains on healthy human cells. When a siglec touches these sialic acid caps, it usually sends a calming, do-not-attack signal inside the immune cell. In effect, siglecs let immune cells feel for a familiar sugar coat that marks a surface as our own.12
Because most siglecs deliver an inhibitory signal, they help keep the immune system from attacking healthy tissue and help dial down inflammation. This same off-switch can be hijacked: some cancers and microbes coat themselves in sialic acid to press the siglec brake and evade immune attack. Siglecs are therefore an active target for new therapies.1
Technical detail
Siglecs are I-type (immunoglobulin superfamily) lectins expressed largely on immune cells that bind sialylated glycans through an N-terminal V-set immunoglobulin domain and, in most members, transduce inhibitory signals through cytoplasmic immunoreceptor tyrosine-based inhibitory motifs.1
Each siglec presents an amino-terminal V-set immunoglobulin domain that binds sialic acid, followed by a variable number of C2-set immunoglobulin domains that extend the receptor from the membrane. The majority of siglecs carry cytoplasmic immunoreceptor tyrosine-based inhibitory motifs that recruit phosphatases such as SHP-1 and SHP-2 upon ligand engagement, delivering an inhibitory tone to the immune cell. A minority couple instead to activating adaptors.1
Siglecs are broadly divided into a conserved group, including sialoadhesin, CD22, myelin-associated glycoprotein, and Siglec-15, and a rapidly evolving CD33-related group whose membership differs between species. Members show preferences for particular sialic acid linkages and underlying glycan contexts, which shapes which cells and glycoconjugates each siglec reads.12
Because dense sialylation is a feature of healthy vertebrate cell surfaces, siglec engagement of these sialic acid caps helps immune cells recognize self and restrain unwanted activation. CD22 tunes B-cell receptor signaling thresholds, and other siglecs modulate the responses of macrophages, neutrophils, natural killer cells, and dendritic cells, contributing to immune tolerance and resolution of inflammation.1
Human relevance
Tumors that display hypersialylated glycans can engage inhibitory siglecs on immune cells to suppress antitumor responses, a mechanism being pursued as a glycoimmune checkpoint.12
By setting inhibitory thresholds on immune cells such as B cells through CD22, siglec signaling contributes to self-tolerance, and disrupted siglec engagement is implicated in inflammatory and autoimmune dysregulation.1
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References