See also Glycan Binding Proteins
Introduction:
Sialic acid (Sia)-binding Ig-like lectins (Siglecs) are a family of glycan-binding proteins (GBPs). They are an immunoglobulin super family lectins with a defining feature of recognizing sialic acid containing structures. Siglecs are I-type (Ig-type) lectins are are characterized by an N-terminal V-set Ig-like domain, which mediates Sia binding, followed by varying numbers of C2-set Ig-like domains.
Siglecs are cell surface receptors of the immunoglobulin super-family that recognize sialic acid containing proteins. Siglecs are primarily expressed by cells of hematopoietic origin. Most Siglecs are considered to be negative regulators of the immune system becasue they contain one or more cytosolic immune receptor tyrosie-based inhibitory motifs (ITIMs).
Families of Siglecs:
Siglecs are a fmaily of immunomodulatory receptors whose funcitons are regulated by their glycan ligands. The Siglec family consists of 15 family members in humans that are expressed on a restricted set of cells in the hematopoietic lineage.
Signlecs can be divided into two groups based on their genetic homology among mammalian species.
(I) Evolutionary conserved Siglecs: include Siglec-1 (Sialoadhesin), 2 (CD22), 4, and 15.
(II) Evolving CD33-related Siglecs: include CD33 related Siglecs, Siglec-3, 5-14 and 16 in primates, and Siglec 3 plus E-H in rodents.
Siglec Signalling:
Through their outmost N-terminal V-set domain, Siglec recognize sialic acid containing glycan ligands on glycoproteins and glycolipids with unique, yet overlapping specificities. Recognition of their ligands can affect cellular signaling through immunreceptor tyrosine based inhibitory motifs (ITIMs) on their cytoplasmic tails. For teh majority of the Siglecs, these ITIMs have the capacity of recruiting phosphatases, therefore, these members are referred to as inhibitory type Siglecs. Exceptions include Siglec-1 and MAG, which lack such a motif and the activatory type Siglecs (Siglecs 14-16) where are associated with immunoreceptor tyrosine based activatory motif (ITAM) bearing adaptor proteins through a positively charge amino aci in their transmembrane region.
Types of Cells and Siglecs Expressed:
Monocytes, monocyte-dervied marophages and monocyte derived DCs: have largely the same Siglec profile, namely high expression of Siglec 3, 7, 9, low Siglec 10 expression and upon stimulation with IFN-alpha expression of Siglec 1.
Downregulation of Siglec 7 and 9 expression on monocyte DCs is observed after stimulation for 48 hours with LPS.
Macrophages: have primarily expression of Siglec 1, 3, 8, 9, 11 and 15-16 depedning on their differentation status.
Conventional DCs: express Siglec 3, 7 and 9, similar to monocyte derived DCs, but in addition also express low levels of Siglec 2 and 15.
Plasmacytoid DCs: express Siglec1 and 5.
Siglecs are also present on ohter immune cells such as B cells, basophils, neutrophils and NK cells.
Functions:
The primary biological functions of CD33rSiglecs remain unkown. One possibility is that they are self recognition molecules that prevent inappropriate activaiton of innate immune cells. An alternative hypothesis is that when unmasked they serve as detectors of invasive Si-expressing bacterai. Several strains of pathogenic bacteria are known to express Neu5Ac on their surfaces., thereby mimicking host cell surfaces and evading detection by both innate and adaptive immune systems. Unmasked Siglecs could thus provide a mechanisms for the innate immune system cells to recognize these camouflaged bacterai. Si-expressing pathogenci bacterai isolated form multiple mammalian species express Neu5Ac but never Neu5Gc. Thus, the pathogen recognition hypothesis predicts that CD33rSiglecs on cells of the innate immune system must recognize Neu5Ac. (Sonnenburg, Glycobiology, 14(4), 339-346, 2004).
Siglec-10 – CD24 interaction: It has been suggested that interaction of Siglec-10 with CD24 protects the host against a lethal response to pathological cell death by discriminating a danger-associated molecular pattern (DAMP) and repressing damage-induced immune responses during a noninfectious inflammatory reactions (Chen et al. 2009). It was discovered that interactions between Siglec-10 and CD24 mediated recognition of “self,” and thus limited damage of host cells by innate immune cells during a noninfectious inflammatory process, in which endogenous DAMPSs such as HMGB1 were involved in a complex with CD24 and Siglec-10. It is likely that the interactions between CD24 and Siglec-10 is between the sialic acid binding site of Siglec-10 and the heavily sialylated glycans of CD24 (Varki, Glycobiology, 19(8) (2009)).