SIGLEC9 Gene: Function, Expression, and Disease Associations

SIGLEC9 (sialic acid binding Ig like lectin 9) is a transmembrane receptor primarily expressed on immune cells, including neutrophils, monocytes, macrophages, and subsets of natural killer (NK) cells and T cells. It belongs to the sialic acid-binding immunoglobulin-like lectin (Siglec) family and contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail. Upon engagement with sialic acid ligands on host cells or pathogens, SIGLEC9 recruits phosphatases such as SHP-1 and SHP-2, leading to inhibition of immune cell activation. It plays a key role in regulating inflammation, preventing autoimmunity, and modulating anti-tumor immunity. SIGLEC9 is also exploited by certain viruses and bacteria to evade immune responses.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Siglec-mediated inhibition of immune cell activation

• Immune checkpoint signaling

• TLR4 signaling (modulation)

• Neutrophil degranulation (regulation)

SIGLEC9 is a 471-amino acid type I transmembrane protein with an N-terminal V-set immunoglobulin-like domain that binds sialic acid, followed by a C2-set domain, a transmembrane region, and a cytoplasmic tail containing one ITIM and one ITIM-like motif. The mature protein is glycosylated and expressed as a monomer on the cell surface. Upon ligand engagement, the ITIMs become phosphorylated by Src family kinases, recruiting SHP-1 and SHP-2 phosphatases that dephosphorylate signaling molecules, thereby attenuating activating signals from receptors such as TLRs, Fc receptors, and cytokine receptors. SIGLEC9 also undergoes proteolytic shedding from the cell surface, generating a soluble form that can modulate immune responses.