CLEC12A
Domain
The immunoreceptor tyrosine-based inhibitor motif (ITIM) is involved in modulation of cellular responses (PubMed:14739280). The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing protein phosphatases, such as PTPN6 and PTPN11 (PubMed:14739280).
Function
Myeloid inhibitory C-type lectin receptor that acts as a negative regulator of myeloid cell activation (PubMed:14739280, PubMed:15238421, PubMed:16239426, PubMed:34234773, PubMed:38367667, PubMed:38386511, PubMed:39143217). Myeloid cell inhibition is required to limit proinflammatory pathways and protect against excessive inflammation (By similarity). Specifically recognizes and binds various structures, such as neutrophil extracellular traps (NETs) or monosodium urate crystals (PubMed:38367667, PubMed:38386511, PubMed:39143217). Also acts as a pattern-recognition receptor for pathogen-associated molecules, such as plasmodium hemozoin or mycobacterial micolic acid (PubMed:31269448, PubMed:36542980). Ligand-binding induces phosphorylation of its ITIM motif, followed by recruitment of tyrosine-protein phosphatases PTPN6 and PTPN11, which counteract tyrosine-protein kinase SYK, thereby preventing myeloid cell activation (PubMed:14739280, PubMed:16239426, PubMed:34234773). Acts as a pattern-recognition receptor for NETs in neutrophils: specifically recognizes DNA in NETs, leading to inhibit neutrophil activation and limit further NET formation (PubMed:39143217). This regulation is essential for controlling key neutrophil responses and limit NET-mediated inflammatory conditions (By similarity). Also recognizes dead cells by acting as a receptor for monosodium urate crystals, leading to down-regulate neutrophil activation (PubMed:38367667, PubMed:38386511). Binding to monosodium urate crystals also promotes the type I interferon response (By similarity). Acts as an inhibitor of natural killer (NK) cell cytotoxicity (PubMed:15238421). Also acts as an ihibitor of dendritic cell maturation in an IL10-dependent manner (PubMed:16239426).
Post-translational modifications
Phosphorylated at Tyr-7 by SRC in the ITIM motif following ligand-binding, promoting recruitment of tyrosine-protein phosphatases PTPN6 and PTPN11.
Highly N-glycosylated; glycosylation varies between cell types.
Tissue Specificity
Preferentially expressed in lymphoid tissues and immune cells, including natural killer (NK) cells, T-cells, dendritic cells and monocytes or macrophages (PubMed:14739280, PubMed:15238421, PubMed:15548716, PubMed:16239426, PubMed:16838277). Detected in spleen macrophage-rich red pulp and in lymph node (at protein level) (PubMed:16838277). Detected in peripheral blood leukocytes, dendritic cells, bone marrow, monocytes, mononuclear leukocytes and macrophages (PubMed:16838277).
Cellular localization
- Cell membrane
- Single-pass type II membrane protein
- Ligand binding leads to internalization (PubMed:16239426). Clusters at phagocytic vesicles upon monosodium urate crystal-binding (PubMed:38367667).
Alternative names
CD371, CLL1, DCAL2, KLRL1, MICL, CLEC12A, C-type lectin domain family 12 member A, C-type lectin-like molecule 1, Dendritic cell-associated lectin 2, Killer cell C-type lectin-like receptor L1, Myeloid inhibitory C-type lectin-like receptor, CLL-1, DCAL-2, hKLRL1