C-type Lectin Domain Family 4, Member E (CLEC4E), also known as Macrophage-Inducible C-type Lectin (MINCLE), is a protein encoded by the CLEC4E gene. This gene is part of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily, which is characterized by a common protein fold and diverse functions, including cell adhesion, cell-cell signaling, glycoprotein turnover, and roles in inflammation and immune response .
The CLEC4E gene is located on chromosome 12p13 in humans and is closely linked to other CTL/CTLD superfamily members within the natural killer gene complex region . The encoded protein is a type II transmembrane protein with a short N-terminal cytoplasmic domain, a single transmembrane domain, and a C-terminal extracellular C-type lectin carbohydrate recognition domain . The transmembrane domain contains a positively charged arginine residue, which mediates association with the Fc receptor gamma chain (FcεRIγ) signaling adaptor .
CLEC4E acts as a pattern recognition receptor (PRR) of the innate immune system, recognizing damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) of bacteria and fungi . Notably, it recognizes mycobacterial trehalose 6,6’-dimycolate (TDM), a cell wall glycolipid with potent adjuvant immunomodulatory functions . Upon ligand binding, CLEC4E forms a functional complex with the signaling adapter Fc receptor gamma chain (FCER1G) in myeloid cells, leading to cytokine and chemokine production through a pathway involving spleen tyrosine kinase (Syk) and caspase recruitment domain family, member 9 (CARD9) .
CLEC4E is expressed on the cell surface of activated macrophages, and its expression is strongly upregulated by inflammatory stimuli . At the transcript level, it is expressed in various tissues, including bone marrow, lymph node, spleen, and lung . It is also transcribed in a wide range of leukocytes, including macrophages, neutrophils, dendritic cells, B cells, CD4+ T cells, CD8+ T cells, and microglia in the brain .
Diseases associated with CLEC4E include frontal sinus cancer and intracranial chondrosarcoma . Its role in recognizing mycobacterial glycolipids and endogenous nuclear protein ligands released from necrotic cells highlights its importance in the immune response to infections and tissue damage . Additionally, CLEC4E is essential for granuloma formation, a characteristic feature of Mycobacterium tuberculosis infection .