C-Type Lectin Receptor MCL Facilitates Mincle Expression and Signaling through Complex Formation

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• C-type lectin receptors (CLRs) on antigen-presenting cells (APCs) recognize pathogen-associated molecular patterns (PAMPs).
• Cord factor (trehalose-6,6'-dimycolate [TDM]) is a potent PAMP from the mycobacterial cell wall.
• Macrophage-inducible C-type lectin (Mincle) and macrophage C-type lectin (MCL) are key CLRs for TDM response, with MCL previously linked to Mincle expression.

Purpose of the Study:

• To elucidate the mechanism by which MCL induces Mincle expression.
• To investigate the role of protein-protein interaction between MCL and Mincle in immune responses.

Main Methods:

• Utilized bone marrow-derived dendritic cells (BMDCs) from wild-type, MCL-deficient, and MCL transgenic mice.
• Stimulated cells with lipopolysaccharide (LPS) or zymosan and assessed Mincle protein and mRNA expression.
• Investigated MCL-Mincle interaction using MCL mutants, focusing on the stalk region and hydrophobic residues.

Main Results:

• MCL-deficient BMDCs showed reduced Mincle protein but not mRNA levels after stimulation.
• BMDCs from MCL transgenic mice exhibited enhanced surface Mincle expression.
• MCL interacted with Mincle via its stalk region, which was essential for enhancing Mincle surface expression.
• A specific MCL mutant (MCL(4S)) lacking hydrophobic residues in the stalk region failed to enhance Mincle expression or restore TDM responses.

Conclusions:

• MCL positively regulates Mincle surface expression through direct protein-protein interaction.
• The stalk region of MCL, particularly its hydrophobic repeat, mediates this interaction and enhances Mincle-mediated signaling.
• This MCL-Mincle interaction amplifies immune responses against TDM.